Vaccine Preventable Diseases in Pediatric Palliative Care - A Multicenter Cross-Sectional Study.

CONTEXT: Vaccine preventable diseases lead to distressful symptoms and complications among pediatric patients receiving specialized home palliative care. There was no data on the vaccination compliance. OBJECTIVES: The objective was to determine the vaccination coverage, discuss the relevance of vaccinations and provide vaccination recommendations in pediatric palliative care. METHODS: Vaccination data were compared in a multicenter cross-sectional study. Expert interviews were conducted to evaluate symptom burden. The vaccination status of patients treated by six German pediatric specialized home palliative care teams was recorded from January 2019 to December 2019. The data were compared to the national immunization schedule and the vaccination rate of a representative German pediatric cohort. Onset of missed vaccination was compared to the date of diagnosis of the life-limiting condition. A risk score was calculated to evaluate the relevance of each individual vaccinations. RESULTS: Vaccination rates of Tdpa, haemophilus influenzae type B, poliomyelitis, hepatitis B, pneumococcal disease, meningococcal diseases type C, and MMR were lower compared to healthy controls. There were no significant differences in varicella. In most cases the discontinuation of recommended immunizations occurred after diagnosis of the palliative condition. Influenza had the highest risk score and was the most frequent vaccine preventable disease in retrospective data. This paper includes a pragmatic proposal for the management of vaccination in this vulnerable population. CONCLUSION: Children and adolescents with life-limiting conditions are at increased risk of vaccine preventable diseases. Individual vaccination counselling is recommended.

Adverse Events in Placebo Arms of Cancer Trials.

BACKGROUND/AIM: Adverse events (AEs) in cancer trials may be caused by the investigational agents or the underlying disease. Determining the causality is challenging, especially in early cancer drug development when a control arm is lacking. MATERIALS AND METHODS: We carried out a systematic literature review of AE frequencies in placebo arms of randomized trials for malignant solid tumors and hematologic malignancies reported in PubMed from 2016 to January 2022. RESULTS: Among 148 placebo arms, the AEs with the highest reported mean frequencies among all publications were: Fatigue (20.1%), nausea (16.3%), diarrhea (14.3%), abdominal pain (12.4%), and anemia (10.9%); AEs resulting in drug discontinuation were reported in 5.6% of placebo-treated patients and serious AEs in 18.7% of placebo patients. CONCLUSION: The data presented here may be used as a benchmark to help assess drug causality in early development cancer studies without a control arm.

Palliative care of older glioblastoma patients in neurosurgery.

PURPOSE: The care of older neurosurgical patients at the end life is a particularly demanding challenge. Especially, the specific needs of very old patients with glioblastoma at the end of life are at risk of being deprived of adequate care. METHODS: Based on a narrative literature review, this article aims to explore key issues of the thematic intersection of geriatric glioblastoma patients, palliative care and neurosurgery. RESULTS AND DISCUSSION: Four key issues were identified: patient-centeredness (need orientation and decision making), early palliative care, advance care planning, and multi-professionalism. Possible benefits and barriers are highlighted with regard to integrating these concepts into neurosurgery. CONCLUSIONS: Palliative care complements neurosurgical care of geriatric glioblastoma multiforme patients to optimise care for this highly vulnerable category of patients.

Fatigue in Cancer Treatment Studies: Analysis of Placebo Arms.

BACKGROUND/AIM: Fatigue and asthenia are common in patients with cancer; and identifying the cause as drug toxicity versus cancer progression is difficult, particularly in clinical trials without control arms. MATERIALS AND METHODS: We carried out a systematic literature review of fatigue in placebo arms of randomized cancer trials reported in PubMed from 2000 to 2021. RESULTS: Fatigue/asthenia were reported in 100 out of 134 placebo cohorts, and the average of reported frequencies was 22.8%, with a range of 0-83%. Grade 3 or higher fatigue/asthenia was reported in 2.3% (0-17%). Fatigue/asthenia was positively correlated with nausea (R=0.683) Conclusion: For detection of drug toxicity, observations should be flagged when they are higher than the maximum reported in the placebo arm, and the assessment should be supplemented by comparing observations in early oncology trials to literature placebo arms, including both sample sizes and event numbers.

