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Background and Objectives: Evidence‐based guidelines on optimal triggers for red blood cell (RBC) transfusion in patients with haematological malignancies exist, but the evidence is weak. Secondary iron overload is an often overlooked chronic complication of RBC transfusions, and also here, guidelines are either lacking or lack international consensus. Our aim was to evaluate the triggers for RBC transfusion support and management of secondary iron overload among haematologists in the Netherlands. Materials and Methods: For this cross‐sectional study, all haematologists and haematologists in training in the Netherlands were sent a web‐based, 25‐question survey including three clinical scenarios. The survey distribution took place between 19 November 2015 and 26 January 2016. Results: Seventy‐seven responses were received (24%), well distributed among community and university hospitals. A wide variation in haemoglobin triggers existed: 5·6–9·5 g/dl (median: 8·0 g/dl). Personalization of this trigger was mostly based on (estimated) cardiopulmonary compensation capacity of patients. About 65% of respondents reported two RBC units per transfusion episode (range 1–3). For monitoring secondary iron overload, serum ferritin was most frequently measured (97%), while a value of 1000–1500 μg/l was the most common cut‐off to initiate treatment (39%). For 81% of respondents, phlebotomies were the first choice of treatment, although often the haemoglobin level was considered a limiting factor. Conclusion: Our results confirm large reported variation in daily practice among haematologists in the Netherlands regarding RBC transfusion support and management of secondary iron overload. Future studies providing better evidence are needed to improve guidelines specific for patients with haematological malignancies. [ABSTRACT FROM AUTHOR]

Many pre-transplant factors are known to influence the outcome of allogeneic stem cell transplantation (SCT) treatment in myelodysplastic syndromes (MDS). However, patient cohorts are often heterogeneous by disease stage and treatment modalities, which complicates interpretation of the results. This study aimed to obtain a homogeneous patient cohort by including only de novo MDS patients who received upfront allogeneic SCT after standard high dose myelo-ablative conditioning. The effect of pre-transplant factors such as age, disease stage, transfusions, iron parameters and comorbidity on overall survival (OS), non-relapse mortality (NRM), and relapse incidence (RI) was evaluated in 201 patients. In this cohort, characterized by low comorbidity and a short interval between diagnosis and transplantation, NRM was the most determinant factor for survival after SCT (47 % after 2-year follow-up). WHO classification and transfusion burden were the only modalities with a significant impact on overall survival after SCT. Estimated hazard ratios (HR) showed a strongly increased risk of death, NRM and RI, in patients with a high transfusion-burden (HR 1.99; P = 0.006, HR of 1.89; P = 0.03 and HR 2.67; P = 0.03). The HR's for ferritin level and comorbidity were not significantly increased. [ABSTRACT FROM AUTHOR]

This study outlines trends in quality of delivered non-Hodgkin's lymphoma (NHL) care in the Netherlands between 2007 and 2011 and to what extend this was influenced by the national Visible Care program, which aimed at increasing transparency by providing insight into the quality of healthcare. We analyzed data collected from medical records in two observational studies, combined into 20 validated quality indicators (QIs) of which 6 were included in the national program. A random sample of 771 patients, diagnosed with NHL in 26 Dutch hospitals, was examined. Multilevel regression analyses were used to assess differences in quality of NHL care and to provide insight into the effect of the national program. We reported improved adherence to only 3 out of 6 QIs involved in the national program and none of the other 14 validated QIs. Improvement was shown for performance of all recommended staging techniques (from 26 to 43 %), assessment of International Prognostic Index (from 21 to 43 %), and multidisciplinary discussion of patients (from 23 to 41 %). We found limited improvement in quality of NHL care between 2007 and 2011; improvement potential (<80 % adherence) was still present for 13 QIs. The national program seems to have a small positive effect, but has not influenced all 20 indicators which represent the most important, measurable parts in quality of NHL care. These results illustrate the need for tailored implementation and quality improvement initiatives. [ABSTRACT FROM AUTHOR]

Objectives: Reduced-frequency dosing strategies of anidulafungin may offer a more convenient way of providing adequate antifungal prophylaxis to patients at high risk of invasive fungal diseases. We aimed to provide the pharmacological rationale for the applicability of reduced-frequency dosing regimens. Methods: We defined two groups of 10 patients that were to receive anidulafungin at 200 mg every 48 h or 300 mg every 72 h. Blood samples were drawn daily and two pharmacokinetic curves were constructed after 1 and 2 weeks of treatment. A population pharmacokinetic model was developed using non-linear mixed-effects modelling. ClinicalTrials.gov identifier: NCT01249820. Results: The AUC over a 6 day period (IQR) for a typical patient on 200 mg every 48 h or 300 mg every 72 h resulted in 348 mg.h/L (310.6-386.7) and 359 mg.h/L (319.1-400.9), respectively, comparable to the licensed regimen [397.0 mg.h/L (352.4-440.5)]. In the final model, the volume of distribution proved to be dependent on the lean body mass and CLof cyclosporine A. All three regimens resulted in comparable dose-normalized exposure over time. Conclusions: We now have sufficient evidence to start using less frequent dosing regimens and demonstrate their value in clinical practice. These less frequently applied infusions enable more personalized care in an outpatient setting with reduced costs. [ABSTRACT FROM AUTHOR]

A cohort of 439 haematopoietic SCT recipients was analysed to determine the incidence of Gram-positive coccal bacteraemia and thromboembolic events associated with the use of central venous catheters (CVCs) and to determine risk factors for these complications. The incidences of persistent coagulase-negative staphylococcal (CoNS) bacteraemia, symptomatic thrombosis and thrombophlebitis were 25%, 9.6% and 6.6%, respectively. Duration of neutropenia (in days, odds ratio (OR) 1.02; P=0.04) and left-sided placement of the CVCs (OR 1.73; P=0.03) were independent risk factors for the occurrence of persistent CoNS bacteraemia, whereas the use of less mucotoxic conditioning regimens was associated with a lower risk (high-dose melphalan (HDM)/BEAM vs other regimens, OR 0.24; P<0.001). Use of TBI, persistent CoNS bacteraemia and tip colonisation were all significantly associated with an increased risk of symptomatic thrombosis (OR 6.03, 3.36 and 2.80, respectively; P0.02). The risk factors found in this cohort of SCT recipients differed from those found in the general cancer population, showing an important role for persisting bacteraemia in the pathogenesis of CVC-associated thrombosis. Therefore, we constructed a new algorithm in order to improve catheter management and prevent these CVC-related complications. [ABSTRACT FROM AUTHOR]

The mortality associated with post-transplant lymphoproliferative disorder (PTLD) induced by EBV infection can be reduced by monitoring EBV by polymerase-chain-reaction and rituximab given pre-emptively. We performed a retrospective analysis of the risk factors for the occurrence of EBV infection/disease and EBV-related mortality among 273 consecutive recipients of a T-cell-depleted allo-SCT during two periods: (a) before the implementation of a comprehensive protocol (2006-2008) and (b) afterwards (2009-2011). EBV infection was detected in 61 (22%) cases, and 28 cases were considered to have had EBV disease. Treatment with antithymocyte globulin was the most important risk factor (odds ratio (OR) 2.4; 95% confidence interval (CI) 1.3-4.2, P=0.001). After implementation of the protocol, in patients experiencing EBV infection, pre-emptive therapy was started more often and sooner (median 3 vs 6 days, P=0.002). Moreover, there were fewer cases of monomorphic PTLD (4/33 (12%) vs 11/28 (39%), P=0.01), and the EBV-related mortality was lower for patients experiencing EBV infection (2/33 (6%) vs 8/28 (29%), OR 0.2; 95% CI 0.05-0.9, P=0.03). The EBV protocol proved feasible and resulted in faster initiation of pre-emptive therapy, the diagnosis in an earlier stage of EBV disease, and decreased EBV-related mortality. [ABSTRACT FROM AUTHOR]

Gastrointestinal (GI) mucositis is a common side effect of intense chemotherapy to prepare patients for hematopoietic SCT. Measuring intestinal damage objectively remains difficult, and clinicians often rely on albumin levels as an indicator of GI mucositis, but citrulline might be a more specific marker, which has in the past been shown to correlate with clinical signs of GI mucositis. We evaluated the courses of albumin and citrulline following different conditioning regimens for SCT and studied their relatedness to the subsequent inflammatory response using C-reactive protein. Patterns of albumin and citrulline differed significantly between myeloablative and non-myeloablative conditioning regimens. After myeloablative regimens, decreasing citrulline levels preceded the occurrence of inflammation unlike albumin levels, which decreased thereafter. Albumin levels were greatly influenced by inflammation, confirming it to be a 'negative acute-phase protein', whereas citrulline levels were not. Citrulline appeared to be a better biomarker of GI mucositis than albumin. Measuring citrulline might prove useful in clinical decision making, in identifying GI mucositis, and it would also be of interest to see how it compares with other biomarkers in the setting of acute GI GVHD. [ABSTRACT FROM AUTHOR]

Haematopoietic stem cell transplantation (SCT) is an expensive lifesaving procedure, which is increasingly performed in patients with haematological diseases. Developments in the protocol for SCT have resulted in cost estimates that require updating. We aimed to calculate actual costs for SCT and to identify major cost drivers by means of a daily practice cost study. We randomly selected 191 patients, treated at three university hospitals, who underwent an autologous (auto) SCT or allogeneic (allo) SCT in 2007, 2008 or 2009. Allo-SCT included sibling donors, matched unrelated donors (MUD) and umbilical cord blood (UCB). Resource use was collected from the hospital registration systems and medical files. The total costs included selection and harvesting of stem cells, transplantation and 1-year follow-up. The average costs per patient were 45,670 € for auto-SCT and 101,919 € for sibling allo-SCT. The costs of transplantations from unrelated donors were much higher: 171,478 € for allo-SCT-MUD and 254,689 € for allo-SCT-UCB. Hospital inpatient days together with laboratory and other activities were the main cost drivers across all types of SCT. Besides, donor search costs were a large cost component in allo-SCT-sib (18 %) and allo-SCT-MUD (12 %). Real-world costs were above routine reimbursement and appropriate financing is necessary to guarantee the continuation of SCT. The costs calculated in this study provide reliable up-to-date input for cost-effectiveness studies and budget revision. [ABSTRACT FROM AUTHOR]

