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Growth hormone function and treatment following bone marrow transplant for neuroblastoma
Abstract
Previously, we reported that 26 children with stage III or IV neuroblastoma (NBL) treated with BMT grew poorly post-BMT and significantly worse than a comparison group of hematologic BMT patients. Furthermore, unlike the hematologic patients, there was no apparent catch-up growth. Six of these previously reported long-term (> 2 years) NBL patients surviving BMT were evaluated with growth hormone (GH) provocative testing, frequent (every 20 min) overnight GH sampling and IGF-1 determinations. Three of 6 patients were GH deficient based on subnormal responses to provocative stimuli and subnormal pooled 12 h GH values. Only one child had completely normal GH testing and his growth was normal. Four patients were tested with recombinant GH for a period of 12-21 months. Three patients demonstrated an improvement in their growth velocity on therapy. However, the overall response to GH treatment was significantly less than the growth response in children who are GH-deficient due to causes other than BMT. In summary, GH deficiency may be a frequent complication of BMT treatment of NBL. It also appears that the BMT treatment protocol employing total body irradiation and high-dose melphalan may induce GH resistance.
... There are now many studies which have shown a significant incidence of GH deficiency (20-70%) following TBI and high-dose CY (Borgstrom & Bolme, 1988;Sanders et al, 1988a;Hovi et al, 1990;Papadimitriou et al, 1991;Ogilvy-Stuart et al, 1992;Olshan et al, 1993;Huma et al, 1995;Brauner et al, 1997). The majority of these studies have reported impaired GH responses to provocative stimuli, although a few groups have described reduced spontaneous GH secretion (Borgstrom, 1988;Hovi et al, 1990). ...
... The majority of the therapeutic results are short-term, usually 1 year, with occasional studies extending to 3 years (Papadimitriou et al, 1991). Furthermore, most series contain relatively small numbers of children and the growth data are documented in insufficient detail, although there is general agreement that there is a significant improvement in height velocity during the first year of GH treatment compared with pretreatment velocity, with responses which range between a modest improvement in growth velocity and frank catchup growth (Borgstrom & Bolme, 1988;Papadimitriou et al, 1991;Olshan et al, 1993;Giorgiani et al, 1995;Huma et al, 1995;Brauner et al, 1997). ...
... The use of cyclosporine and corticosteroid in allogeneic HSCT [40,41] and growth hormone deficiency [7] after TBI were important risk factors. However, the markedly impaired osteocytic differentiation of MSCs harvested from TBI-exposed patients may partly explain why retarded bone growth was found in children in the absence of growth hormone deficiency [42,43] and no Bcatch-up^in growth following adequate growth hormone replacement [43,44]. ...
Total body irradiation (TBI) is frequently used in hematopoietic stem cell transplantation (HSCT) and is associated with many complications due to radiation injury to the normal cells, including normal stem cells. Nevertheless, the effects of TBI on the mesenchymal stromal stem cell (MSC) are not fully understood. Bone marrow-derived MSCs (BM-MSCs) isolated from normal adults were irradiated with 200 cGy twice daily for consecutive 3 days, a regimen identical to that used in TBI-conditioning HSCT. The characteristics, differentiation potential, cytogenetics, hematopoiesis-supporting function, and carcinogenicity of the irradiated BM-MSCs were then compared to the non-irradiated control. The irradiated and non-irradiated MSCs shared similar morphology, phenotype, and hematopoiesis-supporting function. However, irradiated MSCs showed much lower proliferative and differentiative potential. Irradiation also induced clonal cytogenetic abnormalities of MSCs. Nevertheless, the carcinogenicity of irradiated MSCs is low in vitro and in vivo. In parallel with the ex vivo irradiation experiments, decreased proliferative and differentiative abilities and clonal cytogenetic abnormalities can also be found in MSCs isolated from transplant recipients who had received TBI-based conditioning previously. Thus, TBI used in HSCT drastically injury MSCs and may contribute to the development of some long-term complications associated with clonal cytogenetic abnormality and poor adipogenesis and osteogenesis after TBI.
... Patients with neuroblastoma often undergo BMT at a young age and are reportedly at a high risk of developing growth disorders. 19,20 Cranial radiotherapy, which is performed before TBI, has been reported as a high risk factor for growth disorders. 21 The incidence of short stature after TBI is reported to be 25% to 31%. ...
Objectives:
We aimed to evaluate the safety of total body irradiation before bone marrow transplant.
Materials and methods:
We analyzed 110 patients (65 male, 45 female) who underwent total body irradiation for hematopoietic stem cell transplant between May 1998 and March 2013. Median age at total body irradiation was 17 years (range, 1-62 y). Median observation time was 777 days (range, 31-5494 d). Initial diagnoses were acute lymphoblastic leukemia (24 patients), acute myeloid leukemia (26 patients), chronic myeloid leukemia (7 patients), myelodysplastic syndrome (8 patients), malignant lymphoma (13 patients), mucopolysaccharidosis (12 patients), neuroblastoma (10 patients), and other diseases (10 patients). The total fractionated dose used for total body irradiation was 12 Gy in 69 patients and 6.0-10.8 Gy in 29 patients. Single-dose total body irradiation was administered to 12 patients. Most patients (63 of 110) received chemotherapy consisting of cyclophosphamide alone.
Results:
Ocular complications were observed in 29.5% of the patients. Hypothyroidism, interstitial pneumonia, obliterative bronchiolitis, and veno-occlusive disease developed in 8.2%, 1.8%, 0.9%, and 2.7% of patients. Growth abnormality was observed in 10 (20%) of the 50 pediatric patients. The use of a lower dose (< 12 Gy vs 12 Gy) of fractionated total body irradiation did not decrease the incidence of adverse events; however, nonmyeloablative conditioning with low-dose singlefraction total body irradiation reduced the incidence of adverse events. Three patients who underwent total body irradiation as reirradiation therapy achieved long-term survival without adverse events.
Conclusions:
Fractionated total body irradiation given at a lower dose (<12 Gy vs 12 Gy) did not decrease the incidence of adverse events.
... Even when controlled for age, NBL patients after SCT had less response to GH therapy than hematologic malignancies after SCT. 15 Almost all our patients received 13-cisretinoic acid, which is associated with premature epiphyseal closure. 16 We did not have adequate bone age data to assess this. ...
