Survivors Of Childhood Lymphoma Research Articles

Anthracycline-induced cardiotoxicity on regional myocardial work and left ventricular mechanical dispersion in adolescents and young adults in post-lymphoma remission.

Myocardial work (MW) is a new echocardiographic tool with a high sensitivity to detect early and subtle alterations of myocardial function. We aimed to evaluate the late effects of anthracyclines by assessing the global and segmental MW and intraventricular mechanical dispersion from speckle tracking echocardiography in childhood lymphoma survivors (CLS). Thirty-one young adults including CLS and age-matched healthy controls were enrolled. All underwent echocardiography including an evaluation of left ventricular (LV) morphology and regional function. We assessed LV longitudinal (differentiating sub-endocardial and sub-epicardial layers), circumferential strains and twist, global and regional MW index (MWI). LV mechanical dispersion was assessed from the time dispersion of LV longitudinal strain, from myocardial wasted work (MWW) and myocardial work efficiency (MWE). The longitudinal strains both at the level of the sub-endocardium and sub-epicardium were reduced in CLS compared to controls. The global MWI was also decreased (1668 ± 266 vs 1870 ± 264%.mmHg in CLS patients and controls, respectively, p < 0.05), especially on the apical segments. An increase of LV intraventricular mechanical dispersion was observed in CLS. MWW and MWE remained unchanged compared to controls. Our results strongly support that cardiac remodeling is observed in CLS, characterized by a decrease in MW and an increase in LV mechanical dispersion. The apex is specifically altered, but its clinical significance remains uncertain. MW as a complement to strain seems interesting in cancer survivors to detect myocardial dysfunction at early stage and adapt their follow-up.

Fitness and metabolic response to exercise in young adult survivors of childhood lymphoma.

Childhood lymphoma survivors (CLSs) are at high risk of reduced daily activity. This work studied metabolic substrate use and cardiorespiratory function in response to exercise in CLSs. Twenty CLSs and 20 healthy adult controls matched for sex, age, and BMI took an incremental submaximal exercise test to determine fat/carbohydrate oxidation rates. Resting echocardiography and pulmonary functional tests were performed. Physical activity level, and blood metabolic and hormonal levels were measured. CLSs reported more physical activity than controls (6317 ± 3815 vs. 4268 ± 4354 MET-minutes/week, p = 0.013), had higher resting heart rate (83 ± 14 vs. 71 ± 13bpm, p = 0.006), and showed altered global longitudinal strain (- 17.5 ± 2.1 vs. - 19.8 ± 1.6%, p = 0.003). We observed no difference in maximal fat oxidation between the groups, but it was reached at lower relative exercise intensities in CLSs (Fatmax 17.4 ± 6.0 vs. 20.1 ± 4.1mL/kg, p = 0.021). At V̇O2 peak, CLSs developed lower relative exercise power (3.2 ± 0.9 vs. 4.0 ± 0.7 W/kg, p = 0.012). CLSs reported higher levels of physical activity but they attained maximal fat oxidation at lower relative oxygen uptake and applied lower relative power at V̇O2peak. CLSs may thus have lower muscular efficiency, causing greater fatigability in response to exercise, possibly related to chemotherapy exposure during adolescence and childhood. Long-term follow-up is essential and regular physical activity needs to be sustained.

Childhood lymphoma treatment impacts educational outcomes: a registry study from Sweden

