Integrative medicine during the intensive phase of chemotherapy in pediatric oncology in Germany: a randomized controlled trial with 5-year follow up.

BACKGROUND: Integrative medicine is used frequently alongside chemotherapy treatment in pediatric oncology, but little is known about the influence on toxicity. This German, multi-center, open-label, randomized controlled trial assessed the effects of complementary treatments on toxicity related to intensive-phase chemotherapy treatment in children aged 1-18 with the primary outcome of the toxicity sum score. Secondary outcomes were chemotherapy-related toxicity, overall and event-free survival after 5 years in study patients. METHODS: Intervention and control were given standard chemotherapy according to malignancy & tumor type. The intervention arm was provided with anthroposophic supportive treatment (AST); given as anthroposophic base medication (AMP), as a base medication for all patients and additional on-demand treatment tailored to the intervention malignancy groups. The control was given no AMP. The toxicity sum score (TSS) was assessed using NCI-CTC scales. RESULTS: Data of 288 patients could be analyzed. Analysis did not reveal any statistically significant differences between the AST and the control group for the primary endpoint or the toxicity measures (secondary endpoints). Furthermore, groups did not differ significantly in the five-year overall and event-free survival follow up. DISCUSSION: In this trial findings showed that AST was able to be safely administered in a clinical setting, although no beneficial effects of AST between group toxicity scores, overall or event-free survival were shown.

Wishes and Needs at the End of Life­Communication Strategies, Counseling, and Administrative Aspects.

BACKGROUND: Managing the last phase of life properly, i.e., taking care that a patient's wishes are respected at the end of life and beyond, is very important and can relieve the patient and his or her family of unnecessary burdens. METHODS: This review is based on guidelines, reviews, meta-analyses, selected publications, and the authors' own experiences from everyday clinical practice. RESULTS: Most patients want frank information from their physicians about their condition at all times over the course of their treatment, from the moment of diagnosis to the end of their life. This has no lasting adverse effects, but rather enables patients to take decisions that are appropriate to their stage of disease. Early integration in palliative care can improve patients' quality of life, symptom control, and mood. In helping to manage the last phase of life, the physician often serves as a provider of impulses, or else determines which other types of professional should counsel or support the patient. Patients should be enabled to issue directives that reflect their wishes, as well as to choose representatives who are allowed to speak for them. Consideration should also be given to the patient's emotional legacy, e.g., letters or video messages with personal content. CONCLUSION: In the care of patients with life-limiting diseases, more attention should be paid to the management of the last phase of life. Palliative-care physicians can take over this task from other medical disciplines, and early integration in palliative care is recommended.

Safety Considerations in Cannabinoid-Based Medicine.

Cannabinoids are a diverse class of chemical compounds that are increasingly recognized as potential therapeutic options for a range of conditions. While many studies and reviews of cannabinoids focus on efficacy, safety is much less well reported. Overall assessment of the safety of cannabinoid-based medicines is confounded by confusion with recreational cannabis use as well as different study designs, indications, dosing, and administration methods. However, clinical studies in registered products are increasingly available, and this article aims to discuss and clarify what is known regarding the safety profiles of cannabinoid-based medicines, focusing on the medical and clinical safety evidence and identifying areas for future research. The two most well-studied cannabinoids are Δ9-tetrahydrocannabinol (THC), or its synthetic variants (dronabinol, nabilone), and cannabidiol (CBD). Across diverse indications, dizziness and fatigue are generally the most common adverse events experienced by patients receiving THC or combined THC and CBD. Patients receiving THC may experience adverse cognitive effects and impairment in psychomotor skills, with implications for driving and some occupations, while CBD may help to lower the psychotropic effects of THC when used in combination. Studies on dependency and addiction in a medical context are limited, but have shown inconsistent findings regarding misuse potential. Generally, the recommended route of administration is oral ingestion, as smoking medicinal cannabinoid products potentially releases mutagenic and carcinogenic by-products. There are several potential drug-drug interactions and contraindications for cannabinoid-based medicines, which physicians should account for when making prescribing decisions. The available evidence shows that, as with any other class of pharmaceuticals, cannabinoid-based medicines are associated with safety risks which should be assessed in the context of potential therapeutic benefits. Each patient should be assessed on an individual basis and physicians must rely on informed, evidence-based decision-making when determining whether a cannabinoid-based medicine could be an appropriate treatment option.