Due to the poor prognosis of high-risk (HR) neuroblastoma (NBL), scant data exist on late effects after treatment. Recently, protocols utilizing intense multimodal treatment have resulted in improved long-term survival. The objective of this study was to determine the prevalence of late effects in survivors of HR NBL. A retrospective review of clinical data for serial patients completing treatment between September 1994 and October 2007 and surviving for at least 1 year was performed. Therapy included aggressive chemotherapy, surgery, radiation and single or tandem SCT. Oncology follow-up was standard; clinical criteria were utilized for referrals to endocrinology and other services. Fifty-one eligible patients were identified. Median follow-up was 6.1 years (range 1.0-15.2). Height was significantly impacted (ΔZ-score -1.91 in those treated with TBI and -0.77 in those without). Pre-diabetes or diabetes, hypothyroidism and ovarian insufficiency were observed in 50, 59 and 75% of at-risk survivors, respectively. Hearing loss and dental issues were common. Nine patients had relapse of NBL; seven died of progressive disease. As there is a high prevalence of late effects in long-term survivors of HR NBL, close monitoring and further studies after treatment are indicated, and in particular after more modern, non-TBI regimens.Bone Marrow Transplantation advance online publication, 20 January 2014; (2013) 0, 000-000. doi:10.1038/bmt.2013.218.
... Current evidence suggests that almost 100% of children treated with radiation doses above 30 Gy will have blunted GH responses to insulin tolerance test within two to five years after radiation therapy (38). Importantly, children show greater vulnerability to developing GHD than adults, as isolated GHD can be seen more frequently in children treated with cranial irradiation doses as low as [18][19][20][21][22][23][24] or after total body irradiation (TBI) with doses as low as 10 Gy (35,36,(42)(43)(44)(45)(46)(47)(48). ...
Tumors of the central nervous system, the most common solid tumors of childhood, are a major source of cancer-related morbidity and mortality in children. Survival rates have improved significantly following treatment for childhood brain tumors, with this growing cohort of survivors at high risk of adverse medical and late effects. Endocrine morbidities are the most prominent disorder among the spectrum of longterm conditions, with growth hormone deficiency the most common endocrinopathy noted, either from tumor location or after cranial irradiation and treatment effects on the hypothalamic/pituitary unit. Deficiency of other anterior pituitary hormones can contribute to negative effects on growth, body image and composition, sexual function, skeletal health, and quality of life. Pediatric and adult endocrinologists often provide medical care to this increasing population. Therefore, a thorough understanding of the epidemiology and pathophysiology of growth failure as a consequence of childhood brain tumor, both during and after treatment, is necessary and the main focus of this review.
... There have been a number of reports of the relatively shortterm growth pattern of children treated with GH for GH deficiency associated with previous TBI. Several authors (Papadimitriou et of., 1991;Olshan et al., 1993) provide growth data for the first 1-3 years of GH therapy and conclude that GH therapy improved the growth velocity significantly compared with the pretreatment velocity; the growth response however was significantly less than that seen in children with isolated idiopathic GH deficiency treated with GH.Sanders et al. (1988b)conclude simply that the growth responses to GH treatment in their TBI children were disappointing, but provide no data. Borgstrom andBolme (1988)however were more optimistic and conclude that in terms of first year growth the majority of their TBI children benefit from GH therapy. ...
... The first is a direct effect of radiation on the growth plates in vertebral bodies or in the pelvis, mainly manifested as decreased vertebral growth. A second mechanism is resistance to GH or insulin-like growth factor (IGF-1 or somatomedin C) in patients who receive total body irradiation before bone marrow transplantation (329,342,343). ...
... The modest response to GH therapy in our patients was in accordance with the finding of the previously reported NBL patients and clearly poorer than the growth response of GH deficient non-tumor patients. 20 Despite the suboptimal response, our results suggest that treating GH-deficient transplanted NBL patients with substitute hormone therapy might be useful in increasing the final height although this has not yet been reached. Investigation of GH status and start of therapy should not be unnecessarily delayed if the best possible growth result is to be obtained. ...
Impaired growth after TBI prior to BMT has been a constant finding in children with leukemia. The growth of poor-risk neuroblastoma (NBL) survivors treated with myeloablative preparative regimens and ABMT at the Hospital for Children and Adolescents, University of Helsinki, since 1982 is reported. Two separate groups were analyzed: (1) The TBI- patients (n = 15) were conditioned with high-dose chemotherapy only. They had been treated at the age of 1.0-6.3 (mean 3.0) years and the post-ABMT follow-up time was 1.5-14.5 (mean 7.7) years. (2) The TBI+ patients (n = 16) had received TBI in addition to high-dose chemotherapy. They had been treated at the age of 1.3-4. 8 (mean 3.0) years, and the post-ABMT follow-up time was 1.5-8.0 (mean 4.7) years. The height standard deviation score (SDS) was similar for the two groups at the time of diagnosis, -0.3 +/- 1.2 (mean +/- s.d.), and at the time of ABMT, -0.7 +/- 1.1. After transplantation, the height SDS continued to decrease in the TBI+ group, the mean being -2.0 SDS at 5 years after ABMT. In the TBI-group, the mean height SDS remained within -0.7 to -0.9 to the 10 years of follow-up. Five patients received growth hormone (GH) therapy starting 2-6 years after ABMT. They all had low GH secretion in provocative tests. All showed some response to GH therapy. The mean height SDS increased 0.4 SDS during the 3 years following the start of GH therapy, while in the untreated patients a decrease of 0. 8 SDS during the corresponding time (P = 0.009) was observed. We conclude that NBL patients grow poorly following ABMT when TBI is included in the conditioning regimen, but close to normally when treated without TBI. The need for GH therapy should be evaluated early to avoid an unnecessary decrease in final height.
... [1][2][3][4][5][6][7][8][9][10][11][12] The incidence of GH deficiency after hematopoietic cell transplantation (HCT) varies widely, from 20% to 85%; the differences are likely caused by variations in the time of testing, differences in the preparative regimens received, the inclusion of patients with and without cranial irradiation, and inconsistencies in the GH testing methods used. 1,[13][14][15][16][17][18][19] Decreased growth velocity occurs after single-exposure and fractionated-exposure TBI. 3,7,13 Posttransplantation growth rates vary, with some observers reporting the poorest growth rates during the first year after TBI whereas others report the greatest losses in height several years after TBI. ...
