Stefan Balzer

CCL3/MIP-1α is a potent immunostimulator when coexpressed with interleukin-2 or granulocyte-macrophage colony-stimulating factor in a leukemia/lymphoma vaccine

Chemokines orchestrate trafficking of immune effector cells during inflammation. Here we demonstrate that chemokines also serve to potentiate effector cell-mediated antineoplastic immune responses in vaccination strategies. As a critical mediator of inflammation, macrophage inflammatory protein 1alpha (CCL3/MIP-1alpha) attracts and stimulates both antigen-presenting and cytotoxic cells. In the A20 leukemia/lymphoma vaccine model, we explored the efficacy of MIP-1alpha in combination with interleukin-2 (IL-2) or granulocyte-macrophage colony-stimulating factor (GM-CSF). After subcutaneous injection of the MIP-1alpha + IL-2 or MIP-1alpha + GM-CSF combination vaccine, focal but pronounced infiltrates of CD4+ and CD8+ T cells were observed at the vaccination sites. In mice with preestablished leukemia/lymphoma, survival is significantly improved in animals treated with MIP-1alpha + GM-CSF- and MIP-1alpha + IL-2-secreting vaccines. Protection is superior in the MIP-1alpha + GM-CSF group, with the effects of MIP-1alpha and GM-CSF being synergistic. In contrast, suppression of lymphoblast proliferation by single-immunogen vaccines secreting MIP-1alpha, GM-CSF, or IL-2 alone does not translate to improved survival. The systemic protective effects afforded by the MIP-1alpha + IL-2 or MIP-1alpha + GM-CSF combination are mediated by different effector cell populations. In the MIP-1alpha + IL-2 group, antineoplastic defense is mediated by CD8+ T and NK cells, whereas in the MIP-1alpha + GM-CSF group CD4+ T cells are involved in addition to CD8+ cytotoxic T cells, underscoring that T cell help is critical for long-term protection. Thus combination of MIP-1alpha with different cytokines recruits different sets of effector cells into a potent antineoplastic immune response.

Symptoms and management of pediatric patients with incurable brain tumors in palliative home care

INTRODUCTION Brain tumors have the highest disease-related mortality rate of all pediatric cancers. The goal of this study was to determine whether all children with incurable brain tumors cared for by a pediatric palliative care team in a home setting suffer from the same symptoms towards the end of their lives or whether there are differences between the tumor localizations with implications for palliative care. PATIENTS AND METHODS This study was conducted as a retrospective, single center chart review including all patients treated between January 1st 2000 and December 31st 2013. RESULTS 70 children, adolescents and young adults were included in the analysis. Symptom burden was high with a mean number of symptoms of 7.2 per patient. 74% of the symptoms already existed one week before death. Within the last week of life, impaired consciousness (75.7%) most often occurred. Furthermore, symptoms considerably depended on tumor localization. Patients with supratentorial tumors presented more frequently with seizures (p < 0.05), coma (p < 0.01), nausea and emesis (p < 0.01). Ataxia (p < 0.001) occurred most frequently in infratentorial tumors and speech disturbances (p < 0.05), cranial nerve paralysis (p < 0.001), and tetraparesis (p < 0.001) in brain stem tumors. 84.3% of the patients needed analgesics, only 64.4% WHO class III analgesics. Anticonvulsants were given more often in supratentorial tumors (p < 0.01). CONCLUSIONS Caring for a dying child suffering from a brain tumor needs increased awareness of the neurological deterioration. The symptom pattern strongly depends on the tumor localization and significantly differs between supratentorial, infratentorial and brain stem tumors.

Development of a specialised paediatric palliative home care service

In Germany annually 1,500-3,000 children die from life-limiting diseases. Symptoms and course of disease differ considerably depending on the character of the underlying disease. Due to the desire of the children and their families to spend the end of life at home a paediatric palliative home care service was founded at the university childrens hospital of Duesseldorf. In the last 20 years a specialised paediatric palliative team evolved from an unstructured voluntary activity. Prospective aims are an area-wide professional supply of all paediatric palliative patients and the improvement of the cooperation with the resident paediatrician and paediatric palliative nursing services. Furthermore the establishment of networks as well as a proper communication among the professionals is inalienable.