Five patients with adult-onset metachromatic leukodystrophy (MLD) underwent allo-SCT. Conditioning was reduced in intensity and grafts were obtained from voluntary unrelated donors. All but one graft were depleted of T-lymphocytes. Patient age at transplantation varied from 18 to 29 (median, 27) years. Two patients rejected their graft and MLD progressed. The recipient of the unmanipulated graft converted to complete donor chimerism with normalization of arylsulphatase A (ARSA) levels. Despite ARSA normalization, he deteriorated. Another patient was a mixed chimera. Following escalated doses of donor lymphocyte infusions he converted to complete donor chimerism. His levels of ARSA correlated positively with the percentage of donor cells and MLD was not progressive. The fifth patient died after 35 days from complications associated with GVHD. We conclude that results of allo-SCT in symptomatic MLD patients are poor. However, allo-SCT may stop progression of MLD in selected patients. [ABSTRACT FROM AUTHOR]

The Prospective Oral Mucositis Audit was an observational study in 197 patients with multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL) undergoing, respectively, high-dose melphalan or BEAM chemotherapy and autologous SCT at 25 European centres. We evaluated the relationship between severe oral mucositis (SOM; WHO Oral Toxicity Scale grade 3–4) and local and systemic clinical sequelae and medical resource use. SOM occurred in 44% of patients. The duration of SOM (mean 5.3 days) correlated with time to neutrophil engraftment. The following parameters increased gradiently with maximum grade of oral mucositis: duration of pain score 4, opioid use, dysphagia score 4, total parenteral nutrition (TPN) use, incidence and/or duration of fever and infection, and duration of antibiotic use. SOM increased the duration of TPN use by 2.7 days (P<0.001), opioids by 4.6 days (P<0.001), and antibiotics by 2.4 days (P=0.045). SOM prolonged hospital stay by 2.3 days (P=0.013) in MM patients, but not in NHL patients (who tended to have a longer hospital stay). In conclusion, this analysis of prospectively collected observational data provides important insight into the scope and impact of SOM in the European transplant setting.Bone Marrow Transplantation (2009) 43, 141–147; doi:10.1038/bmt.2008.299; published online 8 September 2008 [ABSTRACT FROM AUTHOR]

The matched-control study failed to show a clinical relevant impact of palifermin on intestinal mucositis, although there was a reduced inflammatory response and less febrile neutropenia among patients who had no bacteraemia. [ABSTRACT FROM AUTHOR]

Background: Childhood cancer survivors face high risks of adverse late health effects. Long-term follow-up care for childhood cancer survivors is crucial to improve their health and quality of life. However, implementation remains a challenge. To support implementation of high-quality long-term follow-up care, we explored expected barriers and facilitators for establishing this follow-up care among healthcare providers from four European clinics., Methods: A qualitative study was conducted using four focus groups comprising 30 healthcare providers in total. The semi-structured interview guide was developed based on the Grol and Wensing framework. Data was analyzed following a thematic analysis, combining both inductive and deductive approaches to identify barriers and facilitators across the six levels of Grol and Wensing: innovation, professional, patient, social, organizational and economic and political., Results: Most barriers were identified on the organizational level, including insufficient staff, time, capacity and psychosocial support. Other main barriers included limited knowledge of late effects among healthcare providers outside the long-term follow-up care team, inability of some survivors to complete the survivor questionnaire and financial resources. Main facilitators included motivated healthcare providers and survivors, a skilled hospital team, collaborations with important stakeholders like general practitioners, and psychosocial care facilities, utilization of the international collaboration and reporting long-term follow-up care results to convince hospital managers., Conclusion: This study identified several factors for successful implementation of long-term follow-up care for childhood cancer survivors. Our findings showed that specific attention should be given to knowledge, capacity, and financial issues, along with addressing psychosocial issues of survivors., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

The objective of the study was the analysis of clinical types, outcomes, and risk factors associated with the outcome of adenovirus (ADV) infection, in children and adults after allo-HCT. A total number of 2529 patients (43.9% children; 56.1% adults) transplanted between 2000 and 2022 reported to the EBMT database with diagnosis of ADV infection were analyzed. ADV infection manifested mainly as viremia (62.6%) or gastrointestinal infection (17.9%). The risk of 1-year mortality was higher in adults (p = 0.0001), and in patients with ADV infection developing before day +100 (p < 0.0001). The 100-day overall survival after diagnosis of ADV infections was 79.2% in children and 71.9% in adults (p < 0.0001). Factors contributing to increased risk of death by day +100 in multivariate analysis, in children: CMV seropositivity of donor and/or recipient (p = 0.02), and Lansky/Karnofsky score <90 (p < 0.0001), while in adults: type of ADV infection (viremia or pneumonia vs gastrointestinal infection) (p = 0.0004), second or higher HCT (p = 0.0003), and shorter time from allo-HCT to ADV infection (p = 0.003). In conclusion, we have shown that in patients infected with ADV, short-term survival is better in children than adults. Factors directly related to ADV infection (time, clinical type) contribute to mortality in adults, while pre-transplant factors (CMV serostatus, Lansky/Karnofsky score) contribute to mortality in children., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: A MASCC/ISOO Clinical Practice Statement (CPS) is aimed at generating a concise tool for clinicians, which concentrates practical information needed for the management of oral complications of cancer patients. This CPS is focused on the management of oral manifestations of chronic graft-versus-host-disease (cGVHD)., Methods: This CPS was developed based on critical evaluation of the literature followed by a structured discussion of a group of leading experts, members of the Oral Care Study Group of MASCC/ISOO. The information is presented in the form of succinct bullets and table to generate a short manual about the best standard of care., Results: The treatment goals in oral cGVHD are to relieve pain and xerostomia, improve oral function, prevent secondary infection, prevent deterioration of the dentition, and detect malignant transformation as early as possible. The prevention and treatment measures for oral mucosal lesions, hypofunction of the salivary glands, and sclerodermatous changes in the oral and perioral tissues are detailed, as well as the possible complications and side effects of these interventions., Conclusions: Patients post allogeneic hematopoietic cell transplantations, with cGVHD manifest in the oral and perioral tissues, should be regularly monitored and treated as needed by an oral care practitioner. This CPS provides the clinician with practical tools for examining, preventing, and treating the various sequalae that may affect the oral cavity in these patients., (© 2024. The Author(s).)

Listeriosis is rare after hematopoietic stem cell transplantation (HCT). Little is known about listeriosis in this population. In this retrospective international case-control study, we evaluated 41 listeriosis episodes occurring between 2000 and 2021 in HCT recipients (111 transplant centers in 30 countries) and assessed risk factors for listeriosis by comparisons with matched controls. The 41 listeriosis episodes (all due to Listeria monocytogenes [LM]) occurred in 30 allogeneic (allo)-HCT recipients and 11 autologous (auto)-HCT recipients at a median of 6.2 months (interquartile range [IQR], 1.6 to 19.3 months) post-HCT. The estimated incidence was 49.8/100,000 allo-HCT recipients and 13.7/100,000 auto-HCT recipients. The most common manifestations in our cohort were fever (n = 39; 95%), headache (n = 9; 22%), diarrhea, and impaired consciousness (n = 8 each; 20%). Four patients (10%) presented with septic shock, and 19 of 38 (50%) were severely lymphocytopenic. Thirty-seven patients (90%) had LM bacteremia. Eleven patients (27%) had neurolisteriosis, of whom 4 presented with nonspecific signs and 5 had normal brain imaging findings. Cerebrospinal fluid analysis revealed high protein and pleocytosis (mainly neutrophilic). Three-month mortality was 17% overall (n = 7), including 27% (n = 3 of 11) in patients with neurolisteriosis and 13% (n = 4 of 30) in those without neurolisteriosis. In the multivariate analysis comparing cases with 74 controls, non-first HCT (odds ratio [OR], 5.84; 95% confidence interval [CI], 1.10 to 30.82; P = .038); and lymphocytopenia <500 cells/mm 3 (OR, 7.54; 95% CI, 1.50 to 37.83; P = .014) were significantly associated with listeriosis. There were no statistically significant differences in background characteristics, immunosuppression, and cotrimoxazole prophylaxis between cases and controls. HCT recipients are at increased risk for listeriosis compared to the general population. Listeriosis cause severe disease with septic shock and mortality. Neurolisteriosis can present with nonspecific signs and normal imaging. Lymphocytopenia and non-first HCT are associated with an increased risk of listeriosis, and cotrimoxazole was not protective., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Mucositis is a common and highly impactful side effect of conventional and emerging cancer therapy and thus the subject of intense investigation. Although common practice, mucositis assessment is heterogeneously adopted and poorly guided, impacting evidence synthesis and translation. The Multinational Association of Supportive Care in Cancer (MASCC) Mucositis Study Group (MSG) therefore aimed to establish expert recommendations for how existing mucositis assessment tools should be used, in clinical care and trials contexts, to improve the consistency of mucositis assessment., Methods: This study was conducted over two stages (January 2022-July 2023). The first phase involved a survey to MASCC-MSG members (January 2022-May 2022), capturing current practices, challenges and preferences. These then informed the second phase, in which a set of initial recommendations were prepared and refined using the Delphi method (February 2023-May 2023). Consensus was defined as agreement on a parameter by >80% of respondents., Findings: Seventy-two MASCC-MSG members completed the first phase of the study (37 females, 34 males, mainly oral care specialists). High variability was noted in the use of mucositis assessment tools, with a high reliance on clinician assessment compared to patient reported outcome measures (PROMs, 47% vs 3%, 37% used a combination). The World Health Organization (WHO) and Common Terminology Criteria for Adverse Events (CTCAE) scales were most commonly used to assess mucositis across multiple settings. Initial recommendations were reviewed by experienced MSG members and following two rounds of Delphi survey consensus was achieved in 91 of 100 recommendations. For example, in patients receiving chemotherapy, the recommended tool for clinician assessment in clinical practice is WHO for oral mucositis (89.5% consensus), and WHO or CTCAE for gastrointestinal mucositis (85.7% consensus). The recommended PROM in clinical trials is OMD/WQ for oral mucositis (93.3% consensus), and PRO-CTCAE for gastrointestinal mucositis (83.3% consensus)., Interpretation: These new recommendations provide much needed guidance on mucositis assessment and may be applied in both clinical practice and research to streamline comparison and synthesis of global data sets, thus accelerating translation of new knowledge into clinical practice., Funding: No funding was received., Competing Interests: The authors report no potential conflicts of interests to declare., (© 2024 Published by Elsevier Ltd.)