Growth impairment and growth hormone (GH) deficiency are complications after total body irradiation (TBI) and hematopoietic cell transplantation (HCT). To determine the impact of GH therapy on growth, the final heights of 90 GH-deficient children who underwent fractionated TBI and HCT for malignancy were evaluated. Changes in height standard deviation (SD) from the diagnosis of GH deficiency to the achievement of final height were compared among 42 who did and 48 who did not receive GH therapy. At HCT, GH-treated patients were younger (P = .001), more likely to have undergone central nervous system irradiation (P = .007), and shorter (P = .005) than patients who did not receive GH therapy. After HCT, GH deficiency was diagnosed at 1.5 years (range, 0.8-9.5 years) for GH-treated and 1.2 years (range, 0.9-8.8 years) for nontreated patients. GH therapy was associated with significantly improved final height in children younger than 10 years at HCT (P = .0001), but GH therapy did not impact the growth of older children. Girls (P = .0001) and children diagnosed with acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), or myelodysplastic syndromes (MDS) (compared with acute lymphoblastic leukemia [ALL] or non-Hodgkin lymphoma [NHL]; P = .02) also showed more rapid growth than their counterparts. These data demonstrate that GH therapy improves the final height of young children after fractionated TBI.
... Below average height was noted even when subjects were not diagnosed to be GHD. Despite adequate GH replacement in the patients with GHD, they do not grow as well as patients with isolated GHD, since their long bones have been irradiated as part of the treatment regimen [23,24] . Reports on the longterm outcomes of neuroblastoma survivors who were treated with a single autologous transplant including TBI had similar rates of short physical stature [18,25]. ...
Increasing numbers of children with advanced neuroblastoma are achieving cure. We describe the clinical late effects specific to survivors of stage IV neuroblastoma all similarly treated using tandem autologous peripheral blood stem cell rescue with TBI.
The medical records of 35 neuroblastoma patients treated at CHOP between 1997 and 2001 were examined. Eighteen of the 35 patients died of progressive disease, and 4 were lost to follow-up. Thirteen patients continue to follow-up in our Multidisciplinary Cancer Survivorship Clinic where they are evaluated and monitored by a consistent group of subspecialists that evaluate long-term sequelae. Data on treatment exposures including TBI and treatment related sequelae identified by clinician assessment and/or diagnostic testing were collected.
Results indicate late effects were present in all 13 subjects, 12 of whom suffered from multiple negative sequelae, including issues with growth hormone deficiency, dental problems, osteochondromas and hearing deficiencies, among others, most at higher rates than reported previously.
The findings in this small cohort indicate the need for future prospective studies of this intensive pediatric cancer treatment, and underscore the importance of medical intervention and long-term monitoring of these at-risk subjects to increase overall quality-of-life.
Approximately 650 cases of neuroblastoma are diagnosed in the United States each year. With an incidence of 10.2 cases per million, it is the most common cancer that arises during the first year of life and the most common extracranial solid malignancy, representing 8–10% of all pediatric malignancies. Neuroblastoma is also responsible for 15% of childhood cancer mortality (Attiyeh et al. 2005; Brodeur 1997; Maris 2010). The median age at diagnosis is 17 months, and the incidence of the disease quickly dissipates with increasing age (Fig. 5.1).
Thyroid functionGrowthPubertyGonadal function after pubertyConclusions
Pre-transplant preparative regimens including exposure to high-dose chemotherapy and total body irradiation (TBI) can lead to significant long-term consequences, particularly when these exposures occur during childhood. In children, endocrine dysfunction is a common late effect after hematopoietic cell transplantation (HCT) and can include thyroid dysfunction, thyroid malignancy, growth disturbance, and gonadal dysfunction. The most significant impact has been seen after exposure to TBI (particularly when delivered as single fraction versus fractionated doses). Myeloablative chemotherapy-only conditioning regimens such as busulfan and cyclophosphamide can also lead to endocrine dysfunction although the impact is generally less significant. After HCT, children require close follow-up and monitoring for the development of thyroid dysfunction, growth failure, and gonadal dysfunction such as delayed puberty. Appropriate interventions can ameliorate most endocrine disturbances, although some conditions such as hypothyroidism and thyroid malignancy may have a latency of decades after HCT, hence lifelong surveillance is necessary.
Hematopoietic stem cell transplant (HSCT) is increasingly used for the treatment of both malignancies and nonmalignant diseases. This has been made possible by several factors, including expansion of the unrelated donor pool, advances in mobilization and collection of autologous cells, and reduced intensity conditioning regimens. Although transplant-related mortality and relapse remain obstacles, an increasing number of children are surviving following HSCT. Both the HSCT antecedent therapy and the posttransplant complications have multisystem effects, and understanding and anticipating these are important in caring for the children affected. This chapter will provide a brief overview, as many of these complications are discussed in more depth in other chapters of this book.
This chapter focuses on growth and cognitive issues of children undergoing hematopoietic stem cell transplantation (HSCT). The chapter is split into two sections: one on growth and one on neurocognitive development. Following linear growth, weight and body mass index in children after HSCT is very important. Many pediatric HSCT patients will have poor linear growth and some will benefit from growth hormone (GH) therapy if they are GH-deficient, which is not uncommon. In terms of neurocognitive sequelae, global intellectual functioning is preserved for many patients. Some exceptions are infants receiving HSCT and/or children that received cranial radiation prior to HSCT.
Increased recognition is necessary for the neuroendocrine sequelae of cancer therapy, the contribution of radiation therapy (RT), and an emphasis on early detection and follow-up because of the potential impact on quality of life.
Circulating serum growth hormone (GH) stimulates the production of insulin-like growth factor I (IGF-I) in all tissues. IGF-I mediates GH effects on growth, bone mineralization, and body composition (decreased fat deposition, increased muscle mass).
GH deficiency is commonly believed to be the first hypothalamic–pituitary deficiency to emerge after injury to the hypothalamic–pituitary axis (HPA), followed by deficiencies of gonadotropin, ACTH, and thyroid-stimulating hormone (TSH) due to the radiation dose sensitivities; however, these deficiencies can occur in any order.
The 5- and 10-year estimates of endocrinopathy in patients treated for base of skull tumors with proton therapy were as follows: 72 and 84 % for hyperprolactinemia, 30 and 63 % for hypothyroidism, 29 and 36 % for hypogonadism, and 19 and 28 % for hypoadrenalism.
