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Nutritional support in children treated for advanced adrenocortical carcinoma
Tarek M. Zaghloul1,2 . Luca Pio1 . Ayatullah G. Mostafa3,4 . Huma Halepota1 . Suraj Sarvode Mothid5 . Abdelhafeez H. Abdelhafeez1 · Raul C. Ribeiro6 · Andrew M. Davidoff1
Accepted: 13 January 2025 / Published online: 23 January 2025 @ The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2025
Abstract
Purpose Adrenocortical carcinoma (ACC) is a rare, aggressive pediatric malignancy. Advanced ACC requires multimodal treatment, including surgery and systemic chemotherapy including cisplatin, etoposide, doxorubicin, and mitotane. This is associated with significant gastrointestinal toxicity, resulting in many patients being unable to complete scheduled therapy. Often, supplemental nutrition is required if oral intake during treatment is poor. We assessed the frequency of nutritional supplement use in pediatric patients treated for advanced ACC.
Methods This was a retrospective observational study of patients with ACC treated at St. Jude Children’s Research Hospital over 10 years (2012-2022). Patient demographics, treatment received, and the need for supplemental enteral or parenteral nutrition were reviewed.
Results A total of 18 patients with ACC were treated from 2012 to 2022, with 11 having advanced ACC. 54.5% of patients required supplemental nutrition, both enteral and parenteral. All patients requiring supplemental nutrition were intolerant of oral intake, with a mean weight loss of 13.8% (range: 5.9-35%). Mean duration of nutritional support was 362 +337 days. Patients requiring supplemental nutrition tended to be younger than others (mean age: 4.45±3.63 vs. 9.14±4.59 years; median age: 3.35 vs. 8.40 years; range: 0.90-11.0 vs. 3.30-15.1 years) (p=0.082).
Conclusions Most patients with stage IV ACC require nutritional support during their treatment course, especially younger patients. Preemptive feeding tube placement should be considered to avoid delays in treatment.
Keywords Pediatric · Adrenocortical carcinoma . Gastrostomy · Malnutrition
Abbreviations
Adrenocortical carcinoma
ACC CI Confidence interval
| G tube | Gastrostomy tube |
|---|---|
| NG | Nasogastric |
| NJ | Nasojejunal |
| SD | Standard deviation |
| TPN | Total parenteral nutrition |
☒ Tarek M. Zaghloul tarekmzaghloul@gmail.com
1 Department of Surgery, St. Jude Children’s Research Hospital, MS 133, 262 Danny Thomas Place, Memphis, TN 38105, USA
2 Department of Surgery, National Cancer Institute, Cairo University, Cairo, Egypt
3 Department of Diagnostic Imaging, St. Jude Children’s Research Hospital, Memphis, TN, USA
4 Department of Radiodiagnosis, Faculty of Medicine, Cairo University, Cairo, Egypt
5 Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, USA
6 Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA
Introduction
Adrenocortical carcinoma (ACC) is an aggressive, rare malignant tumor arising from the adrenal cortex that affects adults and children. However, only 25 cases, on average, are reported annually in children in the United States, with an annual incidence of 0.2-0.3 cases per million children [1-3]. Pediatric ACC usually presents in the first 5 years of life, with a strong female predominance [4, 5].
Treatment of advanced (stage III or IV) ACC involves a multimodal approach. There is no consensus on a standard treatment, as almost all of the data come from retrospective
reports. Despite the use of different combinations of chemo- therapy, advanced pediatric ACC has a poor outcome, with the 5-year event-free survival and overall survival being estimated at 7.1% (95% CI, 0.5-27.5) and 15.6 (95% CI, 2.5-39.2), respectively [6-10].
Mitotane is considered a critical component of the multi- modal treatment of advanced ACC. It is administered orally and has limited bioavailability, necessitating monitoring of mitotane plasma levels to keep them below toxic levels while maintaining therapeutic levels [11-13]. However, sev- eral side effects of mitotane, alone or in combination with cisplatin, doxorubicin, and etoposide, have been reported. These include pancytopenia, neutropenic fever, and neuro- toxic side effects, namely attention deficit, impaired balance mechanism, memory dysfunction, and hearing loss. Highly problematic are gastrointestinal side effects, which include nausea, vomiting, anorexia, abdominal pain, diarrhea, and intolerance of oral intake. Patients with such gastrointestinal side effects may require nutritional support to maintain their nutritional status and to avoid interruption of treatment, as reported in several case series [14-21].