[Progressive muscle relaxation in postoperative pain therapy]. / Progressive Muskelrelaxation in der postoperativen Schmerztherapie.

BACKGROUND: Early and optimal treatment of postoperative pain based on a multimodal treatment concept is very important so that subsequent chronification can be avoided. OBJECTIVES: This study investigated the influence of progressive muscle relaxation on the sensation of pain and the need for analgesics after orthopedic interventions. MATERIALS AND METHODS: This nonrandomized pilot study tested 104 patients in the Clinic of Orthopedics at the Saarland University Medical Center in Homburg, Germany. The patients underwent total endoprosthesis (TEP) of the or the knee or spine surgery (laminectomy), and they had the option of choosing to use the technique of progressive muscle relaxation. All patients completed a questionnaire on the first, fourth, and ninth postoperative day. Data were collected on the maximum and minimum intensity of pain, duration of strong pain, length of hospital stay, and use of pain medication. These were compared by means of t tests for the group with progressive muscle relaxation and the group without progressive muscle relaxation. RESULTS: No significant difference was observed between the two groups regarding pain sensation analgesic dosage. There was a tendency for the length of hospital stay to be shorter in the group with progressive muscle relaxation. CONCLUSION: The positive effect of progressive muscle relaxation cannot be confirmed on the basis of the study data. Owing to the varying study design and implementation as well as the inclusion of heterogeneous patient groups, no conclusion can be drawn at present regarding the effectiveness of progressive muscle relaxation in common practice; therefore, further research is necessary.

[Cannabis-based medicines for chronic pain: indications, selection of drugs, effectiveness and safety : Experiences of pain physicians in Saarland]. / Cannabispräparate bei chronischen Schmerzen: Indikationen, Präparateauswahl, Wirksamkeit und Sicherheit : Erfahrungen der saarländischen Schmerztherapeuten.

BACKGROUND: There are uncertainties among physicians with respect to the indications, selection of drugs, effectiveness and safety of cannabis-based medicines for chronic pain. METHODS: All statutory health insurance pain physicians in Saarland were asked to complete a self-developed questionnaire assessing their experiences with cannabis-based medicines, which they prescribed between 10 March 2017 and 30 November 2018 for adult patients with chronic cancer and non-cancer pain. RESULTS: All statutory health insurance pain physicians participated in the survey and 13 out of 20 reported having prescribed cannabis-based medicines. The most frequent reasons for prescriptions in 136 patients (1.9% of the patients of the institutions) were failure of established treatment (73%) and desire of the patient (63%). In 35% of patients the type of pain was nociceptive, in 34% neuropathic, in 29% nociceptive and neuropathic and in 13% nociplastic. Dronabinol was prescribed for 95% of the patients and 71% were responders (clinically relevant reduction of pain or of other symptoms). In 29% of patients treatment was terminated due to either a lack of efficacy or adverse events. CONCLUSION: Statutory health insurance pain physicians in Saarland were reluctant to prescribe cannabis-based medicines. Dronabinol was effective and well-tolerated in the majority of the highly selected patients.

Photobiomodulation therapy in breast cancer-related lymphedema: a randomized placebo-controlled trial.

BACKGROUND: The aim of our study was to examine the effects of photobiomodulation therapy (PBMT) in the treatment of breast cancer-related lymphedema using a compactly designed treatment regime consisting of eight therapy sessions in combination with a cluster laser device covering a total area size of 78.54 cm² over the axillary. METHODS: Forty patients with unilateral lymphedema were enrolled in this double-blind, placebo-controlled trial in order to evaluate effects of PBMT on lymphedema-related pain, quality of life, grip strength and limb volume difference. Subjects received irradiation for ten minutes per session using a cluster laser covering a beam area of 78.54 cm². The applied energy was 384 Joules resulting in an energy density of 4.89 J/cm². RESULTS: Post-treatment, a 50% reduction in median pain scores and an increase in mean quality of life were observed. Mean grip strength was persistently higher after eight sessions of PBMT compared with pretreatment; however, no statistically significant intergroup differences (P > 0.05) were found over the time course. CONCLUSION: PBMT using a compactly designed treatment regime in combination with a cluster laser device did not significantly improve quality of life, pain scores, grip strength and limb volume over the time course.

Severe cyanide poisoning from an alternative medicine treatment with amygdalin and apricot kernels in a 4-year-old child.