Rates of hypothyroidism for adults and children treated for Hodgkin’s lymphoma can be as high as 65 % after radiation doses exceeding 40 Gy to the thyroid gland; lower doses are associated with a lower likelihood of injury.
Primary ovarian failure is characterized by amenorrhoea, hypoestrogenism, and hypergonadotropism.
Altered GH secretion is an important and well-documented cause of poor growth in childhood cancer survivors, particularly in young children after surgery in the suprasellar region, cranial irradiation (>18 Gy), or total body irradiation (>12 Gy).
The symptoms of central adrenal insufficiency can be subtle and include poor weight gain, anorexia, easy fatigability, and poor stamina.
Hypothalamic damage from a tumor or cancer treatment can also result in hypothalamic obesity—unrelenting weight gain that does not respond to caloric restriction or exercise. Peak GH levels after RT decline as an exponential function of time based on mean dose of the hypothalamus.
Routine yearly measurements of TSH and free T4 should be done in all patients who have received cranial irradiation, because the symptoms of central hypothyroidism are often subtle, and TSH secretory dysregulation after irradiation may precede other endocrine disorders.
Any patient identified with GHD should be evaluated for possible ACTH deficiency and for central hypothyroidism.
GnRH agonists are the most effective treatments for precocious puberty, rapid tempo puberty, or normally timed puberty that is inappropriate for height.
Standard treatment for TSH deficiency or for primary hypothyroidism is levothyroxine replacement therapy.
Hydrocortisone is the preferred agent for glucocorticoid replacement in children, because it is least likely to impair growth.
Progressive and irreversible neuro-endocrine dysfunction following radiation-induced damage to the hypothalamic-pituitary (h-p) axis is the most common complication in cancer survivors with a history of cranial radiotherapy involving the h-p axis and in patients with a history of conventional or stereotactic pituitary radiotherapy for pituitary tumours. This review examines the controversy about the site and pathophysiology of radiation damage while providing an epidemiological perspective on the frequency and pattern of radiation-induced hypopituitarism.
Contrary to the previously held belief that h-p axis irradiation with doses less than 40 Gy result in a predominant hypothalamic damage with time-dependent secondary pituitary atrophy, recent evidence in survivors of nonpituitary brain tumours suggests that cranial radiation causes direct pituitary damage with compensatory increase in hypothalamic release activity. Sparing the hypothalamus from significant irradiation with sterteotactic radiotherapy for pituitary tumours does not appear to reduce the long-term risk of hypopituitarism.
Radiation-induced h-p dysfunction may occur in up to 80% of patients followed long term and is often associated with an adverse impact on growth, body image, skeletal health, fertility, sexual function and physical and psychological health. A detailed understanding of pathophysiological and epidemiological aspects of radiation-induced h-p axis dysfunction is important to provide targeted and reliable long-term surveillance to those at risk so that timely diagnosis and hormone-replacement therapy can be provided.
IntroductionThyroid functionGrowthPubertyConclusion
References
Endocrinopathy after therapeutic irradiation represents a treatable late effect of successful cancer therapy and highlights the importance of careful follow-up for adults and children. The endocrine effects of irradiation have been extensively studied and demonstrate the systemic manifestations of late effects after localized or large volume irradiation, the differential sensitivity of functional subunits of the hypothalamus and other critical endocrine organs to radiation dose, the low-dose radiation effects in normal tissues, and the benefit of newer radiation methods and modalities.
Children who have undergone bone marrow transplantation (BMT) often have decreased growth. Growth is a multifactorial process, and the factors that influence growth after BMT are not completely understood. The authors hypothesized that donor type may be a factor influencing growth. Sixty-five children and adolescents who underwent BMT (32 related matched, 33 unrelated matched) were evaluated. Growth velocity (height standard deviation) was assessed prior to and 2 years following BMT. The results indicated that children and adolescents who underwent unrelated matched transplants had lower growth velocity (P < .059) than those with related matched transplants. Those who received the standard conditioning regimen that included total body irradiation (TBI) had a significantly lower growth velocity (P < .045) than those with chemotherapy-only regimens. Significant correlates of growth velocity included younger age at BMT and pre-BMT growth velocity. Thus, donor type, age at BMT, prior treatment, and BMT conditioning regimens that include TBI may all affect growth post-BMT. Careful monitoring of growth velocity is required for patients who have received an unrelated donor BMT.
In der vorgelegten Arbeit wird das Wachstum nach der Transplantation hämatopoetischer Stammzellen und ihrer Konditionierungsverfahren wie Bestrahlung und Chemotherapie an einem gemischtgeschlechtlichen Kollektiv von 58 Patienten im Alter zwischen 6 Monaten und 16,5 Jahren mit hämatologisch-onkologischen Erkrankungen untersucht.
Es handelt sich hierbei um ein Follow-up von 2 bis 10 Jahren, wobei die Veränderung der Körpergröße und des Körpergewichtes zu verschiedenen Zeitpunkten gemessen wird. In der Untersuchung finden einzelne Einflussgrößen wie das Geschlecht, Alter, Grunderkrankung, Organschäden, Ausgangskörpermaße sowie die Art der Transplantation hämatopoetischer Stammzellen und der Bestrahlung besondere Berücksichtigung.
Des Weiteren wurden diagnostische Mittel wie Knochenalter, IGF-I- und IGFBP-3 –Serumspiegel zur Erfassung einer Wachstumsstörung und hinsichtlich ihres prädiktiven Wertes oder der Aussagekraft untersucht.
Als Ergebnis zeigte sich bei etwa der Hälfte (58 %) der Patienten eine Wachstumsstörung. In den beiden nun so entstandenen Patientengruppen waren Patienten jeweils mit verschiedenen Einflussgrößen, bzw. mit potentiell das Wachstum beeinflussenden Faktoren in unterschiedlicher Häufigkeit vorhanden.
Ein signifikanter Einfluss ließ sich nur für die Ganzkörperbestrahlung (TBI), Kombination aus der TBI und der konventionellen Strahlentherapie und den HST- Typ (allogen unverwandt und autolog) als Einflussgröße feststellen. Außerdem ließ es sich feststellen, dass die Kinder im Alter von 6-10 Jahren häufiger eine Wachstumsstörung nach TBI entwickeln, als die in anderen Altersgruppen und dass Patienten nach der allogen verwandten HST häufiger eine Wachstumsstörung nach TBI entwickelten, als nach anderen Transplantationsarten. Alle anderen Therapiemodalitäten sowie Organschäden hatten auf das Wachstum keinen signifikanten Einfluss. Die Endkörpergröße, bzw. das Endgewicht konnten im Rahmen dieser Arbeit wegen des zu kurzen Untersuchungszeitraumes und der zu geringen Patientenzahl nicht untersucht werden.