PurposeThis study aimed to explore educational outcomes in individuals diagnosed with lymphoma in childhood concerning school grade year 9 and attendance in high school and post-compulsory education. Whether sex or age at diagnosis affected the assessed variables was also explored.MethodsData from 174 children born 1988–1996 and diagnosed with lymphoma before age 15 were matched with approximately five controls per patient. The mean time since diagnosis to receiving school year 9 grades was 4.88 years for Hodgkin lymphoma (HL) cases (mean age at diagnosis 10.62, 11.76, and 10.05 years for all, girls, and boys, respectively) and 7.79 years for non-Hodgkin lymphoma (NHL) cases (mean age at diagnosis 7.85, 7.87, and 7.84 years for all, girls, and boys, respectively).ResultsWe observed statistically significant differences between cases and controls in physical education, both for failing (p = 0.041) and the highest grade (p = 0.015). Compared with controls, HL cases were three times more likely to fail mathematics, and significantly fewer individuals in the whole lymphoma (p = 0.011) and NHL (p = 0.035) groups attended the third year of high school.ConclusionsEducational outcomes are impacted for children treated for lymphoma, especially in physical education. Since patients with HL are treated without central nervous system-directed therapy, other factors, such as absence from school, may affect school results. Physical late complications in lymphoma survivors warrant special attention.Implications for Cancer SurvivorsThe problems childhood lymphoma survivors face should be known by schools and parents, to enable their management. Children treated for lymphoma should be closely monitored and included in follow-up programs when needed, for example, to support physical activity.

Adverse Health Outcomes and Associations with Self-Reported General Health in Childhood Lymphoma Survivors

The increased incidence of physical and psychosocial adverse health outcomes (AHOs) in childhood lymphoma survivors (CLSs) is well known, but these AHOs' association with self-reported general health is rarely described. We explored this association among long-term CLSs. In 124 CLSs (Hodgkin: 81; non-Hodgkin: 43; median age: 33 years), physical AHOs were graded based on slightly modified common toxicity criteria for adverse effects (CTCAE)-4 recommendations (Grade 0-3). Psychosocial AHOs (pain, work inability, fatigue, and mental distress) were mainly assessed by validated patient-reported questionnaires (Grade 0-2). The results were related to contemporary self-reported general health. Statistical significance: p < 0.01. At least one physical AHO was found in 120 CLSs, being of Grades 1, 2, and 3, respectively, in 43, 43, and 34 survivors. The prevalence of psychosocial AHOs (Grades 1 or 2) was 63%, being Grade 2 in 62 CLSs. The CLSs described their general health as significantly reduced compared with controls, with the greatest reduction for survivors in whom physical AHOs were combined with moderate to severe psychosocial AHOs. Psychosocial more than physical AHOs impact on CLSs' current self-reported general health. Clinicians responsible for follow-up of CLSs should be aware of the strong reduction of contemporary general health by Grade 2 psychosocial AHOs. The study challenges the use of the physician-assessed CTCAE-4 categories in long-term cancer survivors and emphasizes the need to develop instruments, which reflect both physical and psychosocial AHOs in these individuals.

Experiences with late effects-related care and preferences for long-term follow-up care among adult survivors of childhood lymphoma.

Given childhood cancer survivors' risk of treatment-induced late effects, long-term follow-up care is recommended. We explored experiences with late effects-related care and preferences for long-term follow-up care among adult survivors of childhood malignant lymphoma in Norway. We conducted five focus group interviews with 34 survivors (19 females; 21 Hodgkin/13 non-Hodgkin lymphoma survivors; mean age 39years; mean time from diagnosis 26years). Data was analyzed using principles of thematic analysis. Two main themes were identified: (1) the survivors' experiences with late effects-related care and (2) their preferences for long-term follow-up care. Most of the survivors were dissatisfied with their late effects-related care due to perceptions of poor coordination of healthcare needs in a fragmented system, combined with a perceived lack of knowledge of late effects among themselves and general practitioners (GPs). All survivors valued long-term follow-up care. Oncologists were the preferred care providers, but GPs were considered acceptable providers if they had sufficient knowledge of late effects and routine examinations, short waiting times, and improved GP-oncologist collaboration. Our results suggest that a shared care model of long-term follow-up care involving specialists, GPs, and the survivors themselves is likely to fulfill several of the currently unmet needs among adult survivors of childhood cancers. Improved patient education about late effects and follow-up care would aid self-management. The survivors' concerns regarding lack of sufficient knowledge of late effects among GPs suggest a need for improving access to, and dissemination of, information of late effects.