Objectives: Nocardiosis is a rare but life-threatening infection after hematopoietic cell transplantation (HCT). We aimed at identifying risk factors for nocardiosis after allogeneic HCT and clarifying the effect of trimethoprim-sulfamethoxazole prophylaxis on its occurrence., Methods: We performed a retrospective multicenter case-control study of patients diagnosed with nocardiosis after allogeneic HCT between January 2000 and December 2018. For each case, two controls were matched by center, transplant date, and age group. Multivariable analysis was conducted using conditional logistic regression to identify potential risk factors for nocardiosis. Kaplan-Meier survival curves of cases and controls were compared using log-rank tests., Results: Sixty-four cases and 128 controls were included. Nocardiosis occurred at a median of 9 months after allogeneic HCT (interquartile range: 5-18). After adjustment for potential confounders in a multivariable model, Nocardia infection was associated with tacrolimus use (adjusted odds ratio [aOR] 9.9, 95 % confidence interval [95 % CI]: 1.6-62.7), lymphocyte count < 500/µL (aOR 8.9, 95 % CI: 2.3-34.7), male sex (aOR 8.1, 95 % CI: 2.1-31.5), recent use of systemic corticosteroids (aOR 7.9, 95 % CI: 2.2-28.2), and recent CMV infection (aOR 4.3, 95 % CI: 1.2-15.9). Conversely, use of trimethoprim-sulfamethoxazole prophylaxis was associated with a significantly decreased risk of nocardiosis (aOR 0.2, 95 % CI: 0.1-0.8). HCT recipients who developed nocardiosis had a significantly decreased survival, as compared with controls (12-month survival: 58 % and 90 %, respectively; p < 0.0001)., Conclusions: We identified six factors independently associated with the occurrence of nocardiosis among allogeneic HCT recipients. In particular, trimethoprim-sulfamethoxazole prophylaxis was found to protect against nocardiosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: The aim of the current study was to investigate whether subtypes of chronic fatigue (CF) can be identified in childhood cancer survivors (CCS), and if so, to determine the characteristics of participants with a specific subtype., Methods: Participants were included from the nationwide DCCSS LATER cohort. The Checklist Individual Strength (CIS) was completed to assess fatigue. Participants with CF (scored ≥35 on the fatigue severity subscale and indicated to suffer from fatigue for ≥6 months) were divided into subgroups using two-step cluster analysis based on the CIS concentration, motivation, and physical activity subscales. Differences between groups on demographics, psychosocial, lifestyle, and treatment-related variables were determined using ANOVA and chi-square analyses (univariable) and multinomial regression analysis (multivariable)., Results: A total of 1910 participants participated in the current study (n = 450 with CF; n = 1460 without CF). Three CF subgroups were identified: Subgroup 1 (n = 133, 29% of participants) had CF with problems in physical activity; Subgroup 2 (n = 111, 25% of participants) had CF with difficulty concentrating; and Subgroup 3 (n = 206, 46% of participants) had multi-dimensional CF. Compared to Subgroup 1, Subgroup 2 more often reported sleep problems, limitations in social functioning, and less often have more than two comorbidities. Subgroup 3 more often reported depression, sleep problems, a lower self-esteem, and limitations in social functioning and a lower educational level compared to Subgroup 1., Conclusion: Different subgroups of CCS with CF can be identified based on fatigue dimensions physical activity, motivation and concentration. Results suggest that different intervention strategies, tailored for each subgroup, might be beneficial., (© 2024 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Patients with haematological malignancies might develop life-threatening toxoplasmosis, especially after allogeneic haematopoietic stem-cell transplantation (HSCT). Reactivation of latent cysts is the primary mechanism of toxoplasmosis following HSCT; hence, patients at high risk are those who were seropositive before transplantation. The lack of trimethoprim-sulfamethoxazole prophylaxis and various immune status parameters of the patient are other associated risk factors. The mortality of toxoplasma disease-eg, with organ involvement-can be particularly high in this setting. We have developed guidelines for managing toxoplasmosis in haematology patients, through a literature review and consultation with experts. In allogeneic HSCT recipients seropositive for Toxoplasma gondii before transplant, because T gondii infection mostly precedes toxoplasma disease, we propose weekly blood screening by use of quantitative PCR (qPCR) to identify infection early as a pre-emptive strategy. As trimethoprim-sulfamethoxazole prophylaxis might fail, prophylaxis and qPCR screening should be combined. However, PCR in blood can be negative even in toxoplasma disease. The duration of prophylaxis should be a least 6 months and extended during treatment-induced immunosuppression or severe CD4 lymphopenia. If a positive qPCR test occurs, treatment with trimethoprim-sulfamethoxazole, pyrimethamine-sulfadiazine, or pyrimethamine-clindamycin should be started, and a new sample taken. If the second qPCR test is negative, clinical judgement is recommended to either continue or stop therapy and restart prophylaxis. Therapy must be continued until a minimum of two negative PCRs for infection, or for at least 6 weeks for disease. The pre-emptive approach is not indicated in seronegative HSCT recipients, after autologous transplantation, or in non-transplant haematology patients, but PCR should be performed with a high level of clinical suspicion., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Human metapneumovirus (hMPV) epidemiology, clinical characteristics and risk factors for poor outcome after allogeneic stem cell transplantation (allo-HCT) remain a poorly investigated area., Methods: This retrospective multicenter cohort study examined the epidemiology, clinical characteristics, and risk factors for poor outcomes associated with human metapneumovirus (hMPV) infections in recipients of allo-HCT., Results: We included 428 allo-HCT recipients who developed 438 hMPV infection episodes between January 2012 and January 2019. Most recipients were adults (93%). hMPV infections were diagnosed at a median of 373 days after allo-HCT. The infections were categorized as upper respiratory tract disease (URTD) or lower respiratory tract disease (LRTD), with 60% and 40% of cases, respectively. Patients with hMPV LRTD experienced the infection earlier in the transplant course and had higher rates of lymphopenia, neutropenia, corticosteroid use, and ribavirin therapy. Multivariate analysis identified lymphopenia and corticosteroid use (>30 mg/d) as independent risk factors for LRTD occurrence. The overall mortality at day 30 after hMPV detection was 2% for URTD, 12% for possible LRTD, and 21% for proven LRTD. Lymphopenia was the only independent risk factor associated with day 30 mortality in LRTD cases., Conclusions: These findings highlight the significance of lymphopenia and corticosteroid use in the development and severity of hMPV infections after allo-HCT, with lymphopenia being a predictor of higher mortality in LRTD cases., Competing Interests: Potential conflicts of interest. P. B. declares research grants from Neovii, Riemser, and Medac (to institution); advisory board membership for Novartis, Cellgene, Amgen, Medac, and Servier (personal and to institution); speakers bureau for Miltenyi, Jazz, Riemser, Novartis, and Amgen (to institution); and patent und royalties from Medac. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The purpose of this study was to determine factors associated with chronic fatigue (CF) in childhood cancer survivors (CCS)., Patients and Methods: Participants were included from the Dutch Childhood Cancer Survivor Study (DCCSS) LATER cohort, a nationwide cohort of CCS (≥5 years after diagnosis) and siblings as controls. Fatigue severity was assessed with the 'fatigue severity subscale' of the Checklist Individual Strength ('CIS-fatigue'). CF was defined as scoring ≥35 on the 'CIS-fatigue' and having fatigue symptoms for ≥6 months. Twenty-four parameters were assessed, categorized into assumed fatigue triggering, maintaining and moderating factors. Multivariable logistic regression analyses were carried out to investigate the association of these factors with CF., Results: A total of 1927 CCS participated in the study (40.7% of invited cohort), of whom 23.6% reported CF (compared with 15.6% in sibling controls, P < 0.001). The following factors were associated with CF: obesity [versus healthy weight, odds ratio (OR) 1.93; 95% confidence interval (CI) 1.30-2.87], moderate physical inactivity (versus physical active, OR 2.36; 95% CI 1.67-3.34), poor sleep (yes versus no, OR 2.03; 95% CI 1.54-2.68), (sub)clinical anxiety (yes versus no, OR 1.55; 95% CI 1.10-2.19), (sub)clinical depression (yes versus no, OR 2.07; 95% CI 1.20-3.59), pain (continuous, OR 1.49; 95% CI 1.33-1.66), self-esteem (continuous, OR 0.95; 95% CI 0.92-0.98), helplessness (continuous, OR 1.13; 95% CI 1.08-1.19), social functioning (continuous, OR 0.98; 95% CI 0.97-0.99) and female sex (versus male sex, OR 1.79; 95% CI 1.36-2.37)., Conclusion: CF is a prevalent symptom in CCS that is associated with several assumed maintaining factors, with lifestyle and psychosocial factors being the most prominent. These are modifiable factors and may therefore be beneficial to prevent or reduce CF in CCS., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Many older patients with acute myeloid leukaemia die or cannot undergo allogeneic haematopoietic stem-cell transplantation (HSCT) due to toxicity caused by intensive chemotherapy. We hypothesised that replacing intensive chemotherapy with decitabine monotherapy could improve outcomes., Methods: This open-label, randomised, controlled, phase 3 trial was conducted at 54 hospitals in nine European countries. Patients aged 60 years and older who were newly diagnosed with acute myeloid leukaemia and had not yet been treated were enrolled if they had an Eastern Cooperative Oncology Group performance status of 2 or less and were eligible for intensive chemotherapy. Patients were randomly assigned (1:1) to receive decitabine or standard chemotherapy (known as 3 + 7). For the decitabine group, decitabine (20 mg/m 2 ) was administered for the first 10 days in the first 28-day cycle, followed by 28-day cycles consisting of 5 days or 10 days of decitabine. For the 3 + 7 group, daunorubicin (60 mg/m 2 ) was administered over the first 3 days and cytarabine (200 mg/m 2 ) over the first 7 days, followed by 1-3 additional chemotherapy cycles. Allogeneic HSCT was strongly encouraged. Overall survival in the intention-to-treat population was the primary endpoint. Safety was assessed in all patients who received the allocated treatment. This trial is registered at ClinicalTrials.gov, NCT02172872, and is closed to new participants., Findings: Between Dec 1, 2014, and Aug 20, 2019, 606 patients were randomly assigned to the decitabine (n=303) or 3 + 7 (n=303) group. Following an interim analysis which showed futility, the IDMC recommended on May 22, 2019, that the study continued as planned considering the risks and benefits for the patients participating in the study. The cutoff date for the final analysis presented here was June 30, 2021. At a median follow-up of 4·0 years (IQR 2·9-4·8), 4-year overall survival was 26% (95% CI 21-32) in the decitabine group versus 30% (24-35) in the 3 + 7 group (hazard ratio for death 1·04 [95% CI 0·86-1·26]; p=0·68). Rates of on-protocol allogeneic HSCT were similar between groups (122 [40%] of 303 patients for decitabine and 118 [39%] of 303 patients for 3+7). Rates of grade 3-5 adverse events were 254 (84%) of 302 patients in the decitabine group and 279 (94%) of 298 patients in the 3 + 7 group. The rates of grade 3-5 infections (41% [125 of 302] vs 53% [158 of 298]), oral mucositis (2% [seven of 302] vs 10% [31 of 298]) and diarrhoea (1% [three of 302] vs 8% [24 of 298]) were lower in the decitabine group than in the 3 + 7 group. Treatment-related deaths were reported for 12% (35 of 302) of patients in the decitabine group and 14% (41 of 298) in the 3 + 7 group., Interpretation: 10-day decitabine did not improve overall survival but showed a better safety profile compared with 3 + 7 chemotherapy in older patients with acute myeloid leukaemia eligible for intensive chemotherapy. Decitabine could be considered a better-tolerated and sufficiently efficacious alternative to 3 + 7 induction in fit older patients with acute myeloid leukaemia without favourable genetics., Funding: Janssen Pharmaceuticals., Competing Interests: Declaration of interests MLü received research support to his institution from Janssen and European Organisation for Research and Treatment of Cancer (EORTC); is on the advisory boards for AbbVie, Astex, Janssen-Cilag, Otsuka, and Syros; and is currently working in an ongoing trial with a study drug provided by Cheplapharm. MK received research funding from Merck, Bristol Myers Squibb (BMS), Pierre Fabre, Janssen, and Immunocore. SF received personal funding by BMS and Celgene. AG received a grant for study conduct, and drug supply for Dacogen from Janssen Pharma Educational. JHJ received support for molecular analysis from Janssen and EORTC. FE received personal funding from AbbVie, Incyte, Janssen, Novartis, and Syros. RW received consulting fees from Amgen, BMS, Celgene, Janssen, Kite, Gilead, Novartis, Pfizer, and Sanofi; payment from AbbVie, Amgen, BMS, Celgene, Janssen, Kite, Gilead, Pfizer, and Sanofi; and support for attending meetings or travel from Janssen. HB is secretary of EORTC Leukemia Group; received research funding by the German Jose Carreras Leukemia Foundation and German Research Foundation; and honoraria from AbbVie, BMS, Celgene, Merck, Novartis, and Servier. UD received personal honoraria for participation in a data safety monitoring board from Avencell Europe and data safety monitoring board for an acute myeloid leukaemia CAR-T cell trial from Avencell Europe. FB received payments to his institution from Incyte Biosciences, Takeda, ExCellThera, and MaaT Pharma. SS received funding to his institution from Janssen Pharmaceuticals. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Allogeneic natural killer (NK) cell-based immunotherapy is a promising, well-tolerated adjuvant therapeutic approach for acute myeloid leukemia (AML). For reproducible NK cell immunotherapy, a homogenous, pure and scalable NK cell product is preferred. Therefore, we developed a good manufacturing practice (GMP)-compliant, cytokine-based ex vivo manufacturing process for generating NK cells from CD34 + hematopoietic stem and progenitor cells (HSPC). This manufacturing process combines amongst others IL15 and IL12 and the aryl hydrocarbon receptor antagonist StemRegenin-1 (SR1) to generate a consistent and active NK cell product that fits the requirements for NK cell immunotherapy well. The cell culture protocol was first optimized to generate NK cells with required expansion and differentiation capacity in GMP-compliant closed system cell culture bags. In addition, phenotype, antitumor potency, proliferative and metabolic capacity were evaluated to characterize the HSPC-NK product. Subsequently, seven batches were manufactured for qualification of the process. All seven runs demonstrated consistent results for proliferation, differentiation and antitumor potency, and preliminary specifications for the investigational medicinal product for early clinical phase trials were set. This GMP-compliant manufacturing process for HSPC-NK cells (named RNK001 cells) is used to produce NK cell batches applied in the clinical trial 'Infusion of ex vivo-generated allogeneic natural killer cells in combination with subcutaneous IL2 in patients with acute myeloid leukemia' approved by the Dutch Ethics Committee (EudraCT 2019-001929-27)., (© 2023. The Author(s).)