Die Bestimmung des Knochenalters und IGF-I und IGFBP-3 haben keinen hohen Vorhersagewert und waren für die Detektion von Wachstumsstörungen nicht ausreichend.
Als eine Alternative für das diagnostische Vorgehen wären Statuserhebungen nach einem etwa 2-3-jährigem Intervall nach HST- Abschluss sowie in der Pubertät, oder bei dem Verdacht einer Wachstumsstörung zu empfehlen. Diese sollten z.B. einen Wachstumshormonstimulationstest, Knochenalterbestimmung und eine MRT- Aufnahme des Schädels mit Beurteilung der Hypophyse beinhalten. Routinemäßig ist die Bestimmung von Körperlänge und Körpergewicht ausreichend.
Current therapy for children with medulloblastoma includes craniospinal radiation therapy (CSRT) with or without adjuvant chemotherapy. The difference in growth of children after the two different therapeutic modalities is unknown.
The growth of 38 prepubertal children who survived medulloblastoma was reviewed retrospectively. Fifteen of these patients received CSRT alone; 23 received chemotherapy in addition to the radiation therapy.
The average growth velocity of all patients with medulloblastoma during the 4 years of the study was below the mean for age and sex in all patients except one. Most patients grew at velocities more than two standard deviations below the mean. The overall growth of children who received chemotherapy in conjunction with CSRT was significantly worse than the growth of those who received only CSRT. The children who received chemotherapy showed little or no improvement in growth velocity by year 4; those who did not receive chemotherapy had some improvement.
These findings suggest that chemotherapy potentiates the deleterious effects of radiation on growth.
Chemotherapy (CT) may produce growth impairment, however, the pathogenesis is still unclear.
A series of 25 patients mean age 13.3 years (6.3-19.8), previously treated for malignant solid tumours with only CT and surgery were studied. Growth hormone (GH) reserve was assessed by two different provocative stimuli (Clonidine and L-Dopa). Mean time between completion of treatment and GH evaluation was 18.5 months (2-74 months). At that time, all patients were in complete remission.
GH deficiency (GHD), defined by an impaired GH response to both provocative tests was observed in 11 out of 25 patients (44%). At diagnosis, mean standing height was +0.23 +/- 1.42 SDS in the GHD group (GHD-g) and +0.18 +/- 1.23 SDS in the non-GHD group (n-GHD-g). At the end of therapy, the mean standing height in the GHD-g was -0.31 +/- 1.22 SDS and -0.17 +/- 1.41 in the n-GHD-g, differing from the former group (P = 0.05). For a mean follow-up of 30 months from the end of treatment, the mean standing height was -0.48 +/- 1.23 SDS in the GHD-g and -0.24 +/- 1.51 SDS for the n-GHD-g (P = 0.03). Growth rate at the end of treatment was +0.13 +/- 1.54 in the GHD-g and +0.21 +/- 1.75 in the n-GHD-g. For a mean follow-up of 30 months from the end of treatment, the growth rate was different between GHD-g and n-GHD-g (-0.31 +/- 2.72 vs. -0.21 +/- 1.93, P < 0.05).
1) Growth impairment in children treated because of malignant diseases has a multifactorial etiology, but CT-induced GH deficiency is one potential adverse factor. 2) An endocrine follow-up should be introduced in order to detect and treat hormonal deficiencies as early as possible.
To determine the impact on final adult height of bone marrow transplantation.
The final height of 28 long term survivors (18 males; 10 females), allografted before or at the onset of puberty, at a median age of 10.8 years (range 6.3 to 14.6) and who did not receive growth hormone (GH) treatment or other growth promoting agents, was evaluated. Median follow up period after bone marrow transplantation was 7.9 years (range 3.2 to 11.4), and age at the most recent evaluation 18.1 years (range 15.6 to 24.5). Height values were expressed in standard deviation score (SDS) from the mean of the normal population. Height at bone marrow transplantation was compared with final height as well as with parental genetic height. Patients were divided into three groups: severe aplastic anaemia (SAA): three patients given no radiotherapy; leukaemia-total body irradiation (TBI): 14 patients with acute or chronic leukaemia conditioned with chemotherapy and TBI; leukaemia-TBI with previous cranial radiation therapy (CRT): 11 patients. None of the patients had solid tumour.
There was a decrease in final height SDS compared to pre-transplantation height SDS (paired t test, p < 0.0001). All patients except one reached an adult height above -2.0 SDS. A significant decrease in height SDS was found in the TBI and the CRT groups (paired t test, p = 0.02 and p = 0.0002, respectively). Whereas height SDS value at the time of transplant was higher than the genetic height SDS, final height SDS values were lower.
Despite the decrease in height SDS found after bone marrow transplantation, 27 of the 28 patients spontaneously achieved what is considered to be a normal height SDS (above -2.0 SDS). This should be taken into account when considering GH treatment in children who underwent bone marrow transplantation for malignant haematological diseases.
There has been a dramatic improvement in the treatment of both allogeneic and autologous stem cell transplants, especially in children and young adults. However, attempts to apply more intensive conditioning treatments to the more refractory pediatric malignancies have also increased the risks of deleterious consequences. This review examines the risks, and reports important variations in the toxic effects of using different conditioning techniques.
The effects of cancer therapy on growth are reviewed. The effects of radiation and chemotherapy on growth hormone production and growth hormone responsiveness by peripheral tissues are examined. The effects of radiotherapy and chemotherapy on other endocrine function pertaining to growth also are discussed. An approach to surveillance of pediatric cancer survivors pertaining to growth and development is suggested.
