{"id":62596,"date":"2024-12-30T11:44:07","date_gmt":"2024-12-30T11:44:07","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=62596"},"modified":"2025-01-06T18:09:51","modified_gmt":"2025-01-06T18:09:51","slug":"nutritional-challenges-in-paediatric-oncology-screening-and-managing-malnutrition-and-sarcopenia","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol17no4\/nutritional-challenges-in-paediatric-oncology-screening-and-managing-malnutrition-and-sarcopenia\/","title":{"rendered":"Nutritional Challenges in Paediatric Oncology: Screening and Managing Malnutrition and Sarcopenia"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

Cancer is a\nsignificant cause of mortality among children and adolescents in the United\nStates, ranking as the second most common cause of death for children aged 1\u201314\nyears and the fourth most common cause of death for adolescents aged 15\u201319\nyears. This highlights the impact of cancer on young people and the need for\ncontinued research and support for pediatric and adolescent cancer patients.<\/p>\n\n\n\n

Children who have\ncancer frequently experience malnutrition. Numerous research investigations\nindicated that the incidence of this medical condition ranges widely with\nreports showing that it affects 6\u201351 % of children admitted to hospitals. Malnutrition\nin children with tumors is associated with higher energy needs and losses, as\nwell as reduced intake of essential nutrients.1\u20135 <\/sup>Tumor-secreted\nproinflammatory cytokines increase metabolism and catabolism, leading to\nprotein loss and faster oxidation of energy sources.6-14<\/sup>   Gastrointestinal issues (i.e., vomiting,\nnausea, etc) from chemotherapy toxicity can also contribute to increased energy\nlosses. Chemotherapy can result in changes in taste, reduced appetite, and\nlower nutrient absorption, which may result in decreased appetite.15-28<\/sup>\nAll of these processes lead to neoplastic cachexia, a metabolic syndrome\ninvolving ongoing loss of muscle mass that cannot be fully reversed with\ntypical nutritional aid. 29\u201332<\/sup> This results in anorexia, muscle\nwasting, fatigue, abnormal biochemical levels, functional decline, and\ninadequate weight changes. 33-39<\/sup><\/p>\n\n\n\n

Among other\npredisposing factors, malnutrition of protein-energy can lead to sarcopenia.\nSarcopenia refers to the gradual loss of mass, strength, and skeletal muscle function.\nSarcopenia may occur in young people, such as children with cancer, related to\nmalnutrition, aggravating its side effects and increasing patients’ sensitivity\nto various complications.<\/p>\n\n\n\n

Sarcopenia, in\ncontrast to malnutrition, is a new term in the pediatric literature. Sarcopenia\nin adults, which is a component of malnutrition, is defined as a decrease in\nskeletal muscle mass (SMM) and a decrease in muscle strength or physical\nperformance.40 <\/sup>However, sarcopenia associated with decreased SMM in\npediatrics has only recently been recognized. A pathological condition called\nsarcopenia is defined by a gradual and widespread loss of muscle mass – both\nquantitative and qualitative – as well as a deterioration in physical function.\nIt is a leading cause of mortality, poor quality of life, loss of independence\nand physical disability.41<\/sup> After age 50, muscle mass typically\ndeclines by 0\u20131 percent annually in women and 0.5\u20131 percent in men. This\ncondition is typically associated with age. Nevertheless, certain pathological\nconditions characterized by systemic inflammation, such as cancer, endocrine\ndisorders and chronic inflammatory diseases, can also lead to early development\nof sarcopenia due to the catabolic state that inflammatory cytokines induce in\nskeletal muscle.42,43<\/sup> Sarcopenia and malnutrition may coexist in\npediatric patients with neoplasia, worsening the patient’s prognosis. The\nco-occurrence of two clinical conditions, malnutrition and sarcopenia syndrome,\nhas been documented in the adult literature, with notable overlap in treatment\noutcomes and adverse events.44, 45 <\/sup>Similar concepts regarding loss\nof muscle mass, changes in muscle function, and inadequate nutrient intake\nleading to deficits in fine motor skills, cognition, and nutrition are shared\nin the definitions of malnutrition and sarcopenia.<\/p>\n\n\n\n