Tuberculosis-Associated HLH in an 8-Month-Old Infant: A Case Report and Review.

Hemophagocytic lymphohistiocytosis (HLH) is a rare immunological disease, which can be mistaken for sepsis easily. Among the infectious causes that may trigger secondary HLH, tuberculosis (TBC), a rather rare pathogen nowadays, is typical. To our knowledge, this is the first case report of an infant suffering from TBC-associated HLH-induced acute respiratory failure who was treated successfully using extracorporeal membrane oxygenation. An 8-month-old boy with fever (over the last 8 wk) and pancytopenia was transferred to our institution with acute respiratory failure and for extracorporeal membrane oxygenation therapy. Bone marrow biopsy revealed hemophagocytosis. Immunological work-up for familial HLH was negative. In a desperate search for the cause of secondary HLH, an interferon-gamma release assay for TBC returned positive. However, microscopy for acid-fast bacteria as well as polymerase chain reaction for TBC were initially negative. Despite this, the child was treated with tuberculostatic therapy. TBC was finally confirmed. The child remained on extracorporeal membrane oxygenation for 28 d. Further work-up showed typical lesions of disseminated TBC. The mother was identified as the source of TBC. The boy presents with mild sequelae (fine motor skills). In infants with suspected septicemia, TBC should be considered as differential diagnosis even if the results are initially negative.

Changes in Pain Medication Profile among Patients Admitted to Specialized Home Palliative Care in Relation to Referral Source: An Exploratory Study.

Pain is a common symptom leading to referrals to specialized home palliative care (SHPC) services and is known to affect patients' quality of life. To date, little is known about the impact of referral source on its management. To assess changes to pain medication profile in the course of SHPC and to identify potential differences in relation to referral source. This exploratory study is a retrospective analysis of 501 electronic medical records of a SHPC team in Germany. This included the assessment of baseline pain medication profiles according to the WHO analgesic ladder and changes to analgesic treatment in the course of SHPC with respect to referral source. At the time of admission, 77.4% of patients referred by a hospital and 78.8% of patients referred by the outpatient sector received a fixed analgesic regimen. In all, 61.9% of the inpatient group versus 62.9% of the outpatient group were treated with opioids, and 79.0% received modifications to pain medication at one point in time following admission. Thereby, patients referred by the outpatient sector received significantly earlier modifications and more supplementations of pain medication. Our study suggests positive development in the prescription of opioid analgesics compared to earlier studies in Germany. On the one hand, it highlights the relevance of thorough assessment and responsive evaluation of pain in SHPC, and on the other hand it reveals possible training needs of referring physicians, particularly those working in the outpatient sector. Our results inspired further research examining more closely the links between referral source and pain management.

Progressive or relapsed Burkitt lymphoma or leukemia in children and adolescents after BFM-type first-line therapy.

Children with refractory or relapsed Burkitt lymphoma (BL) or Burkitt leukemia (B-AL) have a poor chance to survive. We describe characteristics, outcome, reinduction, and transplantation approaches and evaluate risk factors among children with progression of a BL/B-AL included in Non-Hodgkin's Lymphoma-Berlin-Frankfurt-Münster studies between 1986 and 2016. Treatment recommendation was reinduction including rituximab from the early 2000s followed by blood stem cell transplantation. The 3-year survival of the 157 children was 18.5 ± 3%. Survival significantly improved from 11 ± 3% before to 27 ± 5% after 2000 (P < .001), allowing for risk factor analyses among the latter 75 patients. Survival of 14 patients with relapse after initial therapy for low-risk disease (R1/R2) was 50 ± 13% compared with 21 ± 5% for 61 patients progressing after R3/R4 therapy (P < .02). A total of 25 of 28 patients with progression during first-line therapy, 31 of 32 with progression during reinduction, 15 of 16 not reaching a complete remission (CR) before transplantation, 9 of 10 treated with rituximab front-line, and all 13 patients not receiving rituximab during reinduction died. Forty-six patients received stem cell transplantation (20 autologous, 26 allogeneic). Survival after a regimen combining rituximab with continuous-infusion chemotherapy followed by allogeneic transplantation was 67 ± 12% compared with 18 ± 5% for all other regimen and transplantations (P = .003). Patients with relapsed BL/B-AL have a poor chance to survive after current effective front-line therapies. Progression during initial or reinduction chemotherapy and initial high-risk disease are risk factors in relapse. Time-condensed continuous-infusion reinduction followed by stem cell transplantation forms the basis for testing new drugs.

