Morbidity and Mortality Associated With Respiratory Virus Infections in Allogeneic Hematopoietic Cell Transplant: Too Little Defense or Harmful Immunity?

The impact on morbidity and mortality of Community Acquired Respiratory Virus (CARV) infections in patients undergoing Allogeneic Hematopoietic Cell Transplant (HCT) is widely studied. Here we give an overview of the current literature on the incidence and chance of progression to severe disease in this highly immune compromised population. We discuss the issue whether it is predominantly direct viral damage that causes clinical deterioration, or that it is in fact the allogeneic immuneresponse to the virus that is most important. This is an important question as it will guide therapeutic decision making. It asks for further collaborative studies focusing on sensitive surveillance with PCR techniques and relating clinical data with parameters of immune reconstitution

Effect of dexamethasone on quality of life in children with acute lymphoblastic leukaemia: a prospective observational study

<p>Abstract</p> <p>Background</p> <p>Glucocorticoids are important in the treatment of childhood acute lymphoblastic leukaemia (ALL). However, cyclic administration of high dose glucocorticoids may cause rapid and substantial changes in quality of life (QoL). The maintenance phase of the Dutch ALL-9 protocol consisted of alternating two weeks on and five weeks off dexamethasone (6 mg/m²/day). The present study was performed to assess the effect of dexamethasone on QoL during treatment for ALL according to this protocol.</p> <p>Methods</p> <p>In a multicentre prospective cohort study, QoL was assessed halfway (T1) and at the end of the two-year treatment (T2). A generic (Child Health Questionnaire) and disease specific (PedsQL™ cancer version) QoL questionnaire were used to assess QoL in two periods: on and off dexamethasone, respectively.</p> <p>Results</p> <p>41 children (56% males) were evaluated, mean age at diagnosis was 5.6 years. The CHQ physical and psychosocial summary scores were significantly lower than population norms. At T1 and T2, overall QoL showed no significant change. However, regarding specific domains (pain, cognitive functioning, emotion/behaviour and physical functioning) QoL decreased over time. QoL was significantly more impaired during periods on dexamethasone.</p> <p>Conclusion</p> <p>Dexamethasone was associated with decreased QoL. At the end of treatment, reported QoL during dexamethasone deteriorated even more on certain scales (pain, cognitive functioning, emotion/behaviour and physical functioning). Knowledge of the specific aspects of QoL is essential to improve counselling and coping in paediatric oncology. Adverse effects of specific drugs on QoL should be taken into account when designing treatment protocols.</p

Association between the magnitude of intravenous busulfan exposure and development of hepatic veno-occlusive disease in children and young adults undergoing myeloablative allogeneic hematopoietic cell transplantation

BACKGROUND Intravenous busulfan is widely used as part of myeloablative conditioning regimens in children and young adults undergoing allogeneic hematopoietic cell transplantation (HCT). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious clinical problem observed with busulfan-based conditioning HCT. The development of VOD/SOS may be associated with busulfan exposure. Getting more insight in the association between busulfan exposure and the development of VOD/SOS enables further optimization of dosing and treatment strategies. OBJECTIVE The objective of this study was to assess the association between the magnitude of busulfan exposure and the occurrence of VOD/SOS in children and young adults undergoing myeloablative conditioning with a busulfan-containing regimen prior to allogeneic HCT. STUDY DESIGN In this observational study we included all patients who received an allogeneic HCT with intravenous busulfan as part of the conditioning regimen at 15 pediatric transplantation centers between 2000 and 2015. The endpoint was the development of VOD/SOS. The magnitude of busulfan exposure was estimated using non-linear mixed effect modelling and expressed as the maximal concentration (Cmax; day 1 and day 1-4 Cmax), cumulative area under the curve (AUC; day 1, highest 1-day AUC in 4 days, and 4-day cumulative AUC), cumulative time above a concentration of 300 µg/L, and clearance on day 1. RESULTS A total of 88 out of 697 patients (12.6%) developed VOD/SOS. The number of alkylators in the conditioning regimen was a strong effect modifier, therefore, we stratified the regression analysis for the number of alkylators. For patients receiving only busulfan as one alkylator (36.3%, n = 253), cumulative busulfan exposure (>78 mg*h/L) was associated with increased VOD/SOS risk (12.6% vs. 4.7%; odds ratio (OR) = 2.95, 95% CI 1.13-7.66). For individuals receiving busulfan with one or two additional alkylators (63.7%, n = 444), cumulative busulfan exposure (≤78 and >78 mg*h/L) did not further increase the risk of VOD/SOS (15.4% vs. 15.2%; OR = 1.03, 95% CI 0.61-1.75). CONCLUSION The effect of the magnitude of busulfan exposure on VOD/SOS risk in children and young adults undergoing HCT is dependent on the number of alkylators. In patients receiving busulfan as the only alkylator, higher cumulative busulfan exposure increased the risk of VOD/SOS, whereas in those receiving multiple alkylators, the magnitude of busulfan exposure did not further increase this risk