Conditioning for bone marrow transplantation (BMT) by total body irradiation frequently causes growth failure. The contribution of growth hormone (GH) deficiency to this failure was assessed in 38 patients given three types of body irradiation: group 1 (n = 18) was given 12 Gy total body irradiation as six fractions, group 2 (n = 14) 10 Gy (one dose) total body irradiation, and group 3 (n = 6) 6 Gy (one dose) thoracoabdominal irradiation, which did not involve the hypothalamic-pituitary area. At the first evaluation, 2.9 +/- 0.2 (SE) years after BMT, the values for the plasma insulin-like growth factor I (IGF-I) and its GH-dependent binding protein (IGFBP-3) were similar in groups 1 and 2 but significantly greater in group 3 (p < 0.02 for IGF-I and 0.01 for IGFBP-3). These values were similar in those patients in groups 1 and 2 who had low GH peaks after stimulation (12 patients: IGF-I, 0.8 +/- 0.2 U/ml; IGFBP-3, 1.6 +/- 0.2 mg/L) and in those with normal GH peaks (20 patients: 1 +/- 0.1 U/ml and 1.8 +/- 0.1 mg/L). The decrease in height 2 years after BMT was significantly (p < 0.01) greater in group 2 than in groups 1 and 3, but 5 years after BMT it was similar in groups 1 and 2 (0.9 +/- 0.2 and 1.4 +/- 0.3 SD), significantly (p < 0.05) greater in group 2 than in group 3 (0.7 +/- 0.2 SD). The individual height changes between BMT and the last clinical evaluation before GH therapy were not correlated with the age at BMT, GH peak after stimulation, plasma IGF-I concentration, or IGFBP-3 concentration. Seven patients with GH deficiency were given GH therapy; their growth rate became normal for age (-2.1 +/- 0.9 SDS before and -0.2 +/- 0.4 SDS for the first year; not significant) without any catch-up growth. We conclude that plasma IGF-I and IGFBP-3 values are of no diagnostic value for GH deficiency after TBI. Their normal or high levels, despite low GH peaks, suggest that bone irradiation induces lesions causing resistance to IGF-I.
The exact contribution of growth hormone (GH) deficiency to the adverse growth outcome, in those receiving cranial irradiation (18-24 Gy) or total-body irradiation for haematological malignancies in childhood, remains difficult to disentangle as nearly always the cause of the growth disturbance is multifactorial: chemotherapy, graft-versus-host disease, hypothyroidism, and skeletal dysplasia may all impact on growth. There are few published data from which one can assess the efficacy of GH replacement on final height in those children who received cranial irradiation (18-24 Gy) and/or total-body irradiation; there is no evidence, however, of an increased risk of leukaemic relapse. Endocrine reassessment in the teenagers, who received cranial irradiation (18-24 Gy) for acute lymphoblastic leukaemia many years earlier, revealed a significant incidence of GH deficiency with the additional suggestion that many had been GH deficient for several years. This raises a number of important questions: What is the best way to organize long-term endocrine follow-up? How often should GH status be reassessed? What are the specific benefits of GH replacement in adult life for such individuals? These and other questions require further study.
Eighty-seven patients had a bone marrow transplantation (BMT) at our institution between 1980 and 1992. We wished to study the endocrine complications that accompany this procedure as long-term survival is now much more common. Forty-three patients were retrospectively available for review and their records were examined for evidence of thyroid, pubertal, and growth complications. Fifteen per cent of the patients showed evidence of thyroid involvement. Pubertal delay or gonadal damage was almost universal in pubertal-aged girls treated with busulfan/cyclophosphamide. Gonadal involvement was more frequent in girls than in boys (70% vs. 47%). Sixty per cent of children were shorter or grew at a slower rate. Sixty-five per cent of the children presented with one or more endocrine complications. These are the combined effects of different treatment regimens (chemotherapy, radiotherapy, combined therapy). It is essential to know the natural history of these patients in order to offer proper guidance and treatment as survival rates are increasing.
The three most common clinical situations which have given rise to diagnostic and therapeutic issues involve the child treated for: (1) a brain tumour or extracranial tumour with radiotherapy (XRT) which includes an XRT dose of > or =30 Gy to the hypothalamic-pituitary axis; (2) acute lymphoblastic leukaemia with a cranial XRT dose of 18-24 Gy, and (3) haematological malignancy or solid tumour requiring total body irradiation (dose 10-14 Gy) and BMT. The decision about the intent to treat and the timing of GH replacement needs to be taken in collaboration with the paediatric oncologist who will provide guidance about overall prognosis and the risk of relapse. After a dose of > or =30 Gy to the hypothalamic pituitary axis the risk of GH deficiency (GHD) 2 years later is very high (>50%) and therefore there is 'solid' epidemiological evidence, which predicts outcome. Therapeutically the choice is whether or not to offer GH replacement at 2 years in the presence of biochemical evidence of GHD but independent of auxology, or wait until the growth rate declines. Diagnostically the IGF-1 SDS is more useful than previously thought, particularly if XRT-induced GHD is severe; there may, however, be systematic discordancy between the GH responses to different pharmacological stimuli (ITT vs. arginine). For irradiated children in categories 2 and 3, greater emphasis is placed on auxology in determining the need for assessment of GH status. Early rather than very precocious puberty is a real issue and needs to be actively treated with a GnRH analogue if final height appears to be significantly compromised.
Deficiency of one or more anterior pituitary hormones may follow treatment with external irradiation when the hypothalamic-pituitary axis falls within the fields of irradiation. Hypopituitarism occurs in patients who receive radiation therapy for pituitary tumours, nasopharyngeal cancer and primary brain tumours, as well as in children who undergo prophylactic cranial irradiation for acute lymphoblastic leukaemia, or total body irradiation for a variety of tumours and other diseases. The degree of pituitary hormonal deficit is related to the radiation dose received by the hypothalamic-pituitary axis. Thus, after lower radiation doses isolated growth hormone deficiency ensues, whilst higher doses may produce hypopituitarism. The timing of onset of the radiation-induced pituitary hormone deficit is also dose-dependent. The main site of radiation damage is the hypothalamus rather than the pituitary, although the latter may be affected directly.
Evaluations of endocrine function following hematopoietic cell transplantation demonstrate that the endocrine function abnormalities observed are related to the type of transplant preparative regimen received. Children given high dose cyclophosphamide (CY) only have normal thyroid function, normal growth and development. Children who received a busulfan (BU) plus CY preparative regimen usually have normal thyroid function, normal prepubertal growth, delayed or absent pubertal development, and blunted post-pubertal growth. Recipients of preparative regimens containing total body irradiation may be anticipated to have some thyroid dysfunction, impaired growth rates and delayed or absent pubertal development. Post-pubertal teens and young adults are likely to have gonadal function recover if they received a preparative regimen with CY only but are likely to have primary gonadal failure if they received a preparative regimen with BU or total body irradiation. Individuals whose gonadal function becomes normal have become parents of normal children. All patients who receive a marrow transplant should be followed long-term for development of endocrine function abnormalities.