Background: Oral mucositis is a frequently seen complication in the first weeks after hematopoietic stem cell transplantation recipients which can severely affects patients quality of life. In this study, a labelled and label-free proteomics approach were used to identify differences between the salivary proteomes of autologous hematopoietic stem cell transplantation (ASCT) recipients developing ulcerative oral mucositis (ULC-OM; WHO score ≥ 2) or not (NON-OM)., Methods: In the TMT-labelled analysis we pooled saliva samples from 5 ULC-OM patients at each of 5 timepoints: baseline, 1, 2, 3 weeks and 3 months after ASCT and compared these with pooled samples from 5 NON-OM patients. For the label-free analysis we analyzed saliva samples from 9 ULC-OM and 10 NON-OM patients at 6 different timepoints (including 12 months after ASCT) with Data-Independent Acquisition (DIA). As spectral library, all samples were grouped (ULC-OM vs NON-OM) and analyzed with Data Dependent Analysis (DDA). PCA plots and a volcano plot were generated in RStudio and differently regulated proteins were analyzed using GO analysis with g:Profiler., Results: A different clustering of ULC-OM pools was found at baseline, weeks 2 and 3 after ASCT with TMT-labelled analysis. Using label-free analysis, week 1-3 samples clustered distinctly from the other timepoints. Unique and up-regulated proteins in the NON-OM group (DDA analysis) were involved in immune system-related processes, while those proteins in the ULC-OM group were intracellular proteins indicating cell lysis., Conclusions: The salivary proteome in ASCT recipients has a tissue protective or tissue-damage signature, that corresponded with the absence or presence of ulcerative oral mucositis, respectively., Trial Registration: The study is registered in the national trial register (NTR5760; automatically added to the International Clinical Trial Registry Platform)., (© 2023. The Author(s).)

Objectives: To describe itraconazole and hydroxy-itraconazole pharmacokinetics following intravenous (IV) administration of a previously developed nanocrystal formulation (NCF) in haematopoietic cell transplant (HCT) recipients for prophylaxis of invasive fungal disease., Methods: In a prospective Phase II study, 10 HCT recipients received itraconazole NCF administered in 2-hour infusions of 200 mg twice daily for 2 days, followed by 200 mg once daily until Day 14. Full pharmacokinetic curves were obtained on Days 7 and 14. Additional samples were collected pre- and post-infusion until Day 6, pre-infusion on Days 10 and 12, and during washout on Days 16, 17, 18, 19 and 28. Itraconazole and hydroxy-itraconazole pharmacokinetics were analysed by non-linear mixed-effects population pharmacokinetic modelling., Results: Four-hundred and seventy-one itraconazole and 471 paired hydroxy-itraconazole concentrations from 10 patients were included for analysis. Data were best described by a semi-mechanistic model with central and peripheral itraconazole compartments and a hydroxy-itraconazole compartment with dissolution of itraconazole drug particles from nanocrystals and first-order distribution and elimination. The final model included interindividual variability on itraconazole clearance and hydroxy-itraconazole clearance., Conclusions: This study provides information on the pharmacokinetic properties of the itraconazole NCF useful for development of this formulation. Our results suggest that itraconazole NCF is a suitable formulation and may warrant renewal in the setting of repurposing. Our findings may be useful for the reformulation of other highly lipophilic compounds as well., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: In order to best prepare medical students for their increasingly complex future career, interdisciplinary higher education is swiftly gaining popularity. However, the implementation of interdisciplinary learning in medical education is challenging. The present study deepens the understanding of the challenges and opportunities inherent to the implementation of an interdisciplinary course. We elucidated the attitudes and beliefs of students participating in a newly developed interdisciplinary minor, in which students of medicine (MS) and communication and information sciences (CISS) were involved., Methods: We conducted four semi-structured focus group interviews, of which two were held before, and two were held after the course. Seven MS and six CISS participated voluntarily. A pre-arranged interview guide was used. The interviews were recorded and afterwards systematically analyzed with the 'constant comparative analysis' technique., Results: The focus group interviews revealed three differences in epistemics between students in terms of 1) curriculum content, 2) educational formats and 3) student's competence perceptions. These factors influenced the way students evaluated themselves, each other and the interdisciplinary course., Conclusions: We conclude that factors that influence interdisciplinary learning are personal epistemics, individual learning preferences, and the synergy that is achieved throughout interdisciplinary learning. Organizing the dialogue among students of different disciplines could make students aware of inequalities, implicated biases and assigned status of different student groups. These empirical results are crucial to tailor interdisciplinary education to each specific discipline and to take interdisciplinary learning to a higher level of maturity., (© 2023. The Author(s).)