Avascular osteonecrosis after hyperthermia in children and adolescents with pelvic malignancies: A retrospective analysis of potential risk factors

Purpose: In children with locally advanced or recurrent malignant tumours, prognosis can be improved by regional deep hyperthermia (RHT) in combination with platin-based chemotherapy. However, because of the increasing number of patients that achieve long-time remission with this therapy, it is necessary to evaluate long-term sequelae of thermochemotherapy. During the years 1993–2004 one has observed avascular osteonecrosis (AON) of the femoral head after RHT in seven children with pelvic germ cell tumours or rhabdomyosarcomas. Methods: Although AON may develop in patients with malignancies treated with chemo- or radiotherapy alone, RHT might nevertheless contribute to the occurrence of AON. In order to determine potential risk factors for AON after RHT, this study analysed the relationship of AON to the patients age, medical history and treatment parameters such as thermal dose equivalent and power output. Results and conclusions: In the present study AON was associated with young age as well as intensity of hyperthermia indicated by high power levels that exceed 20 W per kg body weight and/or application of eight or more heat sessions as well as additional radiotherapy. Based on this observation, it was assumed that an optimized three dimensional thermal field modelling may be helpful to avoid hazardous temperatures in the femoral heads during RHT treatment and to reduce AON of the femoral heads.

Embryonal rhabdomyosarcoma in a patient with a heterozygous frameshift variant in the DICER1 gene and additional manifestations of the DICER1 syndrome

Germline mutations in the DICER1 gene are associated with an inherited cancer predisposition syndrome also known as the DICER1-syndrome, which is implicated in a broad range of tumors including pleuropulmonary blastoma, ovarian Sertoli-Leydig cell tumors, ciliary body medulloepithelioma (CBME), pituitary blastoma, embryonal rhabdomyosarcoma (eRMS), anaplastic renal sarcoma as well as ocular, sinonasal tumors ovarian sex-cord tumors, thyroid neoplasia and cystic nephroma. This study describes a novel, heterozygous frameshift DICER1 mutation in a patient, who is affected by different tumors of the DICER1-syndrome, including eRMS, CBME and suspected pleuropulmonary blastoma type I. By whole-exome sequencing of germline material using peripheral blood-derived DNA, we identified a single base pair duplication within the DICER1 gene (c.3405 dupA) that leads to a frameshift and results in a premature stop in exon 21 (p.Gly1136Arg). The metachronous occurrence of two unrelated tumor entities (eRMS and CBME) in a very young child within a short timeframe should have raised the suspicion of an underlying cancer susceptibility syndrome and should be prompt tested for DICER1.

Critical Situations in Children, Adolescents and Young Adults with Terminal Cancer within the Home Setting.

BACKGROUND Over the course of terminal cancer towards the end-of-life, children may experience symptoms that lead to distressing critical situations (CS) for the child and caregivers. METHODS We analysed the records of 133 children cared for by our paediatric palliative care team (PPCT) from 01/98-12/09. A CS was defined as deterioration of a condition caused by a symptom, which was life-threatening or acutely scaring the patient (pt) or caregivers. RESULTS The majority of pts who died sustained no CS. In 38 (28.6%) pts 45 CS occurred. These accumulated towards the end-of-life (62.2% within the last week). About two-thirds were anticipated. There was no clustering of CS during the night/weekend. Leading symptoms were neurological. In 4 CS a pre-hospital emergency physician was alerted. 5 pts were readmitted to hospital. Most CS (88.9%) could be controlled in the home setting. DISCUSSION Despite anticipation, a relevant number of pts developed CS, which needed either additional medical intervention or other support by the PPCT. Considering the distressing and suffering character of status epilepticus and dyspnoea, it is important to thoroughly address these conditions in palliative care. CONCLUSION Advanced planning, close contact, good communication, detailed parental information, and a 24-h on-call service can reduce CS in children with terminal cancer. CS are mainly manageable within the home setting. Treatment of CS should focus on the childs symptoms and wishes, and the needs of the whole family.