BACKGROUND: The use of complementary and alternative medicine (CAM) is widespread in children with cancer and is poorly regulated. PATIENTS AND METHODS: Case report. RESULTS: We describe a case of severe cyanide poisoning arising from CAM use. A severely agitated, encephalopathic, unresponsive 4-year-old boy (initial Glasgow Coma Scale of 3) with a history of metastatic ependymoma was brought to our emergency department by ambulance services. Initial blood gas analysis demonstrated severe metabolic/lactic acidosis. On detailed questioning of the parents, the use of CAM including intravenous and oral "vitamin B 17" (amygdalin) and oral apricot kernel was reported. After administering sodium thiosulfate, rapid improvement in his medical condition with complete recovery without need for further intensive care treatment was seen. Serum cyanide level was markedly elevated. CONCLUSIONS: Cyanide poisoning can be the cause of severe encephalopathy in children receiving CAM treatment with substances containing cyanogenic glycosides.

Differences in use of complementary and alternative medicine between children and adolescents with cancer in Germany: a population based survey.

BACKGROUND: Use of complementary and alternative medicine (CAM) in children with cancer is common and probably increasing. However, data concerning differences between children and adolescents focusing on prevalence, reasons for use/non-use, costs, adverse effects, and socio-demographic factors are lacking. PROCEDURE: A population-based survey over a 1 year period with 497 participants was conducted. RESULTS: Of the 457 respondents (92%) 322 were children and 135 adolescents (>16 years of age) with malignancies. 31% reported CAM use from the time when being diagnosed, compared to an overall lifetime prevalence rate of 41% before cancer diagnosis. Among CAM users the most prevalent therapies were homeopathy, massage, anthroposophic medicine, acupuncture, and Bach flowers. The main reasons for use were to reduce therapy-related side effects, to strengthen the immune system, to achieve physical stabilization and to increase healing chances. Socio-demographic factors associated with CAM use were higher parental education and higher family income. A majority of CAM users (97%) would recommend CAM use. Most users (78%) informed a physician about CAM use. Side effects were rarely reported (5%), minor and self-limiting. CONCLUSIONS: The high prevalence rates seem to represent the parental or patients needs for additional treatment perceived as successful and devoid of side-effects. Clinical care and the physician-patient relation would profit from an enhanced understanding of CAM and a greater candidness towards the parental needs. Safety and efficacy - especially of CAM with high prevalence rates - should be studied in rigorous basic and clinical research.

The role of EEG recordings in children undergoing cardiac surgery for congenital heart disease.

Neurological dysfunction may occur after corrective cardiac surgery using cardio-pulmonary bypass (CPB) with or without circulatory arrest. Different neurophysiological monitoring systems have been employed to detect neurological complications and possible brain injury in infants and children during and after cardiac surgery. The value of EEG in infants and children at risk for neurological sequelae has not been systematically studied. Sequential performance of 2 EEGs before and after cardiac surgery at a tertiary University Hospital to screen for possible brain injury after cardiac surgery. In addition, a complete neurological examination was performed. In 313 patients (age: 54.2±55.7 months; normal initial EEG) after cardiac surgery CPB (duration of surgery: 146.0±58.9 minutes; aortic cross clamp time: 34.1±19.1 minutes) a 19-channel EEG recording was performed 2.4±1.8 days prior and 11.6±5.3 days after cardiac surgery. An abnormal EEG was detected in only 8 of 313 patients (2.5%; focal slowing(1), generalised slowing (5), epiletiform discharges(2)) after cardiac surgery, while the EEG was normal in the remaining 305 patients (97.5%). In one patient, an intra-cerebral pathology was seen on MRI (ischemic); in 5 patients follow-up EEGs were performed, which revealed normalised findings. None of the 8 patients demonstrated new focal neurological deficits on physical examination, but 33 (9.7%) children demonstrated minor abnormalities (eg, subtle motor asymmetry, increase in muscle tone, etc.), which were unrelated to abnormal EEG findings. According to the used protocol pathological EEG findings were very infrequent in our study cohort. The routine and indiscriminative recording of EEGs in children before and after corrective or palliative cardiac surgery for congenital heart disease using CPB is not recommended. Further intra-operative neuromonitoring methods with immediate intervention should be evaluated.

Sudden unexpected death in epilepsy in children.

