Current recommendations for cancer surveillance in Gorlin syndrome: a report from the SIOPE host genome working group (SIOPE HGWG).

Gorlin syndrome (MIM 109,400), a cancer predisposition syndrome related to a constitutional pathogenic variation (PV) of a gene in the Sonic Hedgehog pathway (PTCH1 or SUFU), is associated with a broad spectrum of benign and malignant tumors. Basal cell carcinomas (BCC), odontogenic keratocysts and medulloblastomas are the main tumor types encountered, but meningiomas, ovarian or cardiac fibromas and sarcomas have also been described. The clinical features and tumor risks are different depending on the causative gene. Due to the rarity of this condition, there is little data on phenotype-genotype correlations. This report summarizes genotype-based recommendations for screening patients with PTCH1 and SUFU-related Gorlin syndrome, discussed during a workshop of the Host Genome Working Group of the European branch of the International Society of Pediatric Oncology (SIOPE HGWG) held in January 2020. In order to allow early detection of BCC, dermatologic examination should start at age 10 in PTCH1, and at age 20 in SUFU PV carriers. Odontogenic keratocyst screening, based on odontologic examination, should begin at age 2 with annual orthopantogram beginning around age 8 for PTCH1 PV carriers only. For medulloblastomas, repeated brain MRI from birth to 5 years should be proposed for SUFU PV carriers only. Brain MRI for meningiomas and pelvic ultrasound for ovarian fibromas should be offered to both PTCH1 and SUFU PV carriers. Follow-up of patients treated with radiotherapy should be prolonged and thorough because of the risk of secondary malignancies. Prospective evaluation of evidence of the effectiveness of these surveillance recommendations is required.

Paraneoplastic limbic encephalitis with SOX1 and PCA2 antibodies and relapsing neurological symptoms in an adolescent with Hodgkin lymphoma.

BACKGROUND: Immune cross-reactivity between malignant and normal tissues causes the rare, so called paraneoplastic syndrome (PS). In approximately 60% of the patients, various onconeural antibodies are detectable in the cerebrospinal fluid (CSF) and are associated with typical tumour entities. METHODS: We report an unusual case of paraneoplastic limbic encephalitis (PLE) in a 17-year-old adolescent with classical Hodgkin lymphoma. RESULTS: He presented with a variety of neurologic and neuropsychiatric symptoms, profound B-symptoms and typical MRI findings including hyperintense lesions with contrast enhancement in the medial temporal lobe and limbic system. Under immunosuppressive therapy and subsequently chemotherapy the neurological situation only temporarily improved and worsened again after interruption of immunosuppression several times. Thus, multiple courses of multidrug immunosuppressive therapy were administered. To date, five years after initial presentation, the young man is able to walk with walking aids and orthoses and is still on oral prednisolone therapy. Analyses of the CSF and serum revealed anti SOX-1 antibodies at initial presentation but PCA-2 antibodies seven months after diagnosis. CONCLUSION: Neurologic and/or neuropsychiatric symptoms combined with typical MRI findings should raise the suspicion of PS and lead to further diagnostics for an underlying tumour even in children.

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 child's symptoms and wishes, and the needs of the whole family.

[Palliative home care of children: an opinion survey of orphaned parents]. / Häusliche Palliativversorgung von Kindern: Eine Meinungsumfrage bei verwaisten Eltern nach unheilbarer onkologischer Erkrankung.

INTRODUCTION: In Germany, 500 children die of malignancies per year. Many families wish to be cared for in a home setting at the end-of-life. METHODS: Families of children who were cared for by the paediatric palliative care team (PPCT) in a home setting between 01.02.2003 to 30.09.2009 were included in the survey. The questionnaire consisted of 87 items with nominal scaled variables and numeric rating scales (NRS; 1-4, lowest to highest satisfaction) as response options. RESULTS: 84 relatives of 49 children participated (response rate 53.2%). Duration of care varied between 3-246 days. All 49 patients died at home. 98.8% of the respondents were satisfied with their decision for home care. The symptoms pain (86.9%) and fatigue (85.7%) were reported most frequently. Satisfaction with symptom control was high (NRS 3.55±0.49). The respondents were satisfied with communication (NRS 3.73±0.57) and end-of-life care (NRS 3.85±0.90). Satisfaction with psychosocial care (NRS 3.24±0.87) was significantly lower (p<0.05). Parents who stayed in contact with the PPCT by phone and in person were more satisfied with aftercare. DISCUSSION: From parental view satisfying home-care of children with cancer is feasible. Symptom control succeeds in a home setting.