Purpose: Oral ulcerative mucositis (UM) and gastrointestinal mucositis (GIM) have been associated with increased likelihood of systemic infection (bacteremia and sepsis) in patients being treated for hematological malignancies. To better define and contrast differences between UM and GIM, we utilized the United States 2017 National Inpatient Sample and analyzed patients hospitalized for the treatment of multiple myeloma (MM) or leukemia., Methods: We utilized generalized linear models to assess the association between adverse events-UM and GIM-among hospitalized MM or leukemia patients and the outcome of febrile neutropenia (FN), septicemia, burden of illness, and mortality., Results: Of 71,780 hospitalized leukemia patients, 1255 had UM and 100 GIM. Of 113,915 MM patients, 1065 manifested UM and 230 had GIM. In an adjusted analysis, UM was significantly associated with increased risk of FN in both the leukemia (aOR = 2.87, 95% CI = 2.09-3.92) and MM cohorts (aOR = 4.96, 95% CI = 3.22-7.66). Contrastingly, UM had no effect on the risk of septicemia in either group. Likewise, GIM significantly increased the odds of FN in both leukemia (aOR = 2.81, 95% CI = 1.35-5.88) and MM (aOR = 3.75, 95% CI = 1.51-9.31) patients. Similar findings were noted when we restricted our analysis to recipients of high-dose condition regimens in preparation for hematopoietic stem-cell transplant. UM and GIM were consistently associated with higher burden of illness in all the cohorts., Conclusion: This first use of big data provided an effective platform to assess the risks, outcomes, and cost of care of cancer treatment-related toxicities in patients hospitalized for the management of hematologic malignancies., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Empiric antifungal therapy is considered the standard of care for high-risk neutropenic patients with persistent fever. The impact of a preemptive, diagnostic-driven approach based on galactomannan screening and chest computed tomography scan on demand on survival and on the risk of invasive fungal disease (IFD) during the first weeks of high-risk neutropenia is unknown., Methods: Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and allogeneic hematopoietic cell transplant recipients were randomly assigned to receive caspofungin empirically (arm A) or preemptively (arm B), while receiving fluconazole 400 mg daily prophylactically. The primary end point of this noninferiority study was overall survival (OS) 42 days after randomization., Results: Of 556 patients recruited, 549 were eligible: 275 in arm A and 274 in arm B. Eighty percent of the patients had AML or MDS requiring high-dose chemotherapy, and 93% of them were in the first induction phase. At day 42, the OS was not inferior in arm B (96.7%; 95% confidence interval [CI], 93.8%-98.3%) when compared with arm A (93.1%; 95% CI, 89.3%-95.5%). The rates of IFDs at day 84 were not significantly different, 7.7% (95% CI, 4.5%-10.8%) in arm B vs 6.6% (95% CI, 3.6%-9.5%) in arm A. The rate of patients who received caspofungin was significantly lower in arm B (27%) than in arm A (63%; P < .001)., Conclusions: The preemptive antifungal strategy was safe for high-risk neutropenic patients given fluconazole as prophylaxis, halving the number of patients receiving antifungals without excess mortality or IFDs. Clinical Trials Registration. NCT01288378; EudraCT 2010-020814-27., Competing Interests: Potential conflicts of interest. J. M. reports consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from MSD, Gilead Sciences, and Pfizer, including participation on a data and safety monitoring board or advisory board (DSMB) for MSD, Gilead, and Pfizer. T. L. reports payment for participation on virtual European Society for Blood and Marrow Transplantation meeting. J. P. D. reports consulting fees from F2G and Gilead Sciences, including payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from F2G, Gilead Sciences, and Pfizer, and unpaid leadership or fiduciary role in other board, society, committee, or advocacy group for the European PCR Initiative Foundation. C. R. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead and Sandoz and support for attending meetings and/or travel for Gilead, MSD, Pfizer, and Sandoz. N. B. reports participation as the chair on a DSMB for the SHORT trial and roles as the president of the Dutch Society of Hematology (unpaid), Treasurer Board member for HOVON (unpaid), chair of the Horizonscan WP Hematology Dutch Healthcare Institute (vacancy fee), and member of the board of supervisors for Matchis (compensation according to Dutch law). D. S. reports grants or contracts from Pfizer, Novartis, BMS, AbbVie, MSD, and Takeda, including consulting fees from Pfizer, Novartis, AbbVie, BMS, Takeda, MSD, Janssen-Cilag, and Astellas; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer, Novartis, AbbVie, BMS, Takeda, MSD, and Janssen-Cilag; support for attending meetings and/or travel from Pfizer, Novartis, BMS, AbbVie, Takeda, MSD, and Janssen-Cilag; and a leadership or fiduciary role for other board, society, committee, or advocacy groups, paid or unpaid for Belgian College for Reimbursement of Orphan Drugs. F. B. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie and Sanofi; support for attending an international meeting from Novartis and Pfizer; and participation on a DSMB or advisory board for some academic studies (no fee) and Maatpharma (paid to institution). W. J. H. reports payment or honoraria for presentations from AbbVie, Amgen, AstraZeneca, Celgene/BMS, Gilead Sciences, and Janssen; support for attending meetings from IPSEN Pharma, Amgen, and Abbvie; and support for attending adboards for Amgen, Astrazeneca, Celgene/BMS, Gilead Sciences Janssen, MSD, and Sanofi-Aventis. B. V. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer, Sanofi, and Al Miral; support for attending meetings and/or travel for ViiV; and participation on a DSMB or advisory board for Pfizer. L. D. reports consulting fees from MSD, Pfizer, and Teva; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from MSD, Pfizer, Teva, and Sandoz; support for attending meetings and/or travel from Sandoz; and participation on an advisory board for Pfizer. C. C. L. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead and Kite and support for attending meetings and/or travel for Gilead and Kite. C. S. P. reports book royalties from Elsevier and Thieme and honoraria for lectures from Canon Medical Systems. R. B. reports consulting fees from Gilead; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead; and support for attending meetings and/or travel for Gilead. P. E. V. reports research grants from ZonMw, Welcome Trust, Eurostars, EORTC, and RIVM; consulting fees from F2G, Gilead Sciences, and Pfizer; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead Sciences and Pfizer. F. L. reports research grants from Merck, Sharpe & Dohme, Gilead, Pfizer, and Novartis and consulting fees (advisory board) from Gilead and Pfizer. P. Y. B. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead Sciences Switzerland AG and Pfizer PFE Switzerland GmbH and support for Gilead Sciences Switzerland Sarl for TIMM, Trends in Medical Mycology. D. H. reports employment with Merck & Co. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: Voriconazole therapeutic drug monitoring (TDM) is recommended based on retrospective data and limited prospective studies. This study aimed to investigate whether TDM-guided voriconazole treatment is superior to standard treatment for invasive aspergillosis., Methods: A multicentre (n = 10), prospective, cluster randomised, crossover clinical trial was performed in haematological patients aged ≥18 years treated with voriconazole. All patients received standard voriconazole dose at the start of treatment. Blood/serum/plasma was periodically collected after treatment initiation of voriconazole and repeated during treatment in both groups. The TDM group had measured voriconazole concentrations reported back, with dose adjustments made as appropriate, while the non-TDM group had voriconazole concentrations measured only after study completion. The composite primary endpoint included response to treatment and voriconazole treatment discontinuation due to an adverse drug reaction related to voriconazole within 28 days after treatment initiation., Results: In total, 189 patients were enrolled in the study. For the composite primary endpoint, 74 patients were included in the non-TDM group and 68 patients in the TDM group. Here, no significant difference was found between both groups (P = 0.678). However, more trough concentrations were found within the generally accepted range of 1-6 mg/L for the TDM group (74.0%) compared with the non-TDM group (64.0%) (P < 0.001)., Conclusions: In this trial, TDM-guided dosing of voriconazole did not show improved treatment outcome compared with standard dosing. We believe that these findings should open up the discussion for an approach to voriconazole TDM that includes drug exposure, pathogen susceptibility and host defence., Clinical Trial Registration: ClinicalTrials.gov registration no. NCT00893555., Competing Interests: Competing interests R.J. Bruggeman has received fees for consulting from Gilead, F2G and Amplyx and has received research grants and given lectures for Gilead, Pfizer, Merck and Astellas. All contracts were with Radboudumc and all payments were with Radboudumc. B.J. Biemond has received research support of Sanquin, Global Blood Therapeutics and Novartis. B.J.A. Rijnders reports grants from Gilead Sciences and personal fees from F2G, outside the submitted work. J.J. Swen reports personal fees from Roche, outside the submitted work. P.E. Verweij reports grants from MSD, Gilead Sciences, F2G and Pfizer and non-financial support from IMMY, outside the submitted work. J.W.C. Alffenaar reports other financial support from Pfizer, MSD and Gilead and grants from MSD, outside the submitted work. All other authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: This guideline was written by a multidisciplinary committee with mandated members of the Dutch Society for Infectious Diseases, Dutch Society for Hematology, Dutch Society for Medical Oncology, Dutch Association of Hospital Pharmacists, Dutch Society for Medical Microbiology, and Dutch Society for Pediatrics. The guideline is written for adults and pediatric patients., Method: The recommendations are based on the answers to nine questions formulated by the guideline committee. To provide evidence-based recommendations we used all relevant clinical guidelines published since 2010 as a source, supplemented with systematic searches and evaluation of the recent literature (2010-2020) and, where necessary, supplemented by expert-based advice., Results: For adults the guideline distinguishes between high- and standard-risk neutropenia based on expected duration of neutropenia (> 7 days versus ≤ 7 days). Where possible a distinction has been made between pediatric and adult patients., Conclusion: This guideline was written to aid diagnosis and management of patients with febrile neutropenia due to chemotherapy in the Netherlands. The guideline provides recommendation for children and adults. Adults patient are subdivided as having a standard- or high-risk neutropenic episode based on estimated duration of neutropenia. The most important recommendations are as follows. In adults with high-risk neutropenia (duration of neutropenia > 7 days) and in children with neutropenia, ceftazidime, cefepime, and piperacillin-tazobactam are all first-choice options for empirical antibiotic therapy in case of fever. In adults with standard-risk neutropenia (duration of neutropenia ≤ 7 days) the MASCC score can be used to assess the individual risk of infectious complications. For patients with a low risk of infectious complications (high MASCC score) oral antibiotic therapy in an outpatient setting is recommended. For patients with a high risk of infectious complications (low MASCC score) antibiotic therapy per protocol sepsis of unknown origin is recommended., (© 2022. The Author(s).)