Causes of early death and treatment-related death in newly diagnosed pediatric acute myeloid leukemia:Recent experiences of the Dutch Childhood Oncology Group

Background: With the current more effective treatment regimens for pediatric acute myeloid leukemia (AML), research on early death (ED), treatment-related mortality (TRM), and toxicity becomes increasingly important. The aim of this study was to give an overview of the frequency, clinical features, and risk factors associated with ED and TRM in first complete remission (CR1) during the last three consecutive treatment protocols of the Dutch Childhood Oncology Group (DCOG) between 1998 and 2014. Methods: Incidence and risk factors associated with ED and TRM in CR1 were retrospectively studied in 245 patients treated according to the Dutch ANLL-97/AML-12 (n = 118), AML-15 (n = 60), or DB AML-01 (n = 67) protocols. Results: The incidence of ED was, respectively, 5.1%, 6.7%, and 3.0% excluding deaths before treatment (P = NS), and 7.4%, 11.1%, and 4.4% including deaths before the onset of treatment. Severe underweight at initial diagnosis was significantly associated with more frequent ED. When relapse was included as a competing risk, cumulative incidence of death in CR1 were 5.9%, 5.0%, and 4.6% for ANLL97, AML15, and DB01, respectively (P = NS). The most important cause of TRM included infectious and SCT-related complications. Conclusion: We report relatively stable rates of ED and TRM in CR1 in the latest completed DCOG protocols for newly diagnosed AML patients. The most important causes of TRM were SCT- or infection-related, warranting further evaluation and awareness

Neutropenia in Barth syndrome:characteristics, risks, and management

PURPOSE OF REVIEW: Barth syndrome (BTHS) is an X-linked disease characterized by defective remodeling of phospholipid side chains in mitochondrial membranes. Major features include neutropenia, dilated cardiomyopathy, motor delay and proximal myopathy, feeding problems, and constitutional growth delay. We conducted this review of neutropenia in BTHS to aid in the diagnosis of this disease, and to improve understanding of both the consequences of neutropenia and the benefits of treatment with granulocyte colony-stimulating factor (G-CSF). RECENT FINDINGS: In 88 patients with BTHS, neutropenia, that is, at least one count below 1.5 × 10/l, was detected in 74 (84%) and 44% had severe chronic neutropenia, with multiple counts below 0.5 × 10/l. The pattern of neutropenia varied between intermittent and unpredictable, chronic and severe, or cyclical with mathematically regular oscillations. Monocytosis, that is, monocytes more than 1.0 × 10/l, was observed at least once in 64 of 85 (75%) patients. G-CSF was administered to 39 of 88 patients (44%). Weekly average G-CSF doses ranged from 0.12 to 10.92 μg/kg/day (mean 1.16 μg/kg/day, median 1.16 μg/kg/day). Antibiotic prophylaxis was additionally employed in 21 of 26 neutropenic patients. Pretreatment bone marrow evaluations predominantly showed reduced myeloid maturation which normalized on G-CSF therapy in seven of 13 examined. Consistent clinical improvement, with reduced signs and symptoms of infections, was observed in response to prophylactic G-CSF ± prophylactic antibiotics. However, despite G-CSF and antibiotics, one adult patient died with multiple infections related to indwelling medical devices and gastrostomy site infection after 15.5 years on G-CSF and a pediatric patient required gastrostomy removal for recurrent abdominal wall cellulitis. SUMMARY: BTHS should be considered in any men with neutropenia accompanied by any of the characteristic features of this syndrome. Prophylaxis with G-CSF ± antibiotics prevents serious bacterial infections in the more severe neutropenic patients although infections remain a threat even in patients who are very compliant with therapy, especially in those with indwelling devices

Excellent leukemia control after second hematopoietic cell transplants with unrelated cord blood grafts for post-transplant relapse in pediatric patients