Sudden unexpected death in epilepsy (SUPEP) is the commonest cause of seizure-related mortality in people with intractable epilepsy. The incidence of SUDEP varies in different epilepsy populations, with lower rates in population-based studies, higher in referral populations and clinical trials of adjunct drugs for complex partial epilepsy, and highest rates for surgical series. Certain risk factors for SUDEP have been identified, with seizure activity being one of the strongest risk factor for SUDEP. Suspected underlying mechanisms include cardiac dysrhythmias, seizure-related apnoea and postictal respiratory arrest. Prevention of SUDEP has centred on seizure control, and SUDEP incidence has been reduced by epilepsy surgery in some studies. In this review, we present epidemiological data, and discuss risk factors and underlying pathophysiological mechanisms that are associated with SUDEP in children.

Mechanisms of disease/hypothesis: neurogenic left ventricular dysfunction and neurogenic pulmonary oedema.

BACKGROUND: Acute onset of cardiovascular dysfunction may be the result of insults to the central nervous and autonomic system. Several cerebral regions (insular cortex, lateral, hypothalamus, and brain stem) have been identified as part of the "central autonomic network". The brain stem plays an integral role in controlling and mediating autonomic tone. PATIENT AND METHODS: Case reports. RESULTS: These two case reports demonstrate the intimate connectivity between the cardiovascular/pulmonary system and the central nervous system in a 13-year-old girl with occipital angiomatosis, but no history of heart disease who developed profound left ventricular dysfunction and pulmonary oedema following pontine haemorrhage, and in a 5-year-old girl who developed severe pulmonary oedema after suffering from status epilepticus. CONCLUSIONS: The two case reports suggest that cardiovascular dysfunction secondary to central nervous insults and neurogenic pulmonary oedema are not two separate clinical entities, but may very well encompass two different presentations of central autonomic disturbances.

Complementary and alternative treatment methods in children with cancer: A population-based retrospective survey on the prevalence of use in Germany.

INTRODUCTION: Few studies have been conducted to date on the prevalence of use of complementary and alternative treatment methods (CAMs) in paediatric oncology, and those that have been conducted are often not representative. We therefore decided to study a representative sample of children with cancer in the German population. PATIENTS AND METHODS: The study took the form of a retrospective survey amongst all parents whose children were first diagnosed with a disease covered by the German Childhood Cancer Registry in 2001. The primary objectives of the survey were to establish the prevalence of use of CAM and the factors related to its use. RESULTS: Of the 1595 questionnaires sent out, 1063 (67%) could be evaluated. 35% of the responders had used CAM. The most frequently used methods were homeopathy, dietary supplements and anthroposophic medicine including mistletoe therapy. Factors which increased the probability of using CAM were the previous use of CAM, higher social status and poor prognosis of the child's disease. The most frequently named reasons for use of CAM were physical stabilisation, strengthening the immune system and improving the chance of cure. Whilst the sources of information about CAM were in most cases not doctors, 71% of users had nevertheless spoken to a doctor about using CAM. The effects of the CAM perceived by the parents were for the most part positive. 89% of the users reported that they would recommend CAM to other parents. CONCLUSIONS: CAMs are administered alongside standard therapy to 35% of children with cancer in Germany, usually by the parents. Prospective studies on the effects and side-effects of the most frequently used methods are urgently needed, and paediatric oncologists should have sufficient knowledge of CAM to enable them to advise parents professionally and competently about these treatments, too.

Homozygous PMS2 germline mutations in two families with early-onset haematological malignancy, brain tumours, HNPCC-associated tumours, and signs of neurofibromatosis type 1.

Heterozygous germline mutations in mismatch repair (MMR) genes MLH1, PMS2, MSH2, and MSH6 cause Lynch syndrome. New studies have indicated that biallelic mutations lead to a distinctive syndrome, childhood cancer syndrome (CCS), with haematological malignancies and tumours of brain and bowel early in childhood, often associated with signs of neurofibromatosis type 1. We provide further evidence for CCS reporting on six children from two consanguineous families carrying homozygous PMS2 germline mutations. In family 1, all four children had the homozygous p.I590Xfs mutation. Two had a glioblastoma at the age of 6 years and one of them had three additional Lynch-syndrome associated tumours at 15. Another sibling suffered from a glioblastoma at age 9, and the fourth sibling had infantile myofibromatosis at 1. In family 2, two of four siblings were homozygous for the p.G271V mutation. One had two colorectal cancers diagnosed at ages 13 and 14, the other had a Non-Hodgkin's lymphoma and a colorectal cancer at ages 10 and 11, respectively. All children with malignancies had multiple café-au-lait spots. After reviewing published cases of biallelic MMR gene mutations, we provide a concise description of CCS, revealing similarities in age distribution with carriers of heterozygous MMR gene mutations.