Background: Patients with haematological malignancies frequently endure neutropenia and gastrointestinal (GI)-mucositis after high-dose chemotherapy. In these patients, ciprofloxacin is used for Gram-negative infection prophylaxis., Objectives: We investigate ciprofloxacin pharmacokinetics after oral administration in patients with haematological malignancies and explore the impact of GI-mucositis on oral bioavailability and clearance in order to assure adequate systemic exposure., Methods: Adult haematological patients from two Dutch University Medical Centres received 500 mg twice daily oral ciprofloxacin for Gram-negative prophylaxis. The ciprofloxacin plasma concentrations were collected at various timepoints after oral ciprofloxacin administration and at various days after completion of chemotherapy. Data obtained after oral and intravenous ciprofloxacin administration in 28 healthy volunteers without mucositis served as a control group (391 samples). For haematological patients the degree of GI-mucositis was assessed using the Daily Gut Score (DGS), plasma citrulline and albumin. Data were analysed by non-linear mixed-effects modelling., Results: In total, 250 blood samples were collected in 47 patients with a wide variety of haematological malignancies between 0-30 days after start of chemotherapy. Mucositis was generally mild [DGS median (IQR) 1 (1-1) and citrulline 16 μmol/L (12-23)]. The time to Cmax was slower in haematological patients compared with healthy volunteers although no association with the degree of mucositis (defined as DGS or citrulline) could be identified. Ciprofloxacin bioavailability and clearance were 60% and 33.2 L/h, respectively., Conclusions: This study supports oral dosing of ciprofloxacin as Gram-negative infection prophylaxis in haematological patients with mild-to-moderate mucositis capable of oral intake., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Earlier studies have suggested that severe intestinal mucositis (IM; citrulline < 10 µmol/L) is an independent risk factor for bloodstream infections (BSI) after cytotoxic therapy. Our aim was to grade IM in patients receiving commonly used chemotherapy and conditioning regimens, and characterize its relationship with BSI incidence. In a retrospective analysis of remission induction (RI) chemotherapy, or conditioning for autologous and allogeneic hematopoietic stem cell transplantation (HSCT; myeloablative conditioning [MAC] and non-myeloablative and reduced-intensity conditioning [NMA/RIC]), data were collected on central venous catheter (CVC) characteristics and BSI. The relationship between BSI occurrence and the degree of IM (determined by citrulline levels) and neutropenia was analyzed. In 626 CVC episodes, 268 (42.8%) laboratory-confirmed BSIs (LCBIs) occurred, classified as mucosal barrier injury (MBI)-LCBIs in 179 (28.6%) episodes, central line-associated BSIs in 113 (18.1%) episodes, and catheter-related BSIs in 55 (8.8%) episodes. In NMA/RIC, the mean duration of hypocitrullinemia was 0.77 days, with LCBI and MBI-LCBI occurring in 11.1% and 4.8% of episodes. In autologous HSCT, RI, and MAC allogeneic HSCT, LCBI and MBI-LCBI occurred frequently (40.0-63.8% and 22.8-53.2% of episodes, respectively) and the mean duration of hypocitrullinemia was significantly higher (9.2-13.8 days). There was a strong correlation between LCBI and the duration of hypocitrullinemia (Pearson's correlation coefficient R = 0.96), as opposed to the relationship between LCBI and the duration of neutropenia (R = 0.42). We conclude that citrulline can be used to grade BSI risk for commonly used intensive treatment regimens., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Nocardiosis is rare after hematopoietic cell transplantation (HCT). Little is known regarding its presentation, management, and outcome in this population., Methods: This retrospective international study reviewed nocardiosis episodes in HCT recipients (1/1/2000-31/12/2018; 135 transplant centers; 33 countries) and described their clinical, microbiological, radiological, and outcome characteristics., Results: We identified 81 nocardiosis episodes in 74 allo- and 7 auto-HCT recipients. Nocardiosis occurred a median of 8 (IQR: 4-18) months post-HCT. The most frequently involved organs were lungs (70/81; 86%) and brain (30/81; 37%); 29 (36%) patients were afebrile; 46/81 (57%) had disseminated infections. The most common lung imaging findings were consolidations (33/68; 49%) or nodules (32/68; 47%); brain imaging findings were multiple brain abscesses (19/30; 63%). Ten of 30 (33%) patients with brain involvement lacked neurological symptoms. Fourteen of 48 (29%) patients were bacteremic. Nocardia farcinica was the most common among molecularly identified species (27%; 12/44). Highest susceptibility rates were reported to linezolid (45/45; 100%), amikacin (56/57; 98%), trimethoprim-sulfamethoxazole (57/63; 90%), and imipenem (49/57; 86%). One-year and last follow-up (IQR: 4-42.5 months) all-cause mortality were 40% (32/81) and 52% (42/81), respectively. In the multivariable analysis, underlying disease not in complete remission (HR: 2.81; 95% CI: 1.32-5.95) and prior bacterial infection (HR: 3.42; 95% CI: 1.62-7.22) were associated with higher 1-year all-cause mortality., Conclusions: Nocardiosis is a late post-HCT infection usually manifesting as a pulmonary disease with frequent dissemination, brain infection, and bacteremia. Brain imaging should be performed in HCT recipients with nocardiosis regardless of neurological symptoms. Overall mortality is high., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objectives: To describe the real-world effectiveness and safety of bosutinib in patients with chronic myeloid leukemia (CML)., Methods: This was a multi-center, retrospective, non-interventional chart review study conducted in 10 hospitals in the United Kingdom and the Netherlands., Results: Eighty-seven patients were included. Bosutinib was the third-line tyrosine kinase inhibitor (TKI) in 33 (38%) and fourth-line in 44 (51%) patients. Median treatment duration was 15.6 months. Among 84 patients in chronic phase (CP) at baseline, 26 (31%) switched to bosutinib due to resistance and 57 (68%) due to intolerance to prior TKIs. Cumulative complete cytogenetic and major molecular response rates in CP patients were 67% and 55%, respectively. After a median follow-up of 21.5 months, nine (11%) patients in CP died; estimated overall survival rates at 1 and 2 years postbosutinib initiation were 95% and 91%, respectively. Overall, 33/87 (38%) patients discontinued bosutinib due to either lack of efficacy/disease progression (17%), adverse events (14%), death (2%), or other reasons (5%). Eighty-two (94%) patients experienced ≥1 adverse event possibly related to bosutinib, most commonly diarrhea (52%)., Conclusions: Bosutinib used in routine clinical practice in heavily pretreated patients with CML is an effective treatment for patients in CP and is generally tolerable., (© 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Background: Early detection and management of late effects of treatment and their impact on health-related quality of life (HRQOL) has become a key goal of childhood cancer survivorship care. One of the most prevalent late effects is chronic fatigue (CF). The current study aimed to investigate the association between CF and HRQOL in a nationwide cohort of CCS., Methods: Participants were included from the Dutch Childhood Cancer Survivor Study (DCCSS) LATER cohort, a nationwide cohort of CCS. Participants completed the Checklist Individual Strength (CIS) to indicate CF (CIS fatigue severity subscale ≥ 35 and duration of symptoms ≥6 months) and the Short Form-36 (SF-36) and TNO (Netherlands Organization for Applied Scientific Research) and AZL (Leiden University Medical Centre) Adult's Health-Related Quality of Life questionnaire (TAAQOL) as measures for HRQOL. Differences in mean HRQOL domain scores between CF and non-CF participants were investigated using independent samples t -tests and ANCOVA to adjust for age and sex. The association between CF and impaired HRQOL (scoring ≥ 2 SD below the population norm) was investigated using logistic regression analyses, adjusting for confounders., Results: A total of 1695 participants were included in the study. Mean HRQOL domain scores were significantly lower in participants with CF. In addition, CF was associated with impaired HRQOL on all of the domains (except physical functioning) with adjusted odds ratios ranging from 2.1 (95% CI 1.3-3.4; sexuality domain) to 30.4 (95% CI 16.4-56.2; vitality domain)., Conclusions: CF is associated with impaired HRQOL, urging for the screening and regular monitoring of fatigue, and developing possible preventative programs and interventions.