1395 - Adverse health outcomes (AHOs) in childhood lymphoma survivors (CLSs): relation to self-reported general health

1395 - Adverse health outcomes (AHOs) in childhood lymphoma survivors (CLSs): relation to self-reported general health

Utility of Global Longitudinal Strain by Echocardiography to Detect Left Ventricular Dysfunction in Long-Term Adult Survivors of Childhood Lymphoma and Acute Lymphoblastic Leukemia

Measuring left ventricular (LV) global longitudinal strain (GLS) is recommended in screening of long-term cancer survivors for cardiotoxicity. However, there are limited data on GLS in this setting, in particular in survivors with apparently normal LV function without risk factors of impaired GLS. In the present study, we measured GLS in 191 adult survivors of childhood lymphoma or acute lymphoblastic leukemia, with normal LV ejection fraction and fractional shortening (FS) and without known hypertension, diabetes mellitus, myocardial infarction, or stroke. We compared GLS in the survivors with 180 controls. Mean GLS was-19.0 ± 2.2% in the survivor group and-21.4 ± 2.0% in the controls (p <0.001). Impaired GLS, defined as mean - 1.96 SDs in the control group, occurred in 53 of 191 survivors (28%). We included survivors with impaired LV ejection fraction and/or FS or traditional risk factors (n= 231 in all) in multiple regression analyses to explore associations with previous cancer treatment. Survivors treated with mediastinal radiotherapy had an odds ratio of impaired GLS of 5.2 (95% confidence interval 2.2 to 12) compared with other survivors. Survivors treated with cumulative anthracycline doses>300mg/m(2) had an odds ratio of 4.8 (95% confidence interval 1.7 to 14) of impaired GLS. In conclusion, this study demonstrates a high proportion of LV dysfunction assessed by GLS in apparently healthy adult survivors of childhood cancer. Impaired GLS wasassociated with previous exposure to mediastinal radiotherapy and high doses of anthracyclines. The prognostic role of measuring GLS in this specific patient population should be examined in prospective studies.

Dose–Effect Relationship of Alkylating Agents on Testicular Function in Male Survivors of Childhood Lymphoma

The purpose of our study was to assess the gonadal function in male survivors of childhood lymphoma. We studied 171 male survivors of childhood lymphoma (83 with B-cell non-Hodgkin lymphoma [B-NHL], 32 with T-cell non-Hodgkin lymphoma [T-NHL], 50 with Hodgkin lymphoma [HL], and 6 with anaplastic large-cell lymphoma [ALCL]), measuring follicle-stimulating hormone [FSH] and luteinizing hormone [LH] levels at a median age of 21.1 (17–30.4) years after a median delay of 9.3 (2–22.4) years from treatment. FSH levels were above normal range (≥10 IU/L) in 42.1% and LH levels ≥8 IU/L in only 8.9% of survivors. In multivariate analysis, only the following chemotherapeutic agents were associated with higher FSH or LH levels: cyclophosphamide (P < .0001, .04), lomustine (CCNU; P = .002, 0.04), and procarbazine (P < .0001, .07). No significant correlation was found between FSH or LH levels and age or pubertal status at diagnosis. Mean FSH level was significantly lower in NHL survivors treated more recently: 6 ± 5.1 IU/L in B-NHL survivors treated since 1986 versus 12.3 ± 5.4 IU/L for those treated before 1981 (P = .0001), and 6.8 ± 9.6 IU/L in T-NHL survivors treated since 1989 versus 9.4 ± 5.7 IU/L for those treated before 1989 (P = .035). In HL, mean FSH level was 12.4 ± 9.9 IU/L following procarbazine containing chemotherapy versus 3.4 ± 1.9 IU/L in the absence of procarbazine and increased significantly with the number of MOPP/OPPA (mechlorethamine, Oncovin [vincristine], procarbazine, and prednisone/Oncovin, procarbazine, and prednisone, and Adriamycin [doxorubicin]) courses received, from 6.8 ± 5.7 IU/L for 1–2 MOPP/OPPA to 12.6 ± 7.5 for 3–4 MOPP/OPPA and 19.6 ± 13.3 for more than 4 MOPP/OPPA (P for trend = .006). Testicular toxicity of alkylating agents on childhood lymphoma survivors is dose dependent and not correlated to diagnosis, age, or pubertal status at diagnosis.

