Complementary, alternative, integrative and dietary therapies for children with Crohn's disease - A systematic review.

Children with diagnosed inflammatory bowel diseases such as Crohn's disease are faced with the daunting prospect of living with a chronic disease. Besides psychological stress, children are suffering from therapy side-effects; in particular, corticosteroid therapies are problematic in the growth phase. This highlights that there is a need for less aggressive alternative therapies for children as well as adolescents living with such chronic conditions. Elemental diets are widely used and accepted therapy options. Several pediatric Crohn's disease patients also use complementary, alternative and integrative therapies to reduce or avoid drug therapies. To survey such therapy options and their efficiency and safety, we performed a systematic literature search and screened databases (Cochrane Library, EMBASE, OvidSP, PubMed, CAMbase, CAM-QUEST, Anthromedics) from their inception to December 2019. In total, seven of 1439 studies fulfilled search criteria. Six RCTs and one retrospective controlled trial investigating elemental diets (Flexical, Elemental 028), semi-elemental diets (Pregomin), polymeric diets (Modulen IBD), whole protein based formulas, and ω-3 fatty acid supplementation were found. Data indicated that diet therapies were equal to or more effective than corticosteroid therapies when used to treat Crohn's disease. Regrettably, we could not identify controlled studies investigating complementary, alternative and integrative medicine approaches. Our review provides an updated overview of controlled studies investigating dietary therapies used in the treatment of pediatric Crohn's disease, and demonstrates that the current study situation does not reflect the actual use of complementary, alternative and integrative therapies. Therefore, clinical trials are necessary to estimate risks and benefits of such therapies. The review indicated that enteral diets and ω-3 fatty acid supplementation may be an effective alternative to corticosteroid treatments for children with Chron's disease.

Complementary and alternative medicine in the treatment of acute bronchitis in children: A systematic review.

OBJECTIVE: Our review summarizes published literature of complementary and alternative medicine (CAM) used for the treatment of acute bronchitis in children. BACKGROUND: Acute bronchitis is one of the most frequent pediatric diseases and has high prevalence for in- and outpatient care. Acute bronchitis is mainly a viral-caused infection, but a high and inappropriate use of antibiotics has been demonstrated in many countries. As CAM therapies might reduce the use of antibiotics and can complement conventional therapies in children, they could be an appropriate treatment option. METHODS: A systematic literature search was conducted using general and complementary and alternative medicine (CAM)-specific databases. A search term including 65 CAM-associated definitions was applied. RESULTS: Literature search revealed 309 articles, whereby 18 articles hit search criteria. These clinical trials were subgrouped into the categories herbal medicine, anthroposophic medicine and homeopathy. The most often studied approaches are herbal remedies, in particular the Pelargonium sidoides extract, EPs® 7630. Its efficacy was demonstrated in three placebo-controlled trials and two observational studies. Anthroposophic approaches (mainly ribwort-containing remedies) were investigated in two controlled trials and three observational studies. Two studies were found investigating the homeopathic remedies Monapax® and Droperteel®. CONCLUSION: Study results indicate a favorable effect of investigated CAM approaches. However, only three of 18 studies were randomized controlled trials (RCTs), so a reliable statement on effectiveness was not possible and further RCTs are indispensable.

An expert consensus-based guideline for the integrative anthroposophic treatment of acute gastroenteritis in children.

OBJECTIVES: Acute gastroenteritis is one of the major causes of hospital admission in childhood. The primary objective of the treatment is rehydration, but conventional drug therapies are limited. Therefore, several pediatricians supplement conventional treatment with complementary and alternative therapies. In the two German departments for pediatric integrative medicine, children suffering from an acute gastroenteritis are treated with supportive therapy based on anthroposophic medicine. However, up to now scientifically validated guidelines for these therapies are lacking. DESIGN: We consulted an expert pool of 50 physicians with expertise in anthroposophic medicine as well as pediatrics and invited them to participate in an online-based Delphi process. Results were analyzed by means of qualitative content analysis with two independent raters using MAXQDA. Using four rounds of questioning, a consensus-based guideline was developed. RESULTS: A strong consensus (>90%) or consensus (>75-90%) was achieved for 14 of 16 subsections. The guideline describes disease characteristics, the most useful diagnostics, drug as well as non-drug treatment recommendations and advises for a good physician-patient interaction. CONCLUSION: The guideline will help clinicians, as well as family doctors, in their daily routine and make anthroposophic medicine more tangible for parents and health insurance companies.