Few studies have assessed late effects in neuroblastoma (NB) survivors, particularly those with advanced stage disease.
Retrospective analysis of a cohort of advanced stage NB survivors followed in a late effect clinic at a single institution. Screening tests to detect late effects were tailored depending on the individual's treatment exposures.
The study included 63 survivors (31 males). The median age at diagnosis was 3.0 years. The median follow-up from diagnosis was 7.06 years. All patients had surgery and received chemotherapy, 89% received radiation therapy (RT), 62% immunotherapy, and 56% autologous stem cell transplant. Late complications were detected in 95% of survivors and included: hearing loss (62%), primary hypothyroidism (24%), ovarian failure (41% of females), musculoskeletal (19%), and pulmonary (19%) abnormalities. The majority of complications were moderate, with only 4% being life-threatening. Survivors who received cisplatin were at greater risk to develop hearing loss compared to those not so treated (OR 9.74; 95% CI: 0.9-101.6). A total dose of cyclophosphamide greater than 7.4 g was associated with ovarian failure (P = 0.02).
Late complications occur frequently in survivors of advanced stage NB. The majority of these problems are of mild-moderate severity. Long-term follow-up (LFTU) and screening of this population is essential.
Radiation-induced damage to the hypothalamic-pituitary (h-p) axis is associated with a wide spectrum of subtle and frank abnormalities in anterior pituitary hormones secretion. While the rapidity of onset of these abnormalities is primarily radiation dose-dependent, their frequency and severity also depend on the length of follow-up. The GH axis is the most vulnerable to radiation damage, and GH deficiency is usually the only neuro-endocrine abnormality following irradiation of the h-p axis with doses <30 Gy. With higher radiation doses (30-50 Gy), the frequency of GH insufficiency can be as high as 50-100% and that of TSH and ACTH around 3-6%. Abnormalities in gonadotrophin secretion are dose-dependent; precocious puberty can occur after radiation dose <30 Gy in girls only, and in both sexes equally with a radiation dose of 30-50 Gy. Gonadotrophin deficiency occurs infrequently, and is usually a long-term complication following a minimum radiation dose of 30 Gy. Hyperprolactinemia has been described in both sexes and all ages, but is mostly seen in young women after intensive irradiation and is usually subclinical. A much higher incidence of gonadotrophin, ACTH and TSH deficiencies, (30-60% after 10 yr) occurs after more intensive irradiation (>70 Gy) used for nasopharyngeal carcinomas and tumors of the skull base, and following conventional irradiation (30-50 Gy) for pituitary tumors. Radiation-induced anterior pituitary hormone deficiencies are irreversible and progressive. Regular testing is mandatory to ensure timely diagnosis and early hormone replacement therapy, to improve linear growth and prevent short stature in children cured from cancer, to preserve sexual function, prevent ill health and osteoporosis, and improve the quality of life.
Radiation-induced damage to the hypothalamic-pituitary (h-p) axis is associated with a wide spectrum of subtle and frank abnormalities in anterior pituitary hormones secretion. The frequency, rapidity of onset and the severity of these abnormalities correlate with the total radiation dose delivered to the h-p axis, as well as the fraction size, younger age at irradiation, prior pituitary compromise by tumour and/or surgery and the length of follow up. Whilst, the hypothalamus is the primary site of radiation-induced damage, secondary pituitary atrophy evolves with time due to impaired secretion of hypothalamic trophic factors and/or time-dependent direct radiation-induced damage. Selective radiosensitivity in the neuroendocrine axes with the GH axis being the most vulnerable to radiation damage accounts for the high frequency of GH deficiency, which usually occurs in isolation following irradiation of the h-p axis with doses less than 30 Gy. With higher radiation doses (30-50 Gy), however, the frequency of GH insufficiency substantially increases and can be as high as 50-100%, and TSH and ACTH deficiency start to occur with a long-term cumulative frequency of 3-6%. Abnormalities in gonadotrophin secretion are dose-dependent; precocious puberty can occur after radiation dose less than 30 Gy in girls only, and in both sexes equally with a radiation dose of 30-50 Gy. Gonadotrophin deficiency occurs infrequently and is usually a long-term complication following a minimum radiation dose of 30 Gy. Hyperprolactinemia, due to hypothalamic damage leading to reduced dopamine release, has been described in both sexes and all ages but is mostly seen in young women after intensive irradiation and is usually subclinical. A much higher incidence of gonadotrophin, ACTH and TSH deficiencies (30-60% after 10 years) occur after more intensive irradiation (>70 Gy) used for nasopharyngeal carcinomas and tumours of the skull base and following conventional irradiation (30-50 Gy) for pituitary tumours. Radiation-induced anterior pituitary hormone deficiencies are irreversible and progressive. Regular testing is mandatory to ensure timely diagnosis and early hormone replacement therapy to improve linear growth and prevent short stature in children cured from cancer, and in adults preserve sexual function, prevent ill health and osteoporosis and improve the quality of life.
Radiation-induced growth hormone deficiency (GHD) is primarily due to hypothalamic damage. GH secretion by the pituitary may be affected either secondary to some degree of quantitative deprivation of hypothalamic input or, if the radiation dose is high enough, by direct pituitary damage. As a consequence, the neurosecretory profile of GH secretion in an irradiated patient remains pulsatile and qualitatively intact. The frequency of pulse generation is unaffected, but the amplitude of the GH pulses is markedly reduced. Over the last 25 years, the final heights achieved by children receiving GH replacement for radiation-induced GHD have improved; these improvements are attributable to refinements in GH dosing schedules, increased use of GnRH analogues for radiation-induced precocious puberty, and a reduced time interval between completion of irradiation and initiation of GH therapy. When retested at the completion of growth, 80-90% of these teenagers are likely to prove severely GH deficient and, therefore, will potentially benefit from GH replacement in adult life. Such long-term GH treatment in patients treated previously for a brain tumor means that critical and continuous surveillance must be devoted to the risk of tumor recurrence and the possibility of second neoplasms.
Long-term survivors of Wilms tumor and neuroblastoma may experience significant late adverse effects from their disease and its therapy. Little is known, however, about the health-related quality of life experienced by these survivors.
Health-related quality of life, measured by the 36-Item Short Form Health Survey (SF-36), was assessed from self-report in adult survivors of Wilms tumor (N = 654) and neuroblastoma (N = 432) who participated in the Childhood Cancer Survivor Study.