Clinical and Molecular Heterogeneity of RTEL1 Deficiency.

Typical features of dyskeratosis congenita (DC) resulting from excessive telomere shortening include bone marrow failure (BMF), mucosal fragility, and pulmonary or liver fibrosis. In more severe cases, immune deficiency and recurring infections can add to disease severity. RTEL1 deficiency has recently been described as a major genetic etiology, but the molecular basis and clinical consequences of RTEL1-associated DC are incompletely characterized. We report our observations in a cohort of six patients: five with novel biallelic RTEL1 mutations p.Trp456Cys, p.Ile425Thr, p.Cys1244ProfsX17, p.Pro884_Gln885ins53X13, and one with novel heterozygous mutation p.Val796AlafsX4. The most unifying features were hypocellular BMF in 6/6 and B-/NK-cell lymphopenia in 5/6 patients. In addition, three patients with homozygous mutations p.Trp456Cys or p.Ile425Thr also suffered from immunodeficiency, cerebellar hypoplasia, and enteropathy, consistent with Hoyeraal-Hreidarsson syndrome. Chromosomal breakage resembling a homologous recombination defect was detected in patient-derived fibroblasts but not in hematopoietic compartment. Notably, in both cellular compartments, differential expression of 1243aa and 1219/1300aa RTEL1 isoforms was observed. In fibroblasts, response to ionizing irradiation and non-homologous end joining were not impaired. Telomeric circles did not accumulate in patient-derived primary cells and lymphoblastoid cell lines, implying alternative pathomechanisms for telomeric loss. Overall, RTEL1-deficient cells exhibited a phenotype of replicative exhaustion, spontaneous apoptosis and senescence. Specifically, CD34+ cells failed to expand in vitro, B-cell development was compromised, and T-cells did not proliferate in long-term culture. Finally, we report on the natural history and outcome of our patients. While two patients died from infections, hematopoietic stem cell transplantation (HSCT) resulted in sustained engraftment in two patients. Whether chemotherapy negatively impacts on the course and onset of other DC-related symptoms remains open at present. Early-onset lung disease occurred in one of our patients after HSCT. In conclusion, RTEL deficiency can show a heterogeneous clinical picture ranging from mild hypocellular BMF with B/NK cell lymphopenia to early-onset, very severe, and rapidly progressing cellular deficiency.

Disseminated oligodendroglial-like leptomeningeal tumors: preliminary diagnostic and therapeutic results for a novel tumor entity [corrected].

Pediatric tumors of the central nervous system composed of oligoid tumor cells showing diffuse leptomeningeal spread without a primary mass lesion seem to represent a novel tumor entity. The terms "diffuse leptomeningeal glioneural tumor" or-preferably-"disseminated oligodendroglial-like leptomeningeal tumor of childhood" (DOGLT) were proposed. Four patients were identified with clinico-neuropathologic findings compatible with DOGLT and a mean follow-up time of 54 months was determined. Seven different biopsies obtained from the four patients were histologically evaluated. Clinical course, diagnostic measures, histopathologic and radiologic features and treatment suggestions were recorded, on the basis of which diagnostic and therapeutic algorithm was proposed. Patients with DOGLT presented with hydrocephalus as first symptom, requiring neurosurgical therapy. Open arachnoid biopsy was necessary to confirm diagnosis. The oligoid cells in a desmoplastic or focally myxoid matrix showed OLIG2-, MAP2-, S-100 and rare HuC/HuD protein-immunopositivity. IDH1 (R132H)- and CD99-immunohistochemistry was negative in all patients. None of the evaluable biopsies of three patients showed chromosome 1p/19q deletion, neither as isolated nor combined allelic loss. Chemotherapy according to the SIOP-LGG 2004 standard induction and consolidation protocol resulted in complete response and partial response, respectively, in 50 % of the patients. However, after discontinuation of chemotherapy, two patients experienced tumor progression and one of them succumbed to the disease after 19 months. Radiological criteria as well as preliminary treatment results are presented after observation of four clinical cases. Prognosis and long-term clinical courses remain to be observed.

Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma.

Glioblastoma (GBM) is a brain tumor that carries a dismal prognosis and displays considerable heterogeneity. We have recently identified recurrent H3F3A mutations affecting two critical amino acids (K27 and G34) of histone H3.3 in one-third of pediatric GBM. Here, we show that each H3F3A mutation defines an epigenetic subgroup of GBM with a distinct global methylation pattern, and that they are mutually exclusive with IDH1 mutations, which characterize a third mutation-defined subgroup. Three further epigenetic subgroups were enriched for hallmark genetic events of adult GBM and/or established transcriptomic signatures. We also demonstrate that the two H3F3A mutations give rise to GBMs in separate anatomic compartments, with differential regulation of transcription factors OLIG1, OLIG2, and FOXG1, possibly reflecting different cellular origins.

Surgical management of stem cell transplantation-related complications in children.

HSCT is an established treatment option for some children with life-threatening diseases, but complications remain a major cause of morbidity and mortality. This retrospective data analysis addresses the surgical issues of children with HSCT-related complications. Between 2002 and 2008, HSCT was performed in 240 children for leukemias/lymphomas (n=135), solid tumors (n=59), immunodeficiencies (n=20), lipid storage diseases (n=10), autoimmune diseases (n=9), and others (n=7). HSCT-related complications requiring surgery occurred in 24 cases (10%) and most often in the leukemias/lymphomas group (18/24 cases): HC (cystoscopic irrigation, n=7), pulmonary aspergilloses (resection, n=7), bone necroses (core decompression, n=3), GvHD bowel (colostomy/PEG, n=2), ICH (drainage, n=2), bilateral kidney abscess (nephrectomies/renal transplantation, n=1), aspergillosis of the maxillary sinus (decompression, n=1), and post-traumatic wound healing disorder (meshed skin transplantation, n=1). Survival was 50% in the group with surgery and 62% in the group without (p=0.275). Even though this difference was not statistically significant, surgical intervention should be encouraged in all cases to achieve favorable results.

Treatment arms summarizing analysis of 220 high-grade glioma studies.

Large phase III studies have identified limited survival benefits with chemotherapy in high-grade glioma. However, numerous clinical trials have been published previously with smaller patient numbers and no control groups. A small positive effect could be missed this way, resulting in premature rejection of possible beneficial treatment. In order to perform a treatment arm summarizing analysis (TASA), a database was created summarizing treatments published between January 1976 and June 2002. In this database, one record represents a cohort of patients treated in the same way. Various patient cohort characteristics such as median age, and outcome measures including median overall survival times (mOS), were documented. Two-hundred and twenty publications were documented with a total number of 17,213 cases treated in 337 treatment groups. There was a statistically significant relationship between the distribution of histological grades (p<0.001) and the outcome, and a better outcome in younger patient populations (p<0.01). However, the known influence of the median Karnowsky performance scale could not be confirmed in this database. The extent of surgery showed a positive influence only when excluding relapse studies, while the positive effect of radiation was clear in all subgroups (p<0.05). Clinical studies that included nitrosurea in the treatment had a significantly better outcome than those with platinum drugs or without chemotherapy. We conclude that TASA, representing a novel way to perform a meta-analysis, is valid since it confirms the known treatment effects and, therefore, has the potential to provide new insights by combining information from different clinical treatment studies.