In this review, we\nwant to emphasize the critical importance of early detection of malnutrition in\npediatric cancer patients and the subsequent optimization of nutritional\ninterventions within this population. This highlights the immense significance\nof regularly assessing the nutritional status and identifying the risk factors\nfor the development of malnutrition. Additionally, the review presents\npractical tools that are highly applicable in daily clinical practice, further\naiding in the battle against malnutrition.<\/p>\n\n\n\n

Materials and Methods<\/strong><\/p>\n\n\n\n

Pathogenesis<\/strong><\/p>\n\n\n\n

Sarcopenia can be\ncaused by various factors and progress through different mechanisms such as\nmuscle fat content, neuromuscular integrity, proteolysis, and protein\nsynthesis. Understanding these mechanisms and their causes can help in\ndesigning intervention trials. Some individuals may have a clear cause for\nsarcopenia, while others may not. Thus, primary and secondary classifications\nare used in clinical practice. Age-related sarcopenia is classified as\nsecondary, while sarcopenia with additional causes is classified as primary.\nThe multifactorial nature of sarcopenia in older adults may make classification\nchallenging for each individual.46-56<\/sup><\/p>\n\n\n\n

Classification<\/strong><\/p>\n\n\n\n

The European Working Group on Sarcopenia in the Elderly (EWGSOP) recommends using the terms “presarcopenia”, “sarcopenia”, and “severe sarcopenia” to classify stages of muscle mass loss in the elderly. Presarcopenia, with low muscle mass but no impact on strength or performance, requires precise measurement methods for diagnosis. Sarcopenia is marked by low muscle mass, strength or performance, while severe sarcopenia meets all three criteria. Understanding these stages aids in selecting appropriate treatments and recovery goals. 57,58<\/sup>  EWGSOP has identified acute and chronic sarcopenia as subcategories, with acute cases lasting less than six months and chronic cases lasting longer. Regular evaluation is crucial to monitor progression and enable early intervention to prevent or slow the effects of sarcopenia (Figure 1).<\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 1: Detection of high-risk patients for malnutrition and sarcopenia<\/strong><\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Evaluation<\/strong><\/p>\n\n\n\n

Early and sufficient\nnutritional intervention can help hospitalized children avoid growth arrest,\nincrease therapy tolerance, improve their quality of life, and shorten their\nhospital stay.59,60<\/sup> <\/p>\n\n\n\n

Screening Tools<\/strong><\/p>\n\n\n\n

To identify children\nat risk and establish an appropriate nutritional support plan, the European\nSociety of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and\nESPEN recommend screening for nutritional risks at the time of hospital admission.61,62<\/sup>\nDespite the fact that a number of pediatric nutritional risk assessments have\nbeen reported in research, screening for nutritional disorders is often not\nperformed and there is no consensus on the \u201coptimal\u201d screening tool.63<\/sup>\nCurrently, there are seven primary screening tools for childhood nutritional\nrisk: PNRS, SGNA, STAMP, PYMS, STRONGkids, and PNST. Patients at risk of\nmalnutrition must undergo a specific nutritional assessment following the\nnutritional risk assessment. It is important to examine growth curves, the\nonset of puberty, psychomotor development, motor skills and swallowing ability,\ngastrointestinal complaints, weight fluctuations, medication intake, eating\nhabits, dietary habits, allergies and food intolerances.64-66<\/sup><\/p>\n\n\n\n

Physical Examination<\/strong><\/p>\n\n\n\n

The physical\nexamination assesses the patient’s general health and looks for evidence of\nspecific nutritional deficiencies. Although no single laboratory test can\nprovide a comprehensive assessment of nutritional status, laboratory data plays\na complementary role in the assessment process. An inflammatory state is often\nassociated with disease-related malnutrition, which may reduce the benefit of\nnutritional interventions. In acute inflammation or catabolic states, levels of\nacute phase proteins are increased, whereas albumin, prealbumin,\nretinol-binding protein and transferrin are reduced.67-73<\/sup><\/p>\n\n\n\n