Left Ventricular Function in Long-Term Survivors of Childhood Lymphoma

Survivors of childhood lymphoma (CL) have markedly increased risk of developing heart failure. Echocardiographic studies after cardiotoxic treatment have primarily demonstrated left ventricular (LV) systolic dysfunction. In the present study, we hypothesized that longer follow-up and a more comprehensive echocardiographic examination would reveal more cardiac abnormalities. We conducted a cross-sectional study with echocardiography 20.4 ± 8.6years after diagnosis in 125 survivors of CL, grouped according to treatment methods, and compared with matched controls. Treatment included mediastinal radiotherapy (median 40.0Gy) in 66 and anthracyclines (median dose 160mg/m(2)) in 92 survivors of CL. Abnormal LV function, left-sided valve dysfunction, or both occurred in 62 patients (50%). Diastolic dysfunction occurred in 29%. Compared with control subjects, mitral annular early diastolic velocities (e') were reduced in patients (septal e' 0.09 ± 0.03 vs 0.12 ± 0.03m/s, p <0.001), and the E/e' ratio was increased, particularly after mediastinal radiotherapy (10.6 ± 6.4 vs 5.6 ± 1.3, p <0.001). Survivors of CL had lower fractional shortening than control subjects (32 ± 6 vs 36 ± 7, p <0.001), but mean ejection fraction was equal and overt systolic dysfunction was infrequent. After mediastinal radiotherapy alone, global longitudinal myocardial strain was lower (p <0.05) compared with other treatment groups. Left-sided valvular dysfunction occurred in 55% of patients after mediastinal radiotherapy. In conclusion, survivors of CL had reduced LV diastolic function assessed by tissue Doppler imaging. This was more pronounced after mediastinal radiotherapy, which also frequently led to valvular disease. Systolic function was normal in most survivors of CL.

Chronic Fatigue in Adult Survivors of Childhood Cancer: Associated Symptoms, Neuroendocrine Markers, and Autonomic Cardiovascular Responses

Chronic fatigue (CF) is a common late effect after childhood cancer. Based on findings among patients with the chronic fatigue syndrome (CFS), this study explored symptoms, neuroendocrine markers, and autonomic cardiovascular responses associated with CFS in childhood cancer survivors. Long-term survivors of childhood lymphoma and acute lymphoblastic leukemia reporting CF were compared with survivors without CF. Data included patient-reported outcomes, clinical examination, head-up tilt test, and neuroendocrine markers in the blood and the urine. Of 102 included survivors, 15 were excluded from comparative analyses because of significant co-morbidity or pregnancy. Of the remaining 87 participants (median age 33.0 years, follow-up time 25.2 years), 35 had CF and 52 did not have CF. Compared with non-CF controls, CF cases reported a significantly (P < 0.01) higher frequency of symptoms typical of the CFS (muscle or joint pain or both and feeling confused/disoriented) and symptoms of autonomic dysfunction (palpitations, feeling intermittently heat and cold, and watery diarrhea). CF cases and controls did not differ regarding autonomic cardiovascular responses to orthostatic stress, but the CF group had lower levels of plasma adrenocorticotrophic hormone (P = 0.002) and higher levels of urine norepinephrine (P = 0.017). Survivors with CF reported a high symptom-burden compared with controls. There were few differences between both the groups regarding biomarkers, but slight alterations of the hypothalamus-pituitary-adrenal axis and sympathetic nervous activity were detected. CF in cancer survivors has features in common with the CFS, but further efforts are required to clarify the pathophysiology.