Retrospective studies have shown that mitotane is effec- tive at increasing event-free survival and progression-free survival in adults [22, 23]. However, data on the efficacy of mitotane in children are limited. Published reports show that outcomes in children are similar to those in adults, yet compliance with mitotane therapy remains a major obstacle to its completion [15, 20].
In view of the gastrointestinal chemotherapy-related complications, its associated morbidity in patients receiv- ing multimodal treatment for advanced ACC [15-20], and the fact that patients with adrenal tumors are at the highest risk of malnutrition among extracranial solid tumor patients [24], this study aimed to analyze nutrition management for those patients.
Methods
This was a retrospective observational study of patients with ACC treated over a 10-year period (2012-2022) at St. Jude Children’s Research Hospital (St. Jude). The study was approved by the St. Jude Institutional Review Board. For each patient, information on their age, sex, and race; the disease stage and treatment received; whether supplemental enteral or parenteral nutritional support was needed; and any related complications was retrieved from the hospital-based cancer registry. The study included patients aged 0-21 years with a diagnosis of stage III or IV ACC who were treated during 2012-2022 in accordance with the COG-ARAR0332 protocol, with induction chemotherapy consisting of doxo- rubicin, etoposide, cisplatin, and mitotane.
Demographics and clinical characteristics were expressed as frequencies and percentages, the mean and standard devi- ation (SD), or the median and range as appropriate. Because of the small sample size, the nonparametric Fisher exact test for categorical data and the Mann-Whitney test for numeri- cal data were used for hypothesis testing, treating P <0.05 as indicating statistical significance. No data were missing for any of the study variables. R statistical software (v4.1.2) was used for analysis.
Results
A total of 18 patients with ACC were treated at St. Jude between 2012 and 2022. Upon analysis, six patients were found to be diagnosed with stage I and II. A sole patient with stage III disease was lost to follow-up and was excluded from the analysis. Eleven patients had advanced (stage IV) disease and were included in the study cohort (Table 1). The mean age of these 11 patients was 6.58 years (range: 0.9-15.1 years).
All patients received chemotherapy consisting of cis- platin, etoposide, doxorubicin, and mitotane due to their advanced disease, except for one patient who died before receiving mitotane. Surgery was performed for nine of the 11 patients (81.8%) and consisted of resection of the primary tumor in all cases. Three of these nine patients (27.3% of the total) also underwent resection of lung metastases.
| Overall (N=11) | |
|---|---|
| Age at diagnosis (years) | |
| Mean (SD) | 6.58 (4.58) |
| Median (min, max) | 5.8 (0.9, 15.1) |
| Sex | |
| Female | 8 (72.7%) |
| Male | 3 (27.3%) |
| Race | |
| White | 10 (90.9%) |
| Asian | 1 (9.1%) |
| Metastases | 11 (100%) |
| Underwent chemotherapy | 11 (100%) |
| Received mitotane | 10 (90.9%) |
| Underwent surgery | 9 (81.8%) |
| Needed any supplementary feeds (NG/G tube/TPN) | 6 (54.5%) |
| Needed NG feeds | 4 (36.4%) |
| Needed G tube | 4 (36.4%) |
| Needed TPN | 2 (18.2%) |
| Time receiving supplemental nutrition (days) | |
| Mean (SD) | 362 (337) |
| Median (min, max) | 245 (90.0, 955) |
Six of the 11 patients (54.5%) required supplemental nutrition. There was no statistically significant difference with respect to sex, ethnicity, presence of comorbidities, or laterality of the tumor between those patients who required supplemental nutrition and those who did not. Younger patients appeared to be more prone to nutritional deficiency. The mean age of patients requiring supplemental nutrition was 4.45 ±3.63 years, as compared with 9.14±4.59 years for those not requiring supplemental nutrition (Tables 2, 3).