Anthropometric Measurements<\/strong><\/p>\n\n\n\n

Although weight is a\nmeasure of a person’s overall nutritional status, a number of factors,\nincluding age, gender, daily intake and fluid intake, can affect a person’s\nweight. Standing patients older than two years should be weighed using a\ndigital scale or a platform scale with movable weights. For patients who cannot\nstand, we use wheelchair or bed scales. When weighing a child under two years\nof age, it is best to place them on a scale on their back and make sure the\nweight is evenly distributed in the center of the scale.74<\/sup> A\ncritical metric for tracking long-term nutritional status is height, whether\nmeasured as length, height, or another variable. When measuring a child under\ntwo years old, he should lie on his back and use an infantometer. If possible,\na vertical stadiometer mounted on the wall is used for children aged two and\nover. The head circumference of babies as young as 36 months can be measured\nusing a flexible tape measure that is wrapped around the head. Head size should\nbe viewed as a measure of nutritional status and brain development.<\/p>\n\n\n\n

Weight-for-height,\nwhich corresponds to BMI in patients over two years of age, can be used as an\nevaluation measure in children under two years of age. The formula for\ncalculating BMI is BMI=weight(kg)\/height2<\/sup> (m2). Due to the\nvariability of age and gender, different specific BMI values \u200b\u200bare available\nfor children. BMI can be used to determine obesity or overweight in children.\nThe World Health Organization (WHO) has approved the use of BMI to measure\nthinness in adolescents, but underweight in children is defined as \u201clow weight\nfor age\u201d and is not determined by BMI. Furthermore, because BMI ignores\nvariations in body composition, it should not be the sole measure of a child’s\nnutritional status under clinical conditions. Mid upper arm circumference\n(MUAC) is a simple measurement that can be taken using a flexible tape measure\npositioned perpendicular to the extended axis of the arm. The midpoint of the\nupper arm, which is located between the olecranon and the acromion, is measured\nand marked. In patients with edema, MUAC is a more accurate measure of body\ncomposition than BMI because it is unaffected by fluid intake.<\/p>\n\n\n\n

To measure the\nthickness of the triceps skinfold, place your thumb and index finger between\nthe skin and subcutaneous fat over the MUAC point. Although it can also be\nhelpful in identifying body fat depots in patients, this parameter is widely\nused in research. A cost-effective, non-invasive method for assessing the\nfunctional status of muscles is the handgrip test, which is performed using a\nportable dynamometer. The patient uses the dynamometer to subject their hand and\nforearm muscles to a series of movements designed to replicate their maximum\nstrength. Grip strength is a useful tool for detecting malnutrition in children\nbecause dietary changes affect muscle function before muscle mass.<\/p>\n\n\n\n

A child’s weight,\nlength, height, weight length, or BMI are expressed as a percentile for age and\nsex on a bell-shaped reference curve constructed from population data. To\ncompare a child’s position with a population of other children similar to him\nor her in terms of age and gender, a percentile is used to indicate the\npercentage of the population that remains above or below the measured value.\nHowever, according to the WHO, Z-scores would be a better way to express\nanthropometric measurements because percentiles do not accurately reflect the\nextent of the patient’s deviation from population norms. Z-scores, which\ncompare each individual anthropometric measurement to data from reference age\ngroups, are more sensitive than percentiles because they express the child’s\ndeviation from the mean in standard deviation (SD).74<\/sup><\/p>\n\n\n\n

Body Composition Asssessment<\/strong><\/p>\n\n\n\n

Body composition can\nbe routinely determined using several methods, including bioimpedance (BIA),\ndual-energy x-ray absorptiometry (DXA), and whole-body potassium counting\n(TBK).75,76<\/sup> Despite the common use of these reference methods, each\nhas certain practical limitations. A non-invasive technique for measuring body\ncomposition that can be used in patients of all ages is dual-energy X-ray\nabsorptiometry (DXA). It is a quick, cost-effective and radiation-safe\nprocedure.77 <\/sup>Another safe, noninvasive, and widely used technique\nfor indirectly determining body composition is bioimpedance analysis (BIA). Its\nbasis is the idea that the body’s ability to conduct an alternating electrical\ncurrent can find a contact resistance (impedance) that is inversely\nproportional to the concentration of electrolyte and water.<\/p>\n\n\n\n