Bone mineral density in survivors of childhood lymphoma

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

Gonadal function and parenthood 20 years after treatment for childhood lymphoma: A cross‐sectional study

Gonadal function decades after treatment for childhood lymphoma (CL) is not well described. This cross-sectional study had two aims: (1) describe long-term gonadal function and fertility in childhood lymphoma survivors (CLSs), and (2) explore anti-Mullerian hormone (AMH) as a measure of ovarian function in CLSs. Seventy-four male and 62 female CLSs participated in a survey consisting of a questionnaire, clinical examination, and blood/semen analysis. Prior treatment was categorized according to gonadotoxicity. Hypogonadism was determined by levels of gonadal hormones based on luteinizing hormone, follicle-stimulating hormone, testosterone (males), AMH (females <40 years), and menstrual status. Fertility was explored according to pregnancies achieved, semen analysis, and AMH. Hypogonadism was observed in 7 of 66 males (11%). Seven of 64 males (11%) were categorized as infertile. Nine of 45 females <40 years (20%) were at risk to develop premature ovarian failure (POF). Twenty of 45 females (44%) showed low-AMH levels indicating decreased fertility. Four "critically low" females reported pregnancies within the preceding 2 years. Sixty-four percent of the males and 93% of the females attempting parenthood had been successful (P = 0.01). Hypogonadism and low-AMH were related to treatment burden. Twenty years after treatment of CL, female CLSs' attempts of pregnancy initiation are mostly successful, while males seem at higher risk of infertility. Hypogonadism is a problem in 10% of the male CLSs. Based on AMH levels, POF is a risk in 20% of the female CLSs. The clinical significance of AMH reflecting true probability of fertility needs further research in cancer survivors.

Cardiac Function in Long-Term Survivors of Childhood Lymphoma

Objectives. We studied long-term effects of therapy for childhood lymphoma on cardiac function. Design and patients. We prospectively evaluated 45 survivors of childhood lymphoma, using clinical parameters, electrocardiography and echocardiography. Further comparisons were made between lymphoma subgroups and between males and females. Results. Mean age at diagnosis was 9.1 years. Mean followup duration was 10.9 years. The NYHA functional class was I in 43 patients and II in 2 patients. A prolonged QTc interval (>0.44 msec) was found in 8 patients. Left ventricular (LV) systolic function and compliance were normal (LV shortening fraction 40 ± 5.6%; cardiac index 2.84 ± 1.13 L/min/m2; E/A wave ratio 2.5 ± 1.3; mean ± S.D.), LV mass was normal (97 ± 40 grams/m2, mean ± S.D.). Mitral regurgitation was observed in 7/45 patients (16%). Asymptomatic pericardial effusions were found in 3/45 (7%) patients. Conclusions. Long-term follow-up shows that most parameters of cardiac function are normal in survivors of childhood lymphoma. This is likely due to relatively low doses of anthracyclines in modern protocol modalities. Abnormalities in mitral valve flow, QTc prolongation and in a small proportion of survivors, and functional capacity necessitate long-term cardiac follow-up of these patients.

Associations between leisure‐time physical activity and health‐related quality of life among adolescent and adult survivors of childhood cancers

Survivors of childhood cancer are at an increased risk for reduced quality of life (QOL), yet few studies have explored factors associated with improving health-related QOL (HRQOL) in this population. We thus explored the relationship between physical activity (PA) and HRQOL among survivors of childhood cancer. A total of 215 survivors of childhood lymphoma, leukemia, and central nervous system cancers completed mailed surveys that elicited information regarding leisure-time PA (LTPA) measured in metabolic equivalents, HRQOL, and diagnostic and demographic factors. Correlations and adjusted regression models were used to explore the relationship between LTPA and HRQOL. In the total sample, modest, yet significant linear associations were observed between LTPA and overall HRQOL (beta=0.17, p<0.01), as well as each of the respective subscales (beta=0.11-0.23 and p's<0.05 to <0.001). Among adolescent survivors of childhood cancer, LTPA was significantly associated with overall HRQOL (beta=0.27), cancer worry (beta=0.36), cognitive function (beta=0.32), body appearance (beta=0.29), and social function (beta=0.27) (all p's<0.05). Among adult survivors of childhood cancer, LTPA was only significantly associated with physical function (beta=0.28, p<0.001). Significant associations exist between LTPA and HRQOL; however, the association was stronger and observed in more domains for adolescent survivors of childhood cancer. More research is needed to determine the antecedents and consequences of PA in this population.