All patients requiring supplemental nutrition were evalu- ated by a multidisciplinary team that included the attending pediatric oncologist, a nutritionist, and a pediatric surgeon to decide which nutrition modality was needed. Indications for nutritional support included malnutrition, as defined by BMI z-score, intolerance of oral intake, or parent’s anticipation of treatment intolerance. Decision regarding the type of nutri- tional support was based on symptoms, anticipated dura- tion of treatment, patient’s, and family’s preference. Enteral nutrition was generally preferred as an initial route. Paren- teral nutrition was provided in patients who did not tolerate
| Nutritional sup- plementation not needed (N=5) | Nutritional sup- plementation needed (N=6) | pa | |
|---|---|---|---|
| Age at diagnosis (years) | |||
| Mean (SD) | 9.14 (4.59) | 4.45 (3.63) | 0.0823 |
| Median (min, max) | 8.40 (3.30, 15.1) | 3.35 (0.900, 11.0) | |
| Sex | |||
| Female | 4 (80.0%) | 4 (66.7%) | 1 |
| Male | 1 (20.0%) | 2 (33.3%) | |
| Ethnicity | |||
| White | 5 (100%) | 5 (83.3%) | 1 |
| Asian | 0 (0%) | 1 (16.7%) | |
| Any comorbidities | |||
| No | 4 (80.0%) | 5 (83.3%) | 1 |
| Yes | 1 (20.0%) | 1 (16.7%) | |
| Laterality of tumor | |||
| Left | 2 (40.0%) | 3 (50.0%) | 1 |
| Right | 3 (60.0%) | 3 (50.0%) | |
| Mitotane | |||
| No | 1 (20.0%) | 0 (0%) | 0.455 |
| Yes | 4 (80.0%) | 6 (100%) | |
| Surgery | |||
| No | 1 (20.0%) | 1 (16.7%) | 1 |
| Yes | 4 (80.0%) | 5 (83.3%) |
ªAll p values are from Fisher’s exact test except for that for age at diagnosis, which is from the Kruskal-Wallis test
enteral feeding. The amount and calories of feeds provided were decided based on tolerance, route used and degree of oral tolerance. Four of the six patients received nasogastric (NG) tube feeds, four received gastrostomy (G) tube feeds, and two received total parenteral nutrition (TPN). Of note, some patients received more than one form of nutritional support during their treatment.
All patients who received supplemental nutrition initially experienced treatment-related complications in the form of nausea, vomiting, or intolerance of oral intake, with a mean weight loss of 13.8% (weight loss is defined as a maximum reduction in body weight observed during treatment relative to the weight at the time of diagnosis). Malnutrition was noted in all patients during the first cycle of chemotherapy, except for one patient who did not exhibit weight loss or malnutrition until 3 months after the start of treatment. The mean duration of supplemental nutrition was 362 days (range: 90-955 days).
All patients who received supplemental nutrition were able to complete their cancer-directed therapy except for one patient whose final scheduled cycle of chemotherapy and mitotane was omitted because they developed neurologic symptoms, including stuttering.
Two of the four patients who received NG feeds reported nausea and vomiting related to the NG tube, which stimu- lated a gag reflex. In one of the four patients, the G tube became dislodged and required surgical replacement. Of the two patients who received TPN during their treatment course, one experienced no complications and the other was lost to follow-up and continued treatment at another facility.
Five of the 11 patients (45.5%) required no supplemental nutrition during their cancer therapy. These patients tended to be older, with a mean age of 9.14±4.59 years, and only one patient had weight loss, related to poor recovery after undergoing a lung metastatectomy. Compared with the other patients, these five patients tended to tolerate mitotane bet- ter, with no gastrointestinal complications. However, mito- tane was discontinued intermittently in two of these patients because of multiple hospitalizations for febrile neutropenia.
The treatment team continued to assess the need for sup- plemental nutrition regularly during and after the completion of therapy. Of the six patients who required nutritional sup- plementation, two died while receiving supplemental nutri- tion, two are currently still receiving it, one had improved oral intake and did not need further supplementation, and one was lost to follow-up.