Fat mass, lacking\nwater and electrolytes, shows strong resistance to high impedance, while\nfree-fat mass, composed of well-hydrated cells, exhibits lower impedance. Air\nwithin the lungs, parenchymal organs, and bones are not considered to be\neffective conductors and are therefore disregarded. Both resistance (R) and\nreactance (Xc) are components of the impedance (Z) that affects the flow of current\nthrough the body. Fat mass and extracellular water (ECW) are the main factors\nthat primarily affect R. Xc, which is the capacity of normal cell membranes to\ntake in an electric charge and then later discharge it, serves as a\nrepresentation of the cellular mass in the body. The early detection of\nsarcopenic status can help with timely initiation of appropriate and tailored\ndietary treatments to address it. Different techniques are available in the\nmedical field to assess muscle mass and diagnose sarcopenia.80 <\/sup>Anthropometric\nmeasurements like weight, BMI, mid-arm circumference, and triceps skinfold\nthickness can be easily influenced by illness and therapy and may not provide\nan accurate evaluation of body composition. Bone densitometry (DXA),\nbioelectrical impedance analysis (BIA), and air displacement plethysmography\n(ADP) are more accurate methods for body composition assessment, but their\nusage is restricted due to the need for specialized staff and equipment.81,82<\/sup><\/p>\n\n\n\n

CT and MRI are the top\nchoices for measuring skeletal muscle mass in adults, with CT being the\npreferred method despite its high radiation levels. The radiation exposure from\nstandard CT scans is a significant disadvantage when evaluating sarcopenia in\nchildren. Although MRI does not involve radiation, it is pricier than CT and\nmight not be as easily accessible for regular monitoring. Yet, kids with\nchronic illnesses frequently undergo imaging as a component of their routine\nhealthcare, enabling the assessment of muscle mass without any extra expenses\nor radiation exposure. 83,84<\/sup><\/p>\n\n\n\n

Results and Discussion<\/strong><\/p>\n\n\n\n

Examining the general\ndevelopment is essential when evaluating body composition in pediatrics, as it\ncan influence the evaluation of sarcopenia in children. In puberty, there are\nsignificant differences in skeletal muscle mass and fat mass proportions,\ndespite similar lean and fat mass in young boys and girls. During puberty, it\nhas been observed that males typically see a larger boost in lean muscle mass\ndue to hormonal factors like growth and sex hormones (estrogens, testosterone),\nwhereas females tend to accumulate more fat mass. 85,86 <\/sup>At present,\nthere is no definitive tool for assessing the decline in motor function in\nchildren undergoing evaluation for sarcopenia. Assessing muscle function in\ninfants with standardized methods is difficult due to several factors\ninfluencing their motor performance, including postural control development,\ncoordination, core stability, and ability to perform specific movements.<\/p>\n\n\n\n

Illnesses can hinder\nthe capability to perform specific muscle evaluations. Even though studies on\nsarcopenia in children are ongoing, evaluations in early childhood still do not\ninclude assessments of motor function. Handgrip and 6-minute walk tests are\nfrequently employed among older children and teenagers to assess upper body\nstrength and overall exercise capacity. These evaluations align with the\nsuggested tests for detecting muscle function deficiencies in adults diagnosed\nwith sarcopenia. While other tests for strength and performance have been used\nwith children, their effectiveness is limited due to the lack of standardized\nprotocols. 87-92<\/sup><\/p>\n\n\n\n

Measuring the psoas\nmuscle area (SMA) from abdominal computed tomography (CT) images at the L3-L4\nand L4-L5 levels is a quick, efficient, and reliable way to determine muscle\nmass.93,94<\/sup> The skeletal muscle index (SMI) is calculated by\nmultiplying the patient’s height squared (m2) by the SMA (cm2<\/sup>).\nSarcopenia may be present if the SMI is below 55 cm2<\/sup>\/m2<\/sup>\nfor men and 39 cm2<\/sup>\/m2<\/sup> for women. Examining the muscle\nmass of adult cancer patients, patients undergoing regular axial tomography\nre-evaluation scans, patients with liver disease, critically ill patients, and\nsurgical patients has become a frequent occurrence. 95-101 <\/sup>Sarcopenia\ndiagnosis has been used in patients with pediatric cancer, inflammatory bowel\ndiseases, type 2 diabetes, end-stage liver disease, and intestinal failure.102-112\n<\/sup>Recently, age- and sex-specific curves for total area of psoas muscle\n(tPMA) have been developed for pediatric patients aged 1 to 16. These curves\nallow for a quick assessment of sarcopenia and calculation of Z-Scores for PMA.113\u2013119<\/sup>\nLurz et al. found that when examining tPMA at the L3\u2013L4 and L4\u2013L5 levels, the\npsoas muscle has a rounder shape, allowing for a more accurate contour design.\nAs a result, tPMA at the L4\u2013L5 level seems to be more important in pediatric\npatients. Additionally, a measurement taken at the L4-L5 reference level gives\na reliable assessment of skeletal muscle and adipose tissue, as this level is commonly\nused to assess visceral adipose tissue.120-125<\/sup> In more recent times,\nMRI has been used to measure the thickness of the temporal muscle as a way to\ndetect sarcopenia, especially in patients with brain tumors.126-128<\/sup><\/p>\n\n\n\n