Comparing thyroid ultrasonography to thyroid function in long‐term survivors of childhood lymphoma

We studied the value of thyroid ultrasonography as a follow-up tool in survivors of childhood lymphomas and correlated morphologic abnormalities with thyroid function tests. A prospective follow-up study of 45 long-term survivors of histology-proved childhood lymphomas was performed. Mean age at diagnosis was 9.1 years (range 2.1-16.4 years) and mean follow-up duration 10.9 years (range 3.9-22.2 years). Among the 26 survivors of Hodgkin disease (HD) who received mantle field irradiation, 14 (54%) had abnormal ultrasonograms. Elevated thyroid-stimulating hormone (TSH) concentrations were found in 14 (54%), and 6 of them (42%) had normal thyroid functions. Six of twelve patients with normal ultrasonograms had abnormal thyroid function, and 5 of 11 patients with normal function had abnormal sonograms. Among the 19 non-HD survivors who did not receive radiotherapy, 18 (95%) had both normal sonograms and normal function. Thus thyroid gland abnormalities were detected in 54% of HD survivors after mantle field irradiation. No correlation between the abnormalities detected on ultrasonography and serum levels of TSH and thyroid hormones were found. Both ultrasound and thyroid function tests independently provide clinically useful information; the former examines gland morphologogy and the latter evaluates hormonal changes associated with thyroid disease. The high frequency of thyroid abnormalities detected by ultrasonography suggests that periodic thyroid ultrasonography is advisable in the follow-up of patients treated with mantle irradiation to screen for morphologic changes that may presage malignant transformation.

Comparing thyroid ultrasonography to thyroid function in long-term survivors of childhood lymphoma

We studied the value of thyroid ultrasonography as a follow-up tool in survivors of childhood lymphomas and correlated morphologic abnormalities with thyroid function tests.A prospective follow-up study of 45 long-term survivors of histology-proved childhood lymphomas was performed. Mean age at diagnosis was 9.1 years (range 2.1-16.4 years) and mean follow-up duration 10.9 years (range 3.9-22.2 years).Among the 26 survivors of Hodgkin disease (HD) who received mantle field irradiation, 14 (54%) had abnormal ultrasonograms. Elevated thyroid-stimulating hormone (TSH) concentrations were found in 14 (54%), and 6 of them (42%) had normal thyroid functions. Six of twelve patients with normal ultrasonograms had abnormal thyroid function, and 5 of 11 patients with normal function had abnormal sonograms. Among the 19 non-HD survivors who did not receive radiotherapy, 18 (95%) had both normal sonograms and normal function. Thus thyroid gland abnormalities were detected in 54% of HD survivors after mantle field irradiation. No correlation between the abnormalities detected on ultrasonography and serum levels of TSH and thyroid hormones were found.Both ultrasound and thyroid function tests independently provide clinically useful information; the former examines gland morphologogy and the latter evaluates hormonal changes associated with thyroid disease. The high frequency of thyroid abnormalities detected by ultrasonography suggests that periodic thyroid ultrasonography is advisable in the follow-up of patients treated with mantle irradiation to screen for morphologic changes that may presage malignant transformation.

Disturbances in oral and dental structures in patients with pediatric lymphoma after chemotherapyA preliminary report

Objective. The purpose of this study was to evaluate the effects of chemotherapy on oral and dental structures and craniofacial growth in 30 survivors of childhood lymphoma. Study Design. Eruption status, root malformations, premature apexification, agenesis, crown anomalies, soft tissue abnormalities, gingival and periodontal status, enamel defects and discolorations, and craniofacial growth status of the subjects were documented and compared with findings in 20 healthy children who served as controls. Results. Statistically significant ( P < .05) differences between the study and control groups were found for plaque index, enamel hypoplasias, discolorations, and agenesis. Conclusions. The results of the study suggest that antineoplastic therapy and/or childhood cancer can result in a higher prevalence of various malformations in teeth. Children treated in the early years of their lives displayed the most severe dental defects, suggesting that immature teeth are at a greater risk of developmental disturbances than fully developed teeth.( Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87:317-21)