Discussion
Malnutrition is a major issue that affects approximately 90% of pediatric patients with solid tumors. Patients with adrenal tumors or central nervous system tumors are at the
| Patient | Age at diagnosis (years) | Sex | % weight loss | Type of nutri- tion support | Indication | Purpose | Duration of nutritional support (days) | Complications | Stop reason |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 2.3 | F | 21 | NG | Poor PO intake (60% of caloric needs), fam- ily requested NG placed before chemo | Nutrition | 120 | Nausea | Death |
| 2 | 2.5 | M | 19.5 | NG advanced to NJ then GT | Moderate malnutrition, BMI z-score: 2.19 | Nutrition and medications | 370 | Nausea | Death |
| 3 | 4.2 | M | 5.9 | GT | Mild malnutri- tion, BMI z-score :- 1.43 | Nutrition and medications | 955 | None | Current |
| 4 | 0.9 | F | 13 | GT | Requested by parents because of anticipated intolerance of treatment | Nutrition and medications | 515 | GT pulled after 5 days, requiring replacement in OR | Current |
| 5 | 5.8 | F | 35 | NG, GT, and TPN | Moderate malnutrition, BMI z-score: 2.32 | Nutrition and medications | 120 | None | Improved oral intake and weight |
| 6 | 11 | F | 13.6 | NG, GT, and TPN | Enteral intoler- ance, mal- nutrition due to malignant hyperthermia and respira- tory failure. NJ because of intoler- ance of trophic NG formula | Nutrition and medications | 90 | None | Lost to follow- up |
NG nasogastric, NJ nasojejunal, GT gastrostomy tube, TPN total parenteral nutrition
highest risk for malnutrition because of the highly intensive therapy [24-26]. Consistent with this, in the present study, malnutrition occurred in 64% of the patients with stage IV ACC, which is mainly attributed to the intensive systemic therapy provided with major gastrointestinal side effects. Pediatric malnutrition is defined as an imbalance between nutrient requirement and intake, which increases the risk of treatment interruption, infection, febrile neutropenia, and mortality [27].
There is a lack of definitive screening tools for early identification of patients with malnutrition. Parameters commonly used to detect malnutrition include anthropo- metric measurements (head circumference, height for age, mid-upper arm circumference, weight for age, weight for height), BMI z-score, oral intake, and changes in growth
velocity [28]. According to the World Health Organization, the BMI z-score is an estimate of the patient’s nutritional status in relation to that of a normally distributed population. It is calculated as (X- m)/SD, where X is the observed value [height, weight, or body mass index (BMI)] and m and SD are, respectively, the mean and standard deviation values of the distribution corresponding to the reference population [29]. In the present study, the nutritional status of patients was assessed using the BMI z-score.
Runco and colleagues analyzed data from the Pediatric Health Information System database from 2015 to 2019, and they found increases in the number of hospital admis- sions and in the mean duration of hospital stay among malnourished patients [24]. Interestingly, younger patients were more prone to hospital admission with a malnutrition
diagnosis. This was also highlighted in our study, reflecting the fact that younger patients are more prone to be affected by malnourishment, although, because of the small number of patients included in our study, this finding was not sta- tistically significant (p=0.082). The same study by Runco et al. found that pediatric patients with solid tumors who also had malnutrition required significantly more opioid use and had higher rates of nausea, vomiting, and use of appetite stimulants [24].
In July 2022, the National Institutes of Health conducted a workshop titled “Nutrition as Prevention for Improved Cancer Health Outcomes,” from which it was reported that 70-75% of adults with a cancer diagnosis develop malnutri- tion. It was recommended that those patients at risk of mal- nutrition should receive better assistance and interventions by specialized nutritionists to optimize their nutritional sta- tus, thereby improving their quality of life and survival and decreasing the rate of treatment-related complications [30].
There is no general consensus on managing malnutrition in pediatric ACC or even in other pediatric diseases. Enteral nutrition and parenteral nutrition are the two main options for those patients. Parenteral nutrition may be associated with catheter-related complications, infection, atrophy of the gut mucosa, cholestasis, hepatic complications, and electro- lyte disturbance, as well as a high financial burden [31]. A retrospective multicenter study conducted in France found that patients undergoing allogeneic stem cell transplants had better outcomes when they received enteral nutrition versus parenteral nutrition [32]. Those receiving enteral nutrition had significantly lower mortality, shorter hospital stays, bet- ter weight gain at discharge, and less frequent edema [32]. In another study in children with congenital heart disease, enteral nutrition was deemed to be the preferred method of nutrition unless contraindicated [33].