Osteonecrosis in paediatric patients with acute lymphoblastic leukaemia treated on Co-ALL-07-03 trial: a single centre analysis.

BACKGROUND: Osteonecroses (ON) are a serious problem after anti-leukaemic treatment in childhood and critically depend on treatment intensity. We analysed ON incidence, risk factors and outcome in patients (pts) from our institution treated according to the CoALL 07-03 trial. METHODS: Between 01.09.2003 and 31.12.2009, 124 children aged 1-18 years were treated, 22 pts with ON (ARCO I-IV) were assessed by retrospective chart review. Follow-up data were collected as of March 2013. RESULTS: 5-year cumulative incidence of ON grade I-IV was 25%. Median age at ALL diagnosis with vs. without ON was 11 years vs. 4.4 years. In logistic multivariate regression analysis, age was the only independent risk factor for ON (p<0.01). 90.9% of the pts with ON presented with ≥2 bilaterally affected joints, most frequent the weight-bearing joints (95.5%). 77.2% developed ON ≥°III acc. to ARCO. 36.4% underwent core decompression, one patient bilateral total hip arthroplasty. As of March 2013, 12 pts still presented with ON-induced symptoms. DISCUSSION: Our data suggest an overall high incidence of ON in pts treated according to trial CoALL 07-03. Cumulative steroid dose in trial CoALL 07-03 was small, thus, the high CI might be triggered by other treatment-related and study population based risk factors. CONCLUSION: ON are a serious problem concerning long-term sequelae with major impact on activities of daily living. Further prospective evaluation is urgently needed to develop risk-adapted diagnostic strategies and preventive and interventional approaches for high-risk pts.

Epidemiology and clinical characteristics of pandemic (H1N1) 2009 influenza infection in pediatric hemato-oncology and hematopoietic stem cell transplantation patients.

BACKGROUND: For children with hemato-oncologic diseases, especially after hematopoietic stem cell transplantation (HSCT), the risk for developing complications related to pandemic influenza A (H1N1) 2009 (pH1N1) infection is largely unknown. METHODS: A retrospective chart study was performed of pH1N1 cases diagnosed between October 2009 to January 2010 in the hemato-oncologic unit of the University Children's Hospital of Düsseldorf, Germany. FINDINGS: In total, 21 children were diagnosed with laboratory-confirmed pH1N1; in 16 patients with malignancies (acute leukemia 7, lymphoma 4, solid tumors 2, others 3) and in 5 with benign hematologic disorders. Five patients had undergone prior HSCT, although 1 patient was diagnosed during conditioning therapy with high-dose chemotherapy in preparation for haploidentical HSCT. Most frequent symptoms were fever (>38.5°C) and cough (in 100%), and rhinorrhea (57%). The 2 patients acquiring pH1N1 infection under high-dose or intensive chemotherapy did not require intensive care or mechanical ventilation, and both recovered under antiviral therapy. Oseltamivir was administered to 11 patients; in 1 patient, therapy was switched, on a compassionate-use basis, to intravenous zanamivir because of lack of clinical improvement after oseltamivir therapy. Complications were hospitalization (19%), demand of oxygen supplementation, delay/interruption of antineoplastic therapy, and prolonged administration of antibiotics and antipyretics. CONCLUSION: In the investigated patient population, pH1N1 was mild in most cases, but was associated with substantial morbidity in a proportion of patients and led to interruption and delay in anticancer treatment.

Severe encephalopathy, lactic acidosis, vegetative instability and neuropathy with 5-Fluorouracil treatment - pyrimidine degradation defect or beriberi?