BackgroundPatients with leukemia relapse after allogeneic hematopoietic cell transplant (HCT) have poor survival due to toxicity and disease progression. A second HCT often offers the only curative treatment.MethodsWe retrospectively reviewed our bi-institutional experience (MSKCC-USA; Utrecht-NL) with unrelated cord blood transplantation (CBT) for treatment of post-transplant relapse. Overall survival (OS) and event-free survival (EFS) were evaluated using the Kaplan-Meier method, treatment-related mortality (TRM) and relapse were evaluated using the competing risk method by Fine-Gray.ResultsTwenty-six patients age &lt; 21 years received a second (n=24) or third (n=2) HCT with CB grafts during the period 2009-2021. Median age at first HCT (HCT1) was 11.5 (range: 0.9-17.7) years and all patients received myeloablative cytoreduction. Median time from HCT1 to relapse was 12.8 (range 5.5-189) months. At CBT, median patient age was 13.5 (range 1.4-19.1) years. Diagnoses were AML: 13; ALL: 4, MDS: 5, JMML: 2; CML: 1; mixed phenotype acute leukemia: 1. Sixteen patients (62%) were in advanced stage, either CR&gt;2 or with active disease. Median time from HCT1 to CBT was 22.2 (range 7-63.2) months. All patients engrafted after CBT. Thirteen patients developed acute GvHD; 7 had grade III or IV. With a median survivor follow-up of 46.6 (range 17.4-155) months, 3-year OS was 69.2% (95% CI 53.6-89.5%) and 3-year EFS was 64.9% (95% CI 48.8-86.4%). Eight patients died, 3 of AML relapse and 5 due to toxicity (respiratory failure [n=4], GvHD [n=1]) at a median time of 7.7 (range 5.9-14.4) months after CBT. Cumulative incidence of TRM at 3 years was 19.2% (95% CI 4.1-34.4%). Notably, all TRM events occurred in patients transplanted up to 2015; no toxicity-related deaths were seen in the 16 patients who received CBT after 2015. Cumulative incidence of relapse was 15.9% (95% CI 1.6-30.2%) at 3 years, remarkably low for these very high-risk patients.ConclusionsSurvival was very encouraging following CB transplants in pediatric patients with recurrent leukemia after first HCT, and TRM has been low over the last decade. CBT needs to be strongly considered as a relatively safe salvage therapy option for post-transplant relapse

Clinical characteristics and survival patterns of subsequent sarcoma, breast cancer, and melanoma after childhood cancer in the DCOG-LATER cohort

PURPOSE: Childhood cancer survivors are at increased risk of developing subsequent malignant neoplasms (SMNs). We compared survival and clinical characteristics of survivors with SMNs (sarcoma, breast cancer, or melanoma) and a population-based sample of similar first malignant neoplasm (FMN) patients.METHODS: We assembled three case series of solid SMNs observed in a cohort of 5-year Dutch childhood cancer survivors diagnosed 1963-2001 and followed until 2014: sarcoma (n = 45), female breast cancer (n = 41), and melanoma (n = 17). Each SMN patient was sex-, age-, and calendar year-matched to 10 FMN patients in the population-based Netherlands Cancer Registry. We compared clinical and histopathological characteristics by Fisher's exact tests and survival by multivariable Cox regression and competing risk regression analyses.RESULTS: Among sarcoma-SMN patients, overall survival [hazard ratio (HR) 1.88, 95% confidence interval (CI) 1.23-2.87] and sarcoma-specific mortality (HR 1.91, 95% CI 1.16-3.13) were significantly worse compared to sarcoma-FMN patients (foremost for soft-tissue sarcoma), with 15-year survival rates of 30.8% and 61.6%, respectively. Overall survival did not significantly differ for breast-SMN versus breast-FMN patients (HR 1.14, 95% CI 0.54-2.37), nor for melanoma-SMN versus melanoma-FMN patients (HR 0.71, 95% CI 0.10-5.00). No significant differences in tumor characteristics were observed between breast-SMN and breast-FMN patients. Breast-SMN patients were treated more often with mastectomy without radiotherapy/chemotherapy compared to breast-FMN patients (17.1% vs. 5.6%).CONCLUSIONS: Survival of sarcoma-SMN patients is worse than sarcoma-FMN patients. Although survival and tumor characteristics appear similar for breast-SMN and breast-FMN patients, treatment differs; breast-SMN patients less often receive breast-conserving therapy. Larger studies are necessary to substantiate these exploratory findings.</p