Enteral routes of nutrition include NG tubes and G tubes. There is a lack of definitive guidelines for identifying the best method of nutritional support for pediatric patients with solid tumors. Retrospective studies of the appropriateness of patient selection for pediatric G tubes found that 15% of G tubes were used for less than 6 months. One of the main factors influencing the use of G tubes rather than NG tubes is the long-term need for enteral feeding access and the disease chronicity, despite the higher risk of complications with G tubes [34]. Our patient cohort required long-term nutritional support for a mean of 362 days (range: 90-955 days).
Although G-tube placement is considered a safe proce- dure, it is nevertheless associated with potential complica- tions. Minor complications (reported in 43-74% of cases) include granulation tissue formation, local infection, or leakage at the G-tube site. Major complications (reported in 2-32% of cases) include early dislodgement of the tube and peritonitis, which can be life threatening [35, 40]. There were no reports of minor complications in our patient cohort,
and only one of the four patients who received a G tube required it to be replaced in the operating room (after it became dislodged on postoperative day 5).
Gastro-cutaneous fistula is a potential complication that may require surgical closure, which adds to the cost and morbidity associated with G-tube placement [36, 37]. The reported rates of operative closure of gastro-cutaneous fis- tulae among the pediatric population range from 7.7 to 32% [38-40]. However, there were no reports of gastro-cutaneous fistula in our study cohort. The most important predictor of gastro-cutaneous fistula is the duration of G-tube perma- nence [40].
The main limitation of this study was related to the ret- rospective design. Although our study reviewed one of the largest single-center cohorts of pediatric ACC, the small number of patients limited our analysis. The small patient cohort is justified by the rarity of pediatric ACC. Larger international collaborative studies are required to determine the best approach to nutritional management for pediatric patients with these tumors.
Conclusion
ACC is a rare, aggressive pediatric malignancy that requires aggressive treatment including chemotherapy and mitotane, which is usually not well tolerated among children. The data from our study reflect the need to consider an intervention for patients with advanced ACC to support their nutritional status. Whenever possible, we recommend using enteral nutrition rather than parenteral nutrition. The use of G tubes is considered safe, and they can be placed using minimally invasive techniques such as laparoscopy or percutaneous endoscopic gastrostomy. Nutritional support in the form of prophylactic pretreatment G tubes is highly encouraged to avoid malnutrition and long-term treatment interruption, especially in younger patients. In our institute, we have started offering prophylactic G tubes to patients diagnosed with advanced ACC as a measure to improve their treatment outcomes. A larger, multicenter study is recommended to further assess the need for G tubes in these patients, given the rarity of the disease.
Acknowledgements This work was supported by the American Leba- nese Syrian Associated Charities (ALSAC). The authors thank Keith A. Laycock, PhD, ELS, for the scientific editing of the manuscript.
Author’s contributions T.Z., L.P, A.M and H.H. designed the data col- lection instruments, collected data, and critically reviewed and revised the manuscript. S.M. carried out the initial analyses, and critically reviewed and revised the manuscript. A. A, R. R., and A.D. concep- tualized and designed the study, coordinated and supervised data col- lection, and revised the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.
Funding No specific funding was received for this work.
Data availability The authors confirm that the data supporting the find- ings of this study are available within the article and its supplementary materials.
Declarations
Conflict of interest The authors have no conflicts to declare.