We present the case of a 19-year-old female with nasopharyngeal carcinoma, who received two courses of chemotherapy with 5-fluorouracil (5-FU) in combination with folic acid and cisplatin. Upon developing esophageal strictures in the course of her radiotherapy, she required total parenteral nutrition. In the course of therapy, the patient developed severe multisystem failure with encephalopathy, lactic acidosis, vegetative instability and neuropathy. The treatment with 5-FU can lead to severe toxicity due to enzyme deficiencies in the degradation of pyrimidines, but it can also lead to thiamine deficiency with the classic symptoms of beriberi. Beriberi is a rare disorder, usually attributed to malnutrition or alcoholism. 5-FU has been shown to induce thiamine depletion. Reduced food intake or total parenteral nutrition devoid of vitamin supplements may aggravate symptoms. We were unable to find a genetic cause for increased 5-FU toxicity in our patient, ruling out deficiencies of dihydropyrimidine dehydrogenase, dihydropyrimidinase or ß-ureidopropionase and double-strand break repair deficits. We come to the conclusion that, even without any definable enzyme deficiency, treatment with 5-FU can lead to high toxicity due to thiamine deficiency if vitamin supplementation is not undertaken.

[Development of a specialised paediatric palliative home care service]. / Die Entwicklung einer spezialisierten ambulanten pädiatrischen Palliativversorgung.

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 children's 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.

Clumps and streams in the local dark matter distribution.

In cold dark matter cosmological models, structures form and grow through the merging of smaller units. Numerical simulations have shown that such merging is incomplete; the inner cores of haloes survive and orbit as 'subhaloes' within their hosts. Here we report a simulation that resolves such substructure even in the very inner regions of the Galactic halo. We find hundreds of very concentrated dark matter clumps surviving near the solar circle, as well as numerous cold streams. The simulation also reveals the fractal nature of dark matter clustering: isolated haloes and subhaloes contain the same relative amount of substructure and both have cusped inner density profiles. The inner mass and phase-space densities of subhaloes match those of recently discovered faint, dark-matter-dominated dwarf satellite galaxies, and the overall amount of substructure can explain the anomalous flux ratios seen in strong gravitational lenses. Subhaloes boost gamma-ray production from dark matter annihilation by factors of 4 to 15 relative to smooth galactic models. Local cosmic ray production is also enhanced, typically by a factor of 1.4 but by a factor of more than 10 in one per cent of locations lying sufficiently close to a large subhalo. (These estimates assume that the gravitational effects of baryons on dark matter substructure are small.).

[Surgery of primary malignant bone tumors]. / Operative Therapie primär maligner Knochentumoren.

The term primary malignant bone tumors covers a diversity of entities. Tumor resection is preferable in most. In some, surgery alone is sufficient, in others therapy will be based on a combined modality concept. Resection plays the essential role in those tumors treated by surgery alone, e.g., primary osseous fibrosarcoma. The combined modality approach in osteosarcomas or Ewing's tumors provides for additional elements of local therapy (radiotherapy) or systemic treatment (chemotherapy). The relevance of surgery for local control varies in these latter diagnoses. In highly malignant osteosarcoma, where wide margin surgery is of utmost importance, only 10-20% of patients will survive longer than 5 years without aggressive systemic chemotherapy. Radiotherapy in these patients is only indicated when "marginal" or "less than marginal" surgery is expected. In terms of efficacy, radiotherapy is inferior to surgery. In disseminated osteosarcoma, a curative treatment approach will also provide for surgical removal of all metastases. Treatment of primary malignant fibrous histiocytoma (MFH) of bone is identical to osteosarcoma therapy. Since radiotherapy appears to be marginally more effective than in osteosarcoma, both modalities of local therapy are used. Systemic chemotherapy adds an additional benefit for improved survival. Therapy for Ewing's tumor also follows a combined modality approach. The introduction of systemic chemotherapy has raised 5-year survival rates from less than 10% to above 60%. The role of surgery is currently subject to debate. At present, the use of surgery or irradiation for local control is tailored to the individual patient's needs.