Female reproductive function after treatment of childhood acute lymphoblastic leukemia

Background The aim was to evaluate self-reported reproductive characteristics and markers of ovarian function in a nationwide cohort of female survivors of childhood acute lymphoblastic leukemia (ALL), because prior investigations have produced conflicting data. Procedure Self-reported reproductive characteristics were assessed by questionnaire among 357 adult 5-year survivors, treated between 1964 and 2002, and 836 controls. Ovarian function was assessed by serum levels of anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), and inhibin B and by antral follicle count (AFC). Differences between controls and (subgroups of) survivors (total group, chemotherapy [CT]-only group, CT and radiotherapy [RT] group) were analyzed. Results Survivors treated with CT only do not differ from controls regarding timing of menarche, virginity status, desire for children, or pregnancy rates. Compared to controls, the CT+RT group was at significantly increased risk of a younger age at menarche (P < .01), virginity, an absent desire for children, and lower pregnancy rates (odds ratio [OR] [95% CI]: 0.3 [CI 0.1-0.6], 0.5 [0.3-0.9], and 0.4 [0.2-0.9], respectively). Survivors in the CT-only group were significantly younger at the birth of their first child. Pregnancy outcomes were not significantly different between any (sub)groups. Survivors treated with total body irradiation (TBI) or hematopoietic stem cell transplantation (HSCT) are at increased risk of abnormal markers of ovarian function. Conclusion Reproductive function of ALL survivors treated with CT only does not differ from controls. However, survivors additionally treated with RT seem to be at an increased risk of certain adverse reproductive outcomes. Providing personalized counseling about (future) reproductive health risks in this group is imperative

TIMELESS Forms a Complex with PARP1 Distinct from Its Complex with TIPIN and Plays a Role in the DNA Damage Response

SummaryPARP1 is the main sensor of single- and double-strand breaks in DNA and, in building chains of poly(ADP-ribose), promotes the recruitment of many downstream signaling and effector proteins involved in the DNA damage response (DDR). We show a robust physical interaction between PARP1 and the replication fork protein TIMELESS, distinct from the known TIMELESS-TIPIN complex, which activates the intra-S phase checkpoint. TIMELESS recruitment to laser-induced sites of DNA damage is dependent on its binding to PARP1, but not PARP1 activity. We also find that the PARP1-TIMELESS complex contains a number of established PARP1 substrates, and TIMELESS mutants unable to bind PARP1 are impaired in their ability to bind PARP1 substrates. Further, PARP1 binding to certain substrates and their recruitment to DNA damage lesions is impaired by TIMELESS knockdown, and TIMELESS silencing significantly impairs DNA double-strand break repair. We hypothesize that TIMELESS cooperates in the PARP1-mediated DDR

Self-reported outcomes on oral health and oral health-related quality of life in long-term childhood cancer survivors—A DCCSS-LATER 2 Study

Purpose: The present study aimed to determine the prevalence of self-reported oral problems and the oral health–related quality of life (OHRQoL) in childhood cancer survivors (CCS). Methods: Patient and treatment characteristics of CCS have been collected in a cross-sectional study, part of the multidisciplinary DCCSS-LATER 2 Study. To assess self-reported oral health problems and dental problems, CCS filled out the ‘Toegepast-Natuurwetenschappelijk Onderzoek’ (TNO) oral health questionnaire. OHRQoL was assessed by the Dutch version of the Oral Health Impact Profile-14 (OHIP-14). Prevalences were compared with two comparison groups from the literature. Univariable and multivariable analyses were performed. Results: A total of 249 CCS participated in our study. The OHIP-14 total score had a mean value of 1.94 (sd 4.39), with a median score of 0 (range 0–29). The oral problems ‘oral blisters/aphthae’ (25.9%) and ‘bad odor/halitosis’ (23.3%) were significantly more often reported in CCS than in comparison groups (12% and 12%, respectively). The OHIP-14 score was significantly correlated with the number of self-reported oral health problems (r =.333, p&lt;0.0005) and dental problems (r =.392, p &lt;0.0005). In multivariable analysis, CCS with a shorter time since diagnosis (10-19 years vs. ≥30 years) had a 1.47-fold higher risk of ≥1 oral health problem. Conclusion: Though the perceived oral health is relatively good, oral complications following childhood cancer treatment are prevalent in CCS. This underlines that attention to impaired oral health and awareness on this topic is mandatory and regular visits to the dentist should be a part of long-term follow-up care.</p