References
1. McAteer JP, Huaco JA, Gow KW (2013) Predictors of survival in pediatric adrenocortical carcinoma: a Surveillance, Epidemi- ology, and End Results (SEER) program study. J Pediatr Surg 48(5):1025-1031
2. Michalkiewicz E, Sandrini R, Figueiredo B, Miranda EC, Caran E, Oliveira-Filho AG et al (2004) Clinical and outcome charac- teristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry. J Clin Oncol 22(5):838-845
3. Ribeiro RC, Pinto EM, Zambetti GP, Rodriguez-Galindo C (2012) The International Pediatric Adrenocortical Tumor Regis- try initiative: contributions to clinical, biological, and treatment advances in pediatric adrenocortical tumors. Mol Cell Endocrinol 351(1):37-43
4. Pinto EM, Chen X, Easton J, Finkelstein D, Liu Z, Pounds S et al (2015) Genomic landscape of paediatric adrenocortical tumours. Nat Commun 6(1):6302
5. Riedmeier M, Decarolis B, Haubitz I, Müller S, Uttinger K, Börner K et al (2021) Adrenocortical carcinoma in childhood: a systematic review. Cancers (Basel) 13(21):5266
6. Rodriguez-Galindo C, Krailo MD, Pinto EM, Pashankar F, Wel- don CB, Huang L et al (2021) Treatment of pediatric adreno- cortical carcinoma with surgery, retroperitoneal lymph node dissection, and chemotherapy: the Children’s Oncology Group ARAR0332 protocol. J Clin Oncol 39(22):2463
7. Else T, Williams AR, Sabolch A, Jolly S, Miller BS, Hammer GD (2014) Adjuvant therapies and patient and tumor characteristics associated with survival of adult patients with adrenocortical car- cinoma. J Clin Endocrin Metab 99(2):455-461
8. Terzolo M, Angeli A, Fassnacht M, Daffara F, Tauchmanova L, Conton PA et al (2007) Adjuvant mitotane treatment for adreno- cortical carcinoma. N Engl J Med 356(23):2372-2380
9. Berruti A, Grisanti S, Pulzer A, Claps M, Daffara F, Loli P et al (2017) Long-term outcomes of adjuvant mitotane therapy in patients with radically resected adrenocortical carcinoma. J Clin Endocrin Metab 102(4):1358-2365
10. Ribeiro RC, Figueiredo B (2004) Childhood adrenocortical tumours. Eur J Cancer 40(8):1117-1126
11. Haak HR, Hermans J, Van de Velde CJ, Lentjes EG, Goslings BM, Fleuren GJ et al (1994) Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients. Br J Cancer 69(5):947-951
12. Daffara F, de Francia S, Reimondo G, Zaggia B, Aroasio E, Por- piglia F et al (2008) Prospective evaluation of mitotane toxicity in adrenocortical cancer patients treated adjuvantly. Endocr Relat Cancer 15(4):1043-1053
13. Baudin E, Pellegriti G, Bonnay M, Penfornis A, Laplanche A, Vassal G et al (2001) Impact of monitoring plasma 1,1-dichlo- rodiphenildichloroethane (o, p’DDD) levels on the treatment of patients with adrenocortical carcinoma. Cancer 92(6):1385-1392
14. Montgomery DA, Welbourn RB (1965) Adrenocortical carcinoma treated with o, p’-DDD. Br Med J 1(5446):1356-1368
15. De León DD, Lange BJ, Walterhouse D, Moshang T (2002) Long- term (15 years) outcome in an infant with metastatic adrenocorti- cal carcinoma. J Clin Endocrinol Metab 87(10):4452-4456
16. Goto T, Miyako K, Kuromaru R, Ihara K, Torisu H, Sanefuji M et al (2008) Case report: adjuvant therapy with a high dose of mitotane for adrenocortical carcinoma in a 4-year-old boy. Clin Pediatr Endocrinol 17(3):71-74
17. Ribeiro RC, Michalkiewicz EL, Figueiredo BC, DeLacerda L, Sandrini F, Pianovsky MD et al (2000) Adrenocortical tumors in children. Brazil J Med Biol Res 33(10):1225-1234
18. Zancanella P, Pianovski MAD, Oliveira BH, Ferman S, Piovezan GC, Lichtvan LL et al (2006) Mitotane associated with cisplatin, etoposide, and doxorubicin in advanced childhood adrenocortical carcinoma: mitotane monitoring and tumor regression. J Pediatr Hematol Oncol 28(8):513-524
19. Kamilaris CDC, Hannah-Shmouni F, Stratakis CA (2020) Adreno- cortical tumorigenesis: lessons from genetics. Best Pract Res Clin Endocrinol Metab 34(3):101428
20. Zekri W, Hammad M, Rashed WM, Ahmed G, Elshafie M, Adly MH et al (2020) The outcome of childhood adrenocortical car- cinoma in Egypt: a model from developing countries. Pediatr Hemato Oncol 37(3):198-210