Advance care planning and outcome in pediatric palliative home care

Pediatric advance care planning seeks to ensure end-of-life care conforming to the patients/their families’ preferences. To expand our knowledge of advance care planning and “medical orders for life-sustaining treatment” (MOLST) in pediatric palliative home care, we determined the number of patients with MOLST, compared MOLST between the four “Together for Short Lives” (TfSL) groups and analyzed, whether there was a relationship between the content of the MOLST and the patients’ places of death. The study was conducted as a single-center retrospective analysis of all patients of a large specialized pediatric palliative home care team (01/2013-09/2016). MOLST were available in 179/198 children (90.4%). Most parents decided fast on MOLST, 99 (55.3%) at initiation of pediatric palliative home care, 150 (83.4%) within the first 100 days. MOLST were only changed in 7.8%. Eighty/179 (44.7%) patients decided on a Do Not Attempt Cardio-Pulmonary Resuscitation (DNACPR) order, 58 (32.4%) on treatment limitations of some kind and 41 (22.9%) wished for the entire spectrum of life-sustaining measures (Full Code). Most TfSL group 1 families wanted DNACPR and most TfSL group 3/4 parents Full Code. The majority (84.9%) of all DNACPR patients died at home/hospice. Conversely, all Full Code patients died in hospital (80% in an intensive care setting). The circumstances of the childrens’ deaths can therefore be predicted considering the content of the MOLST. Regular advance care planning discussions are thus a very important aspect of pediatric palliative home care.

End-of-life care in children with hematologic malignancies

Introduction Hematologic malignancies (HM) represent the most common neoplasms in childhood. Despite improved overall survival rates, they are still a major contributor to cancer death in children. Aims To determine the proportion of children with HM in pediatric palliative care (PPC) and to identify the clinical characteristics and symptoms in comparison to children with extracranial solid tumors (non HM patients). Patients and Methods This study was conducted as a single-center retrospective cohort study of patients in the care of a large specialized PPC team. Results Fifteen HM and 50 non HM patients were included. Symptoms in which HM patients scored significantly higher than non HM patients were mucositis, difficulty moving, somnolence, fatigue, petechiae and paleness. Blood transfusions were more frequently administered to HM patients, but large external hemorrhage was not observed in any child. A large variety of drugs and appliances were needed by the patients, with morphine being the most frequently prescribed drug. During the study period, a much larger and over the years even increasing number of HM patients (not in the care of the PPC team) died in hospital with an (assumed) curative intent, with two thirds dying in the ICU. Conclusions Children with HM were referred to outpatient PPC with almost the full clinical picture of advanced leukemia. Noteworthy, the number of children with HM dying at home is decreasing in our center, instead a substantial proportion received high-intensity medical hospital care including novel anticancer therapies. These patients thus seem to be at an increased risk of dying in hospital as the right time to transfer them to palliative care is oftentimes missed.

Hyperthermia Associated Osteonecrosis in Young Patients with Pelvic Malignancies

INTRODUCTION Progressive and non-juvenile avascular osteonecrosis (AVN) is a rare condition in children. During the last decade, some data indicate that regional deep hyperthermia therapy (RHT) combined with either chemo- and / or radiotherapy in malignancies is associated with AVN in young patients. In this study, we present our data on AVN following RHT in children with intra-pelvic malignancies. MATERIAL AND METHODS Localization, extent of AVN, and associated joint effusions were evaluated via MRI and X-ray findings in 37 patients treated with RHT and chemotherapy +/- additional radiotherapy for intra-pelvic malignancies in our study. AVN was classified in accordance to the Association Research Circulation Osseus (ARCO). In addition, the recurrence of sarcoma after RHT, the number of total joint replacements, and level of activity including sport activities were recorded in all patients. The mean follow-up was 6.2 years (SD: 4.1, range: 1-12 years). RESULTS Eight out of 37 pediatric patients treated with RHT and chemotherapy +/- additional radiotherapy showed AVN of the femoral head within our follow-up period. Five out of the eight children developed bone marrow edema within 6 months after RHT procedure and three additional patients within the first year. All patients except one showed a rapid progression of AVN from ARCO stage 0 to the post-collapse-stages III and IV in our study. Seven out of eight AVN patients survived without evidence of further malignancy. Although advanced stages of AVN were observed in our patient group, they were able to still maintain a high quality of life. No patients in our group have undergone total hip replacement thus far. CONCLUSION Based on our findings, we hypothesize a high risk of AVN in young children who receive RHT for pelvic sarcoma. However, further clinical investigation needs to be done to prove our hypothesis.