High-dose chemotherapy causes intestinal inflammation and subsequent breakdown of the mucosal barrier, permitting translocation of enteric pathogens, clinically manifesting as fever. Antibiotics are mainstay for controlling these complications, however, they are increasingly recognized for their detrimental effects, including antimicrobial resistance and dysbiosis. Here, we show that mucosal barrier injury induced by the mucotoxic chemotherapeutic agent, high-dose melphalan (HDM), is characterized by hyper-active IL-1b/CXCL1/neutrophil signaling. Inhibition of this pathway with IL-1RA, anakinra, minimized the duration and intensity of mucosal barrier injury and accompanying clinical symptoms, including diarrhea, weight loss and fever in rats. 16S analysis of fecal microbiome demonstrated a more stable composition in rats receiving anakinra, with reduced pathogen expansion. In parallel, we report through Phase IIA investigation that anakinra is safe in stem cell transplant patients with multiple myeloma after HDM. Ramping-up anakinra (100-300 mg administered intravenously for 15 days) did not cause any adverse events or dose limiting toxicities, nor did it change time to neutrophil recovery. Our results reinforce that strengthening the mucosal barrier may be an effective supportive care strategy to mitigate local and systemic clinical consequences of HDM. We are now conducting a Phase IIB multicenter, placebo-controlled, double-blinded trial to assess clinical efficacy of anakinra (AFFECT-2).Trial registration: ClinicalTrials.gov identifier: NCT03233776., (© 2022. The Author(s).)

HEV infection is an emerging cause of acute and chronic hepatitis in stem cell transplant (SCT) recipients. We performed a retrospective observational study among EBMT centers with the aim of describing characteristics, management and outcome of HEV after SCT. There were 34 cases of HEV infection from 12 centers in 6 countries, diagnosed in median 4.5 months after SCT; 20 of acute and 14 of chronic infection. Non-hepatic findings possibly associated with HEV infection were present in 9 (26%). Patients with chronic infection had more characteristics associated with severely immunocompromised status. Ribavirin was provided to 16 patients (47%; 40% with acute and 57% with chronic infection), in median for 75 days. Three (19%) patients discontinued it due to side effects. HEV-RNA clearance occurred in 29 patients (85%; 85% in acute and 86% in chronic infection). HEV was considered a cause of death in 3 (9%), with 2 cases with late diagnosis. Reduction of immunosuppression in those receiving it, and ribavirin treatment in those with chronic infection were associated with shorter time to HEV-RNA clearance. Policy on HEV testing varied between the centers. In conclusion, acute and chronic HEV hepatitis should be promptly diagnosed and managed in SCT recipients., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Competing Interests: EFS reports grants form AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Bayer, Merck Sharp & Dphme, Eli Lilly, Daiichi Sankyo, Roche, Novartis, Takeda, Pharmamar; received consulting fees from Eli Lilly; and received payments or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events for Boehringer Ingelheim, AstraZeneca, Daiichi Sankyo, and Novartis, all outside the submitted work. EEV reports grants from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis Oncology, GlaxoSmithKline, Merck Sharp & Dohme, Novartis , Pfizer, Roche, and Sanofi, all outside the submitted work. All other authors declare no competing interests. The DRUG Access Protocol is supported by all participating pharmaceutical companies: Bayer, Roche, and Sanofi. No company had a role in writing of the manuscript or decision to submit it for publication. EEV, HJB, and EFS led the DRUG Access Protocol trial as principal investigators. HG and HMWV functioned as co-principal investigators for the trial. LJZ and SBvWvD-K wrote the manuscript. LJZ, GFdW, and BSG coordinated the trial. SBvWvD-K and AAMGP-vR functioned as representatives on behalf of the health insurance companies during trial design. LT, THLT, and JEdB represented the Dutch National Health Care Institute during trial design. NB, ANMW, FALME, and EFS functioned as representatives of the Dutch Medical Societies for Oncology, Pulmonology and Haematology during trial design. LJZ and SBvWvD-K contributed equally as first authors.

Background: Fatigue is often reported by patients with childhood cancer both during and after cancer treatment. Several instruments to measure fatigue exist, although none are specifically validated for use in childhood cancer survivors (CCS). The aim of the current study was to present norm values and psychometric properties of the Checklist Individual Strength (CIS) and Short Fatigue Questionnaire (SFQ) in a nationwide cohort of CCS., Methods: In total, 2073 participants were included from the Dutch Childhood Cancer Survivor Study (DCCSS) LATER cohort. Normative data, construct validity, structural validity, and internal consistency were calculated for the CIS and SFQ. In addition, reliability and a cutoff score to indicate severe fatigue were determined for the SFQ., Results: Correlations between CIS/SFQ and vitality measures asking about fatigue were high (>0.8). Correlations between CIS/SFQ and measures of different constructs (sleep, depressive emotions, and role functioning emotional) were moderate (0.4-0.6). Confirmatory factor analysis resulted in a four-factor solution for the CIS and a one-factor solution for the SFQ with Cronbach's alpha for each (sub)scale showing good to excellent values (>0.8). Test-retest reliability of the SFQ was adequate (Pearson's correlation = 0.88; ICC = 0.946; weighted Cohen's kappa item scores ranged 0.31-0.50) and a cut-off score of 18 showed good sensitivity and specificity scores (92.6% and 91.3%, respectively)., Conclusion: The current study shows that the SFQ is a good instrument to screen for severe fatigue in CCS. The CIS can be used as a tool to assess the multiple fatigue dimensions in CCS., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Patients with relapsed and/or refractory multiple myeloma (RRMM) generally have limited treatment options and a poor prognosis. Previous trials demonstrated that pomalidomide combined with low-dose dexamethasone (Pd) is effective in these patients with significant responses and improved progression-free survival (PFS). Pd has been approved in RRMM patients who received ≥2 prior lines of therapy. Here, we present the results of a population-based study of patients with RRMM treated with Pd in The Netherlands from time of pomalidomide approval. Using the nationwide Netherlands Cancer Registry, data from all nontrial patients with RRMM treated with Pd were collected. Data were analyzed of response, PFS, and overall survival (OS). A total of 237 patients were included in this analysis. Previous treatment consisted of a proteasome inhibitor in 227 patients (96%) and/or an immune-modulating agent in 235 patients (99%). One hundred forty patients (59%) were refractory to an immune-modulating agent in their last line of therapy. Median time from diagnosis to treatment with Pd was 4.9 years (interquartile range, 2.7-7.9), and the median number of prior treatments was 4 (interquartile range, 3-5). Median PFS and OS for all patients were 3.6 months (95% confidence interval [CI], 3.1-3.8) and 7.7 months (95% CI, 5.7-9.7), respectively. For patients achieving ≥PR, median PFS and OS were 10.6 months (95% CI, 8.3-12.9) and 16.3 months (95% CI, 13.6-23.2), respectively. This nationwide, population-based registry study confirms data shown in pivotal clinical trials on Pd. PFS in this analysis is comparable to PFS observed in those clinical trials., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

The current guidelines for prevention of infections in hematopoietic stem cell transplantation (HSCT) do not specify which central venous catheter (CVC) insertion site should be preferred in allogeneic HSCT recipients-internal jugular vein (IJV) or subclavian vein (SCV). We designed a multicenter prospective observational study comparing the risk of infectious and non-infectious complications between the two most common sites of CVC insertion (IJV and SCV) in allogeneic HSCT. There were in total 232 consecutive patients (86 IJV and 146 SCV) who underwent adult allogeneic HSCT reported from 11 centers in 8 countries. The center independent analysis of central line associated/related blood stream infections with ECDC criteria has shown statistically significant difference favoring SCV (23% IJV vs 13% SCV (OR 2.03 (1.01-4.06), p = 0.047)). The differences in CLABSI per 1000 days of CVC use favored SCV over IJV (7.93/1000 days IJV vs 2.79/1000 days SCV, p = 0.002). The frequency of all non-infectious complications was similar in both arms-13% IJV and 12% SCV (OR 1.1 (0.5-2.5), p = 0.8). This multicenter prospective study showed statistically significant lower confirmed number of CLABSI per 1000 days of CVC use without higher risk of noninfectious complications related to the subclavian insertion site in allogeneic HSCT recipients., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Conditioning therapy with high-dose melphalan (HDM) is associated with a high risk of gut toxicity, fever and infections in haematopoietic stem cell transplant (HSCT) recipients. However, validated preclinical models that adequately reflect clinical features of melphalan-induced toxicity are not available. We therefore aimed to develop a novel preclinical model of melphalan-induced toxicity that reflected well-defined clinical dynamics, as well as to identify targetable mechanisms that drive intestinal injury., Methods: Male Wistar rats were treated with 4-8 mg/kg melphalan intravenously. The primary endpoint was plasma citrulline. Secondary endpoints included survival, weight loss, diarrhea, food/water intake, histopathology, body temperature, microbiota composition (16S sequencing) and bacterial translocation., Results: Melphalan 5 mg/kg caused self-limiting intestinal injury, severe neutropenia and fever while impairing the microbial metabolome, prompting expansion of enteric pathogens. Intestinal inflammation was characterized by infiltration of polymorphic nuclear cells in the acute phases of mucosal injury, driving derangement of intestinal architecture. Ileal atrophy prevented bile acid reabsorption, exacerbating colonic injury via microbiota-dependent mechanisms., Conclusion: We developed a novel translational model of melphalan-induced toxicity, which has excellent homology with the well-known clinical features of HDM transplantation. Application of this model will accelerate fundamental and translational study of melphalan-induced toxicity, with the clinical parallels of this model ensuring a greater likelihood of clinical success.