21. Motte E, Rothenbuhler A, Gaillard S, Lahlou N, Teinturier C, Coutant R et al (2018) Mitotane (op’DDD) restores growth and puberty in nine children with Cushing’s disease. Endocr Connect 7(12):1280-1287
22. Hescot S, Debien V, Hadoux J, Drui D, Haissaguerre M, de la Fouchardiere C et al (2023) Outcome of adrenocortical carcinoma patients included in early phase clinical trials: results from the French network ENDOCAN-COMETE. Eur J Cancer 189:112917
23. Pan L-H, Yen C-C, Huang C-J, Ng X-N, Lin L-Y (2023) Prognos- tic predictors of adrenocortical carcinoma: a single-center thirty- year experience. Front Endocrinol (Lausanne) 14:1134643
24. Runco DV, Stanek JR, Yeager ND, Belsky JA (2022) Malnutri- tion identification and management variability: an administrative database study of children with solid tumors. JPEN J Parenter Enteral Nutr 46(7):1559-1567
25. Zimmermann K, Ammann RA, Kuehni CE, de Geest S, Cignacco E (2013) Malnutrition in pediatric patients with cancer at diag- nosis and throughout therapy: a multicenter cohort study. Pediatr Blood Cancer 60(4):642-649
26. Arends J, Baracos V, Bertz H, Bozzetti F, Calder PC, Deutz NEP et al (2017) ESPEN expert group recommendations for action against cancer-related malnutrition. Clin Nutr 36(5):1187-1196
27. Huysentruyt K, Hulst J, Bian F, Shamir R, White M, Galera- Martinez R et al (2019) Opinions and practices of healthcare professionals on assessment of disease associated malnutri- tion in children: results from an international survey. Clin Nutr 38(2):708-714
28. Mehta NM, Corkins MR, Lyman B, Malone A, Goday PS, Carney L et al (2013) Defining pediatric malnutrition: a paradigm shift toward etiology-related definitions. JPEN J Parenter Enteral Nutr 37(4):460-481
29. Martinez-Millana A, Hulst JM, Boon M, Witters P, Fernandez- Llatas C, Asseiceira I et al (2018) Optimisation of children z-score calculation based on new statistical techniques. PLoS ONE 13(12):e0208362
30. Hiatt RA, Clayton MF, Collins KK, Gold HT, Laiyemo AO, Parker Truesdale K et al (2023) The Pathways to Prevention (P2P) Program: nutrition as prevention for improved cancer outcomes. J Natl Cancer Inst 115(8):886-895
31. Cangelosi MJ, Auerbach HR, Cohen JT (2011) A clinical and economic evaluation of enteral nutrition. Curr Med Res Opin 27(2):413-422
32. Gonzales F, Bruno B, Alarcón Fuentes M, De Berranger E, Guim- ber D, Behal H et al (2018) Better early outcome with enteral rather than parenteral nutrition in children undergoing MAC allo- SCT. Clin Nutr 37(6):2113-2121
33. Alakeel YS, Ismail WW, Alrubayan NI, Almajed MA (2021) Parenteral versus enteral nutrition in children with post-surgical congenital heart disease. Int J Health Sci (Qassim) 15(3):34-40
34. Jackson JE, Theodorou CM, Vukcevich O, Brown EG, Beres AL (2022) Patient selection for pediatric gastrostomy tubes: are we placing tubes that are not being used? J Pediatr Surg 57(3):532-537
35. El-Matary W (2008) Percutaneous endoscopic gastrostomy in children. Can J Gastroenterol 22(12):993-998
36. Kutiyanawala MA, Hussain A, Johnstone JM, Everson NW, Nour S (1998) Gastrostomy complications in infants and children. Ann R Coll Surg Engl 80(4):240-243
37. Crosby J, Duerksen D (2005) A retrospective survey of tube- related complications in patients receiving long-term home enteral nutrition. Dig Dis Sci 50:1712-1717
38. Wyrick DL, Bozeman AP, Smith SD, Jackson RJ, Maxson RT, Kelley KR et al (2013) Persistent gastrocutaneous fistula: factors affecting the need for closure. J Pediatr Surg 48(12):2506-2510
39. El-Rifai N, Michaud L, Mention K, Guimber D, Caldari D, Turck D et al (2004) Persistence of gastrocutaneous fistula after removal of gastrostomy tubes in children: prevalence and associated fac- tors. Endoscopy 36(08):700-704
40. Gordon JM, Langer JC (1999) Gastrocutaneous fistula in children after removal of gastrostomy tube: incidence and predictive fac- tors. J Pediatr Surg 34(9):1345-1346
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