Clinicians should\ncombine nutrition assessment with screening for sarcopenia to properly evaluate\nthese two connected nutritional issues and ultimately enhance patients’\nclinical outcomes. Several malnutrition screening tools are accessible,\nincluding the Malnutrition Screening Tool (MST), Malnutrition Universal\nScreening Tool (MUST), the short version of the Mini-Nutritional Assessment\n(SF-MNA), and Nutrition Risk Screening-2002 (NRS-2002).129-132<\/sup><\/p>\n\n\n\n

Indicators of history\nand physical examination are often seen in both tools, such as unintentional\nweight loss, reduced food consumption, digestive issues, and impairment in\ndaily functioning. Additional studies are needed to establish the accuracy and\neffectiveness of this evaluation tool among various patient groups and\nenvironments.<\/p>\n\n\n\n

Recent advances in\nmuscle biology have unveiled new insights into the molecular mechanisms of\nsarcopenia and potential nutritional treatments. While the conventional\nrecommendation for preventing age-related muscle weakness and loss involves a\ncombination of resistance training and amino acid-containing supplements, it’s\nbeen found that protein-only supplements have little impact on sarcopenia\nsymptoms. Candidate substances like catechins, soy isoflavones, and ursolic\nacid show promise in combating sarcopenia. These compounds have a crucial role\nin regulating proteins responsible for aging and inflammation-related signalling\npathways. This regulation is key in the development of sarcopenia and its\nassociated pathogenesis. Understanding these\npathways and how they are affected by these compounds can provide valuable\ninsights into potential interventions for sarcopenia and age-related\ninflammation. <\/p>\n\n\n\n

Certain compounds derived from plants or food, known as phytochemicals, have been attracting attention for their remarkable antioxidant properties. Numerous in vivo and in vitro studies have unveiled the potential of phytochemicals, particularly polyphenols, in facilitating muscle recovery and potentially serving as a treatment for muscle atrophy. In various models of muscle damage, whether caused by pathological conditions or exhaustive exercise, compounds like curcumin and sulforaphane (SFN) have demonstrated their effectiveness in preventing or minimizing injuries to skeletal muscle mass. These remarkable compounds activate cytoprotective signaling pathways and trigger an optimal antioxidant response, combating inflammation and promoting the restoration of skeletal muscle. Specifically, curcumin has shown promising results in preventing muscle atrophy by inhibiting protein synthesis, primarily by regulating ubiquitin ligases. <\/p>\n\n\n\n