We assessed the incidence and outcome of early candidemia after hematopoietic stem cell transplant (HSCT). The analysis included all first HSCTs performed from 2000 to 2015 in adult and pediatric patients with a non-leukemic disease and recorded in the EBMT registry. Overall survival (OS), non-relapse mortality (NRM), and relapse mortality (RM) were evaluated. Candidemia was diagnosed in 420 of 49,852 patients at a median time of 17 days post HSCT (range 0-100), the cumulative incidence being 0.85%. In 65.5% of episodes, candidemia occurred by day 30 after HSCT. The mortality rate by day 7 was 6.2%, whereas 100-day NRM was higher (HR 3.47, p < 0.0001), and 100-day OS was lower (HR 3.22, p < 0.0001) than that of patients without candidemia. After a median follow-up of 4.3 years, 5-year OS, NRM, and RM for patients with and without candidemia were 50.5% vs. 60.8%, p < 0.0001, 28.2% vs.18.8%, p < 0.0001, and 25.3% vs. 27.2%, p = 0.4, respectively. In conclusion, in non-leukemic transplant patients, the occurrence of an early episode of candidemia is rare but it is still associated with a negative effect on the outcome.

Purpose: To determine the safety of tipifarnib in combination with escalating doses of bortezomib and to determine the maximum tolerated dose in patients with untreated high-risk MDS and oligoblastic acute myeloid leukemia, who were not eligible for intensive therapy., Experimental Design: In a "3 + 3″ design, patients received fixed doses of tipifarnib 200 mg bid (days 1-21) and escalating doses of bortezomib (days 8, 15, 22) every 4 weeks in 4-6 cycles., Results: The combination was tolerated well by the 11 patients in this study without reaching the maximum tolerated dose. Myelosuppression was the most frequent side effect, but usually of short duration. Interestingly a complete response with or without complete count recovery was observed in three patients and three additional patients had stable disease. The median duration of overall survival was 449 days. Two patients were still alive at 4.0 and 4.3 years, including one patient in continuing CR., Conclusions: The combination of tipifarnib and bortezomib was tolerated well and appeared to have clinical activity in patients with high-risk MDS and AML with low counts of marrow blasts. Our results warrant further evaluation in a phase II study., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The aim of this multicentre, longitudinal study was to determine salivary changes in relation to oral mucositis (OM) in multiple myeloma patients following high-dose melphalan and autologous hematopoietic stem cell transplantation (ASCT). Unstimulated and stimulated whole-mouth saliva samples (UWS and SWS) were collected before ASCT, 1×/wk during the hospitalisation phase, and 3 and 12 months post-ASCT. During the hospitalisation period OM was scored 3×/wk (WHO system). Flow rate, pH, total protein concentration (Nanodrop), albumin, lactoferrin, neutrophil defensin-1 (HNP1), total IgA and S100A8/A9 (ELISA) were determined. Mixed models were used to evaluate differences between ulcerative (u)OM (≥2 WHO, n = 20) and non-uOM (n = 31) groups. Until 18 days after ASCT, flow rate, pH, total IgA and HNP1 levels decreased in UWS and/or SWS, while log lactoferrin levels were significantly increased (UWS: p = 0.016 95% CI [0.36, 3.58], SWS: p < 0.001 95% CI [1.14, 3.29]). Twelve months post-ASCT, salivary protein levels were similar to baseline except for log total IgA, which was higher (UWS: p < 0.001 95% CI [0.49, 1.29], SWS: p < 0.001 95% CI [0.72, 1.45]). No differences between uOM and non-uOM groups were observed. Changes in salivary proteins indicated an inflammatory reaction in salivary glands coinciding with mucosal and systemic reactions in response to high-dose melphalan.

Background: Little is known about characteristics of seasonal human coronaviruses (HCoVs) (NL63, 229E, OC43, and HKU1) after allogeneic stem cell transplantation (allo-HSCT)., Methods: This was a collaborative Spanish and European bone marrow transplantation retrospective multicenter study, which included allo-HSCT recipients (adults and children) with upper respiratory tract disease (URTD) and/or lower respiratory tract disease (LRTD) caused by seasonal HCoV diagnosed through multiplex polymerase chain reaction assays from January 2012 to January 2019., Results: We included 402 allo-HSCT recipients who developed 449 HCoV URTD/LRTD episodes. Median age of recipients was 46 years (range, 0.3-73.8 years). HCoV episodes were diagnosed at a median of 222 days after transplantation. The most common HCoV subtype was OC43 (n = 170 [38%]). LRTD involvement occurred in 121 episodes (27%). HCoV infection frequently required hospitalization (18%), oxygen administration (13%), and intensive care unit (ICU) admission (3%). Three-month overall mortality after HCoV detection was 7% in the whole cohort and 16% in those with LRTD. We identified 3 conditions associated with higher mortality in recipients with LRTD: absolute lymphocyte count <0.1 × 109/mL, corticosteroid use, and ICU admission (hazard ratios: 10.8, 4.68, and 8.22, respectively; P < .01)., Conclusions: Seasonal HCoV after allo-HSCT may involve LRTD in many instances, leading to a significant morbidity., (© 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.)

Background: A debilitating late effect for childhood cancer survivors (CCS) is cancer-related fatigue (CRF). Little is known about the prevalence and risk factors of fatigue in this population. Here we describe the methodology of the Dutch Childhood Cancer Survivor Late Effect Study on fatigue (DCCSS LATER fatigue study). The aim of the DCCSS LATER fatigue study is to examine the prevalence of and factors associated with CRF, proposing a model which discerns predisposing, triggering, maintaining and moderating factors. Triggering factors are related to the cancer diagnosis and treatment during childhood and are thought to trigger fatigue symptoms. Maintaining factors are daily life- and psychosocial factors which may perpetuate fatigue once triggered. Moderating factors might influence the way fatigue symptoms express in individuals. Predisposing factors already existed before the diagnosis, such as genetic factors, and are thought to increase the vulnerability to develop fatigue. Methodology of the participant inclusion, data collection and planned analyses of the DCCSS LATER fatigue study are presented., Results: Data of 1955 CCS and 455 siblings was collected. Analysis of the data is planned and we aim to start reporting the first results in 2022., Conclusion: The DCCSS LATER fatigue study will provide information on the epidemiology of CRF and investigate the role of a broad range of associated factors in CCS. Insight in associated factors for fatigue in survivors experiencing severe and persistent fatigue may help identify individuals at risk for developing CRF and may aid in the development of interventions.

Letermovir (LMV) is licensed for prophylaxis of CMV infection in allogeneic hematopoietic cell transplant adult CMV-seropositive patients. Due to its favorable safety profile, LMV brings potential for use in other clinical situations, outside the approved indication. The objective of the study was to analyze the efficacy and safety of the use of LMV in off-label indications in EBMT centers. A total of 49 patients were reported including 44 adults and 5 children. LMV was administered for: secondary prophylaxis (37 adults, 3 children), primary prophylaxis (2 children), pre-emptive treatment (5 adults), and therapy of CMV disease (2 adults; pneumonia, colitis). Cyclosporine was concomitantly used in 26 patients. Overall, LMV was used for a median 112 days (range: 10-473). Cumulative incidence of breakthrough infections during secondary prophylaxis was 10.1% (95% CI = 3.1-21.9). Prophylactic treatment with LMV resulted in 94.9% (95% CI = 81.0-98.7), and 81.9% (95% CI = 65.7-90.9) probability of, respectively, 60 and 120-day survival without CMV infection in patients receiving secondary prophylaxis. During therapy of CMV infection/disease, probability of 60 and 120-day overall survival was 100% and 71.4% (95% CI = 25.8-92.0), respectively. No breakthrough infection occurred in children on LMV prophylaxis. Adverse events were reported in 15/49 (30.4%) patients: the most common being nausea/vomiting (22.4%). In conclusion, the efficacy of the use of LMV as secondary prophylaxis was high, and the preliminary experience with the use of LMV for the treatment of patients with refractory CMV infection/disease was positive. Our data showed that higher dose or prolonged therapy did not result in increased rate of adverse events.

Purpose: Cancer-related fatigue is a burdensome late effect of cancer treatment. A pilot study showed the effectiveness of cognitive-behavioral therapy (CBT) in fatigued survivors of childhood cancer (CCS). The aim of this study is to investigate whether the six cognitive-behavioral factors that are addressed during CBT differ in CCS compared with patients with chronic fatigue syndrome (CFS) and survivors of adult-onset cancer (ACS). Levels of self-esteem, optimism, and depressive symptoms, variables that are also related to fatigue, were also compared between groups. Methods: Retrospective analyses were performed on 34 CCS (ages 11-42 years), 102 patients with CFS, and 95 ACS who were referred for evaluation of severe fatigue. Fatigue severity, possible cognitive-behavioral fatigue maintaining factors, depressive symptoms, self-esteem, and optimism were assessed using questionnaires and actigraphy. Results: No significant differences were found in the factors coping with the experience of having had cancer, fear of cancer recurrence, physical activity, and in levels of self-esteem and optimism. CCS attributed their fatigue significantly more often to psychosocial causes and reported fewer problems in sleep/rest compared with patients with CFS. Compared with ACS, CCS reported significantly more social support, more problems in sleep/rest, and more depressive symptoms. Conclusions: There is substantial overlap in cognitive-behavioral factors that can maintain fatigue between CCS and CFS patients or ACS. Also differences were found regarding attribution of fatigue, the sleep/rest pattern, social support, and depressive symptoms that might have clinical implications when CBT for fatigue is provided to CCS.