Taraxacum officinale extract shows antitumor effects on pediatric cancer cells and enhance mistletoe therapy.

OBJECTIVES: While Taraxacum officinale (dandelion) extracts showed antitumor effects on adult cancer cells, effects on pediatric tumor cells as a single agent or in combination with mistletoe extracts are hitherto unknown. MATERIAL AND METHODS: The anti-proliferative effects of an aqueous fermented Taraxacum officinale extract (Taraxacum) on a pediatric cancer cell line panel were assessed by cell viability assays (MTT). In two neuroblastoma cell lines, SH-SY5Y and Kelly, the effects on cell cycle distribution (PI staining), mitochondrial integrity (MitoTracker staining), invasion (Boyden chamber assay) and migration (Scratch-assay) as well as the synergistic effects of the co-treatment of Taraxacum and mistletoe preparations (Iscucin® Tiliae or Iscucin® Pini) were investigated. RESULTS: All tested cancer cell lines were more susceptible to Taraxacum than the normal human fibroblast cell line, NHDF-C. In neuroblastoma cell lines Taraxacum caused apoptosis and loss of mitochondrial integrity as well as an inhibition of invasion and migration. The simultaneous therapy of Taraxacum and the mistletoe extracts revealed synergistic effects. CONCLUSION: This preclinical data support the use of Taraxacum as a potential adjuvant application in pediatric oncology.

Prolonged cytotoxic effect of aqueous extracts from dried viscum album on bladder cancer cells.

Aqueous extracts from whole dried mistletoe (Viscum album L., Iscucin) are often used in anti-cancer treatment. We studied the effect of extracts obtained from mistletoe bushes that grew on different host trees on bladder cancer cells by means of MTT-colorimetric cell proliferation/survival assays. The extracts possessed concentration-dependent cytotoxic properties whose extent varied with the host tree, but did not always correlate with the corresponding mistletoe lectin content. A 2-hours treatment of bladder cancer cells triggered a later, strong cytotoxic effect. This prolonged effect suggests that instillation with Iscucin has therapeutic potential for bladder cancer patients.

Paediatric medulloblastoma cells are susceptible to Viscum album (Mistletoe) preparations.

BACKGROUND: Medulloblastoma constitute more than 20% of all paediatric brain tumours and are the most common malignant brain tumours in children. Adjuvant chemotherapy has seen a strong increase in the use of complementary medicine for cancer treatment. Evidence for cytotoxic and apoptotic effects of Viscum album (Mistletoe) in vitro is available, however, no data concerning paediatric tumours, especially paediatric brain tumours, has been provided so far. MATERIALS AND METHODS: In order to compare the receptiveness of medulloblastoma cells to different Viscum album preparations, in vitro cytotoxic effects of eight Viscum album extracts on four different paediatric medulloblastoma cell lines were analysed by MTT-Tests. Lectin contents of the extracts were determined to correlate them with the mitochondrial activity of mistletoe-treated cells. Flowcytometric analyses with Annexin V-FITC staining were carried out to quantify the amount of apoptotic cells compared to necrotic and viable cells. RESULTS: Data obtained with the medulloblastoma cell lines, Daoy, D342, D425 and UW-288-2, treated with Viscum album preparations from eight dissimilar host trees (Iscucin Abietis, Pini, Populi, Mali, Salicis, Crataegi, Quercus and Tiliae), indicated a significant growth-inhibition of all cell lines, yet the cell susceptibility was dissimilar against the different extracts. The decrease in mitochondrial activity and increase in apoptosis correlated with the lectin content of the used preparation in a dose-dependent manner. CONCLUSION: These in vitro results show that paediatric medulloblastoma cells respond to Viscum album preparations, by undergoing cell death through apoptosis and that this growth-inhibition correlates with the lectin content of the used preparation.

Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in neuroblastoma cells correlates with a loss of caspase-8 expression.