Moreover,\ncurcumin has demonstrated remarkable myogenic and mitochondrial qualities in\nboth in vitro and in vivo studies. Currently, a variety of natural compounds,\nincluding terpenoids (such as ursolic acid, celastrol, and tanshinone IIA),\npolyphenols (like resveratrol, curcumin, and urolithin A), flavonoids (such as\nquercetin and apigenin), alkaloids (like tomatidine and magnoflorine), and\nvitamin D, are known for their ability to enhance muscle strength, increase\nmuscle mass, facilitate muscle stem cell differentiation, promote mitochondrial\nbiogenesis, and reduce hydrogen peroxide production and inflammation in\nskeletal muscles. These compounds have pleiotropic functions, but some of them\nalso have specific targets and can regulate distinct signaling pathways. For\ninstance, ursolic acid, resveratrol, curcumin, berberine, and others stimulate\nAMPK-mediated PGC-1\u03b1 expression, inhibit the nuclear factor\nkappa-light-chain-enhancer of activated B cells (NF-\u03baB), and activate\nmitogen-activated protein kinase (MAPK) pathways associated with protein\ncatabolism, thereby facilitating muscle myogenesis. Despite these promising\nfindings, the efficacy of natural products compared to synthetic drugs is\nhindered by the limited research on their molecular mechanisms,\nbioavailability, and clinical trials. Nevertheless, herbal medicines and their\npurified components, such as polyphenols and alkaloids, continue to hold\nsignificant potential in the realm of muscle recovery and overall well-being.\nAdditionally, further research is needed to fully elucidate the mechanisms\ninvolved and to identify specific compounds that can effectively target these\npathways.133-139<\/sup> <\/sup>One\nlimitation of using natural products is that the studies often use amounts that\nexceed what would be consumed through typical food sources. This means that the\neffects observed may not accurately represent real-life scenarios.\nAdditionally, the issue of bioavailability, such as in the case of curcumin, must\nbe taken into account. However, this is not a concern with SFN found in\nbroccoli, as other factors like preparation and cooking play a role. Lastly, it\nis crucial to conduct more studies involving human subjects. While research on\ncell lines and animal models is valuable for understanding the mechanisms of\naction, it is imperative to fully comprehend how these active compounds affect\nthe human biological system.140<\/sup><\/strong><\/p>\n\n\n\n

Conclusion<\/strong><\/p>\n\n\n\n

Malnutrition in cancer\npatients significantly impacts survival rates by lowering disease-free\nsurvival, increasing treatment-related mortality, and reducing chemotherapy\ntolerance. Malnutrition also negatively affects physical, emotional, and social\nwell-being, hindering recovery and making cancer treatment more challenging. <\/p>\n\n\n\n

Distinguishing between\nprimary and secondary sarcopenia can be beneficial in a clinical setting, as it\ncan aid in promptly starting suitable and personalized dietary interventions to\nmanage it. This review outlines the current status of evaluating skeletal\nmuscle function in children and adolescents with cancer and explores the impact\nof nutritional strategies in treating pediatric cancer patients.<\/p>\n\n\n\n

Comprehensive\nnutritional support is crucial to alleviate these negative impacts and improve\ntreatment outcomes and patient well-being.<\/p>\n\n\n\n

Acknowledgement<\/strong><\/p>\n\n\n\n

The authors thank \u201cFondazione per l\u2019Oncologia\nPediatrica ONLUS\u201d for their dedicated patient care and scientific support.<\/p>\n\n\n\n

Funding Sources<\/strong><\/p>\n\n\n\n

The author(s) received no financial support for the\nresearch, authorship, and\/or publication of this article<\/p>\n\n\n\n

Conflict of Interest<\/strong><\/p>\n\n\n\n

The author(s) do not have any conflict of interest.<\/p>\n\n\n\n

Data Availability Statement<\/strong><\/p>\n\n\n\n

This statement does not apply to this article.<\/p>\n\n\n\n

Ethics Statement<\/strong><\/p>\n\n\n\n

This research did not involve human participants, animal subjects, or any material that requires ethical approval <\/p>\n\n\n\n

Informed Consent Statement<\/strong><\/p>\n\n\n\n

This study did not involve human participants, and therefore, informed consent was not required <\/strong><\/p>\n\n\n\n

Clinical Trial Registration<\/strong><\/p>\n\n\n\n

This research does not involve any clinical trials<\/p>\n\n\n\n

Author contributions<\/strong><\/p>\n\n\n\n

Stefano Mastrangelo, Antonio Ruggiero: Conceptualization, Methodology, Writing \u2013 Original Draft. <\/p>\n\n\n\n

Alberto Romano, Palma Maurizi, Daniela Rizzo, Giorgio Attin\u00e0: Data Collection, Analysis, Writing \u2013 Review & Editing. <\/p>\n\n\n\n

Antonio Ruggiero, Giorgio Attin\u00e0, Daniela Rizzo, Alberto Romano: Visualization, Supervision, Project Administration. <\/p>\n\n\n\n

Antonio Ruggiero, Stefano Mastrangelo: Funding Acquisition, Resources, Supervision<\/p>\n\n\n\n

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