Laser acupuncture in children with headache: a double-blind, randomized, bicenter, placebo-controlled trial.

To investigate whether laser acupuncture is efficacious in children with headache and if active laser treatment is superior to placebo laser treatment in a prospective, randomized, double-blind, placebo-controlled trial of low level laser acupuncture in 43 children (mean age (SD) 12.3 (+/-2.6) years) with headache (either migraine (22 patients) or tension type headache (21 patients)). Patients were randomized to receive a course of 4 treatments over 4 weeks with either active or placebo laser. The treatment was highly individualised based on criteria of Traditional Chinese medicine (TCM). The primary outcome measure was a difference in numbers of headache days between baseline and the 4 months after randomization. Secondary outcome measures included a change in headache severity using a 10 cm Visual Analogue Scale (VAS) for pain and a change in monthly hours with headache. Measurements were taken during 4 weeks before randomization (baseline), at weeks 1-4, 5-8, 9-12 and 13-16 from baseline. The mean number of headaches per month decreased significantly by 6.4 days in the treated group (p<0.001) and by 1.0 days in the placebo group (p=0.22). Secondary outcome measures headache severity and monthly hours with headache decreased as well significantly at all time points compared to baseline (p<0.001) and were as well significantly lower than those of the placebo group at all time points (p<0.001). We conclude that laser acupuncture can provide a significant benefit for children with headache with active laser treatment being clearly more effective than placebo laser treatment.

Hypothesis: Possible role of retinoic acid therapy in patients with biallelic mismatch repair gene defects.

A boy showing symptoms of a Turcot-like childhood cancer syndrome together with stigmata of neurofibromatosis type I is reported. His brother suffers from an infantile myofibromatosis, and a sister died of glioblastoma at age 7. Another 7-year-old brother is so far clinically unaffected. The parents are consanguineous. Molecular diagnosis in the index patient revealed a constitutional homozygous mutation of the mismatch repair gene PMS2. The patient was in remission of his glioblastoma (WHO grade IV) after multimodal treatment followed by retinoic acid chemoprevention for 7 years. After discontinuation of retinoic acid medication, he developed a relapse of his brain tumour together with the simultaneous occurrence of three other different HNPCC-related carcinomas. We think that retinoic acid might have provided an effective chemoprevention in this patient with homozygous mismatch repair gene defect. We propose to take a retinoic acid chemoprevention into account in children with proven biallelic PMS2 mismatch repair mutations being at highest risk concerning the development of a malignancy.

Squamous cell carcinoma of the tongue in a 13-year-old girl with Fanconi anemia.

We report the case of a 13-year-old girl with squamous cell carcinoma (SCC) of the tongue. Fanconi anemia with a yet unknown complementation group had been diagnosed at the age of 5 years. Organ involvement included intestinal atresia, renal dysfunction due to crossed renal atopia, and tubular acidosis type II. Because of repeated bleeding complications frequent transfusions, and severe infections, bone marrow transplantation (BMT) from a matched unrelated donor was done at the age of 11 years. The girl did not suffer from graft-versus-host disease and had complete hematologic reconstitution after transplantation. Two years after BMT a SCC of the tongue developed without nodal or systemic metastasis. The tumor could be completely resected and no functional disturbances remained. No further treatment was given and the patient is in complete remission 6 months after diagnosis. This is one of the youngest children reported with SCC of the tongue after BMT for Fanconi anemia so far.

Intraindividual propofol dosage variability in children undergoing repetitive procedural sedations.

The authors prospectively assessed intraindividual variability in propofol dosage for induction of sedation in repetitive procedures in children with malignancies. A total of 80 procedures were performed in 24 children. Primary outcome measure was the intraindividual propofol dose required to achieve adequate sedation. Intraindividual variability in propofol dosage required to achieve adequate sedation was 0.0-2.2 mg.kg-1. Twenty-five percent of the patients had a dose range of 0.0-0.5 mg x kg-1; 37.5%, >0.5-1.0 mg x kg-1; and 37.5% >1.0-2.2 mg x kg-1. Due to remarkable intraindividual differences, propofol dosage should be titrated toward the desired level of sedation.