Disruption of apoptotic pathways may be involved in tumor formation, regression, and treatment resistance of neuroblastoma (NB). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in cancer cell lines, whereas normal cells are not sensitive to TRAIL-mediated apoptosis. In this study we analyzed the expression and function of TRAIL and its agonistic and antagonistic receptors as well as expression of cellular FLICE-like inhibitory protein and caspase-2, -3, -8, -9, and -10 in 18 NB cell lines. Semiquantitative RT-PCR revealed that TRAIL-R2 and TRAIL-R3 are the main TRAIL-receptors used by NB cells. Sensitivity to TRAIL-induced apoptosis did not correlate with mRNA expression of TRAIL receptors or cellular FLICE-like inhibitory protein. Surprisingly, caspase-8 and caspase-10 mRNA expression was detected in only 5 of 18 NB cell lines. Interestingly, only these five NB cell lines were susceptible to TRAIL-induced apoptosis in a time- and dose-dependent manner. Treatment with 5-aza-2'-deoxycytidine restored mRNA and protein expression of caspase-8 and TRAIL sensitivity of resistant cell lines, suggesting that gene methylation is involved in caspase inactivation. The TRAIL system seems to be functional in NB cells expressing caspase-8 and/or caspase-10. Because many cytotoxic drugs induce caspase-dependent apoptosis, failure to express caspase-8 and/or caspase-10 might be an important mechanism of resistance to chemotherapy in NB.

Resistance to TRAIL-induced apoptosis in primitive neuroectodermal brain tumor cells correlates with a loss of caspase-8 expression.

TNF-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in adult malignant glioma and various other human solid tumor models but not in normal tissues. To characterize the TRAIL death pathway in childhood primitive neuroectodermal brain tumor (PNET), 8 human PNET cell lines were tested for TRAIL-induced apoptosis. TRAIL-sensitivity of the PNET cell lines was correlated with mRNA expression levels of TRAIL, its agonistic (TRAIL-R1, TRAIL-R2) and antagonistic (TRAIL-R3, TRAIL-R4) receptors, cellular FLICE-like inhibitory protein (cFLIP), caspase-3 and caspase-8. Three of 8 PNET cell lines tested were susceptible to TRAIL-induced apoptosis. Sensitivity to TRAIL-induced apoptosis did not correlate with mRNA expression of TRAIL receptors or cFLIP. However, all TRAIL-sensitive PNET cell lines expressed caspase-8 mRNA and protein, while none of the five TRAIL-resistant PNET cell lines expressed caspase-8 protein. Treatment with the methyltransferase inhibitor 5-aza-2'-deoxycytidine restored mRNA expression of caspase-8 and TRAIL-sensitivity in formerly TRAIL-resistant PNET cells, suggesting that gene methylation inhibits caspase-8 transcription in these cells. We conclude, that loss of caspase-8 mRNA is an important mechanism of TRAIL-resistance in PNET cells. Treatment with recombinant soluble TRAIL, possibly in combination with methyltransferase inhibitors, represents a promising therapeutic approach for PNET that deserves further investigation.

Expression of Apo-3 and Apo-3L in primitive neuroectodermal tumours of the central and peripheral nervous system.

Deregulation of apoptosis has been implicated in the pathogenesis, spontaneous regression and treatment resistance of neuroblastoma. A newly recognised member of the tumour necrosis factor (TNF)-family of death receptors known as Apo-3 has been mapped to human chromosome 1p36.3, a region commonly deleted in aggressive neuroblastoma. Based on its localisation and function, Apo-3 is a candidate for the putative neuroblastoma tumour suppressor gene. Therefore we analysed mRNA expression of the Apo-3 receptor/ligand (Apo-3/Apo-3L) system in a representative panel of 18 neuroblastoma cell lines, 41 primary neuroblastoma and 13 ganglioneuromas/ganglioneuroblastomas by semi-quantitative RT-PCR. We compared the level of expression with the well-established prognostic factors age, stage, histology, MYCN-amplification and TrkA expression, as well as outcome. For comparison, we studied Apo-3/Apo-3L expression in 27 central nervous system (CNS) primitive neuroectodermal tumours/medulloblastomas (PNET/medulloblastoma) and in six normal brain samples. Neuroblastoma cell lines with 1p deletion and MYCN-amplification expressed significantly lower levels of Apo-3 (P=0.009 and P=0.03, respectively) compared with neuroblastoma cell lines without 1p deletion or MYCN-amplification. The mean expression level of Apo-3L was significantly higher in ganglioneuromas/ganglioneuroblastomas compared with neuroblastomas (P=0.001) and in normal brain compared with PNET/medulloblastoma (P<0.0001). Expression of Apo-3L was significantly associated with survival in neuroblastomas (P<0.049) and in PNET/medulloblastomas (P=0.01). Expression of Apo-3 was significantly associated with survival in PNET/medulloblastomas (P=0.03). Thus, the Apo-3 receptor/ligand system might be involved in the regulation of apoptosis in neuroblastomas and PNET.