More than 90% of the study population was 18-34 years old at interview, and 58% were females. There was no significant difference on any SF-36 subscale or summary scale between the two diagnostic groups. On average, survivors reported no decrement on the Physical Component Summary scale of the SF-36 when compared to population norms. However, both groups scored significantly below the population mean score (50) on the Mental Component Summary Scale of the SF-36 (Wilms tumor mean = 41.66, standard error = 2.19, P < 0.0001; neuroblastoma mean = 42.41, standard error = 2.23, P < 0.0001) reflecting decreased emotional health. Independent risk factors for lower scores on this scale included female gender, Native American race, unemployment, and household income below $20,000.
Adult survivors of childhood Wilms tumor and neuroblastoma do not differ from population norms on most health-related quality of life (HRQL) measures. These data, however, indicate that the emotional well being of adult survivors may be compromised. Health care providers should be aware of the risk of adverse outcomes in emotional health even many years after treatment and cure.
In January 1997 we introduced a protocol for the treatment with GH of children with impaired growth after unfractionated total body irradiation (TBI). This study is an evaluation of that protocol.
Between January 1997 and July 2005, 66 patients (48 male) treated for haematological malignancies had at least two years of disease-free survival after TBI-based conditioning for stem cell transplantation (SCT). Stimulated and/or spontaneous GH secretion was decreased in 8 of the 29 patients tested because of impaired growth. Treatment with GH (daily dose 1.3 mg/m2 body surface area) was offered to all 29 patients and initiated in 23 of them (17 male). The main outcome measure was the effect of GH therapy on height standard deviation scores (SDS) after onset of GH therapy, estimated by random-effect modelling with corrections for sex, age at time of SCT and puberty (data analysed on intention-to-treat basis).
At time of analysis, median duration of therapy was 3.2 years; median follow-up after start of GH therapy was 4.2 years. The estimated effect of GH therapy, modelled as nonlinear (logit) curve, was +1.1 SD after 5 years. Response to GH therapy did not correlate to GH secretion status.
GH therapy has a positive effect on height SDS after TBI, irrespective of GH secretion status.
Deficiencies in anterior pituitary hormones secretion ranging from subtle to complete occur following radiation damage to the hypothalamic-pituitary (h-p) axis, the severity and frequency of which correlate with the total radiation dose delivered to the h-p axis and the length of follow up. Selective radiosensitivity of the neuroendocrine axes, with the GH axis being the most vulnerable, accounts for the high frequency of GH deficiency, which usually occurs in isolation following irradiation of the h-p axis with doses less than 30 Gy. With higher radiation doses (30-50 Gy), however, the frequency of GH insufficiency substantially increases and can be as high as 50-100%. Compensatory hyperstimulation of a partially damaged h-p axis may restore normality of spontaneous GH secretion in the context of reduced but normal stimulated responses; at its extreme, endogenous hyperstimulation may limit further stimulation by insulin-induced hypoglycaemia resulting in subnormal GH responses despite normality of spontaneous GH secretion in adults. In children, failure of the hyperstimulated partially damaged h-p axis to meet the increased demands for GH during growth and puberty may explain what has previously been described as radiation-induced GH neurosecretory dysfunction and, unlike in adults, the ITT remains the gold standard for assessing h-p functional reserve. Thyroid-stimulating hormone (TSH) and ACTH deficiency occur after intensive irradiation only (>50 Gy) with a long-term cumulative frequency of 3-6%. Abnormalities in gonadotrophin secretion are dose-dependent; precocious puberty can occur after radiation dose less than 30 Gy in girls only, and in both sexes equally with a radiation dose of 30-50 Gy. Gonadotrophin deficiency occurs infrequently and is usually a long-term complication following a minimum radiation dose of 30 Gy. Hyperprolactinemia, due to hypothalamic damage leading to reduced dopamine release, has been described in both sexes and all ages but is mostly seen in young women after intensive irradiation and is usually subclinical. A much higher incidence of gonadotrophin, ACTH and TSH deficiencies (30-60% after 10 years) occur after more intensive irradiation (>60 Gy) used for nasopharyngeal carcinomas and tumors of the skull base, and following conventional irradiation (30-50 Gy) for pituitary tumors. The frequency of hypopituitarism following stereotactic radiotherapy for pituitary tumors is mostly seen after long-term follow up and is similar to that following conventional irradiation. Radiation-induced anterior pituitary hormone deficiencies are irreversible and progressive. Regular testing is mandatory to ensure timely diagnosis and early hormone replacement therapy.
Dietary dehydroepiandrosterone (DHEA) inhibits the proliferation of syngeneic bone marrow cells (BMC) infused into lethally irradiated mice. Potential mechanisms for suppression of hematopoiesis were evaluated and the findings were as follows: (i) depletion of NK, T, B or macrophage cells failed to reverse suppression by DHEA; (ii) stem cell stimulation by erythropoietin, growth hormone, interleukin-2, Friend leukemia virus, or cyclophosphamide failed to reverse suppression; (iii) supplementation of fatty acids, mevalonate, or deoxyribonucleotides, which are dependent upon glucose-6-phosphate dehydrogenase function, did not enhance BMC growth in mice fed DHEA; (iv) DHEA downstream metabolites 4-androstenedione and 17beta-estradiol, as well as the synthetic steroid, 16alpha-chloroepiandrosterone (but not testosterone or 5-androstene-3beta,17beta-diol), also inhibited BMC growth. Tamoxifen antagonized the effects of 17beta-estradiol but not DHEA; (v) dietary DHEA causes hypothermia, but housing of DHEA-fed mice at 34 degrees C to maintain normal body temperature did not reverse suppression; (vi) DHEA leads to a decrease in food intake in rodents. Pair-feeding control diet to mice fed DHEA mimicked the effects of dietary DHEA; (vii) adrenalectomy and orchiectomy decrease the levels of stress and sex hormones, respectively. Neither procedure affected the ability of food restriction or DHEA feeding to inhibit hematopoiesis; (viii) growth of GR-3 NM pre-B leukemia cells in unirradiated mice was also suppressed by DHEA or food restriction. We conclude that DHEA, by reducing food intake in mice, inhibits bone marrow and leukemia cell growth. The precise mechanism(s) by which reduced food intake per se inhibits hematopoiesis is not known, but may involve an increased rate of cellular apoptosis.
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