Loss of caspase-8 mRNA expression is common in childhood primitive neuroectodermal brain tumour/medulloblastoma.

Upon binding of tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL), the agonistic TRAIL receptors DR4 and DR5 activate caspase-8 leading to apoptosis. In primitive neuroectodermal brain tumour (PNET) cell lines, TRAIL-induced apoptosis was recently shown to correlate with caspase-8 mRNA expression (Grotzer MA, Eggert A, Zuzak TJ, et al. Oncogene 2000, 19, 4604-4610). In this study, we analysed the expression of the TRAIL death pathway in 27 primary PNET/medulloblastoma. As shown by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR), all PNET/medulloblastoma evaluated expressed DR5, the adapter protein FADD and caspase-3, but only 48% expressed caspase-8. The mRNA expression of caspase-8 was significantly lower in primary PNET/medulloblastoma compared with normal brain samples. PCR revealed >75% methylation of the caspase-8 promoter region in three of seven PNET cell lines and in 55% of the primary PNET/medulloblastoma evaluated. In the PNET cell lines, the methylation status correlated with the caspase-8 mRNA expression. We conclude that loss of caspase-8 gene expression is common in PNET/medulloblastoma suggesting that suppression of death receptor induced apoptosis may play an important role in the pathogenesis of this common childhood brain tumour.

Outcome in children with brain tumours diagnosed in the first year of life: long-term complications and quality of life.

OBJECTIVE: To study the outcome in children with brain tumours diagnosed in the first year of life, we followed up 27 consecutive children who were diagnosed between 1980 and 2005 in a single institution. METHODS: Tumour control and neurological, endocrine and cognitive complications and their impact on behavioural and emotional adjustment and health-related quality of life (HRQoL) were comprehensively assessed in 11 survivors (mean follow-up time 12.3 years). RESULTS: Persistent neurological complications occurred in 9/11 patients, endocrine and growth complications in 4/11, and cognitive deficits leading to school problems/impaired choice of occupation in 8/10. Behavioural and psychological adjustment problems were reported by 4/6 patients and 7/10 parents. HRQoL as rated by patients and their parents was considerably lower than that of healthy controls. In comparison with healthy controls, social functioning was rated by the patients and the parents as the QoL dimension most affected. HRQoL was lowest for patients with high-grade tumour histology and more intense therapy. CONCLUSION: Long-term survivors of brain tumours diagnosed in the first year of life are not only at great risk of neurological and cognitive complications, but also of social isolation thereby substantially decreasing self-rated HRQoL.

Resistance to TRAIL-induced apoptosis in neuroblastoma cells correlates with a loss of caspase-8 expression.

BACKGROUND: Disruption of apoptotic pathways may be involved in tumor formation, regression, and treatment resistance of neuroblastoma (NB). TNF-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in cancer cell lines. PROCEDURE: In this study we analyzed the expression and function of TRAIL, its agonistic and antagonistic receptors, and important intracellular signaling elements in 18 NB cell lines. RESULTS: Semiquantitative RT-PCR revealed that TRAIL-R2 and TRAIL-R3 are the main TRAIL-receptors used by NB cells. Sensitivity to TRAIL-induced apoptosis did not correlate with mRNA expression of TRAIL receptors or cFLIP. Surprisingly, caspase-8 and caspase-10 mRNA was detected in only 5 of 18 NB cell lines. Interestingly, only these five NB cell lines were susceptible to TRAIL-induced apoptosis in a time- and dose-dependent manner. CONCLUSIONS: Treatment with 5-aza-2'-deoxycytidine restored mRNA expression of caspase-8 and -10 and TRAIL sensitivity of resistant cell lines, suggesting that gene methylation is involved in caspase inactivation. Since many cytotoxic drugs induce caspase-dependent apoptosis, failure to express caspase-8 and/or caspase-10 might be an important mechanism of resistance to chemotherapy in NB.