A systematic review on safety and surgical and anesthetic risks of elective abdominal laparoscopic surgery in infants to guide laparoscopic ovarian tissue harvest for fertility preservation for infants facing gonadotoxic treatment.

Background: Infertility is an important late effect of childhood cancer treatment. Ovarian tissue cryopreservation (OTC) is established as a safe procedure to preserve gonadal tissue in (pre)pubertal girls with cancer at high risk for infertility. However, it is unclear whether elective laparoscopic OTC can also be performed safely in infants <1 year with cancer. This systematic review aims to evaluate the reported risks in infants undergoing elective laparoscopy regarding mortality, and/or critical events (including resuscitation, circulatory, respiratory, neurotoxic, other) during and shortly after surgery. Methods: This systematic review followed the Preferred reporting Items for Systematic Review and Meta-Analyses (PRISMA) reporting guideline. A systematic literature search in the databases Pubmed and EMbase was performed and updated on February 15th, 2023. Search terms included 'infants', 'intubation', 'laparoscopy', 'mortality', 'critical events', 'comorbidities' and their synonyms. Papers published in English since 2000 and describing at least 50 patients under the age of 1 year undergoing laparoscopic surgery were included. Articles were excluded when the majority of patients had congenital abnormalities. Quality of the studies was assessed using the QUIPS risk of bias tool. Results: The Pubmed and Embase databases yielded a total of 12,401 unique articles, which after screening on title and abstract resulted in 471 articles to be selected for full text screening. Ten articles met the inclusion criteria for this systematic review, which included 1778 infants <1 years undergoing elective laparoscopic surgery. Mortality occurred once (death not surgery-related), resuscitation in none and critical events in 53/1778 of the procedures. Conclusion: The results from this review illustrate that morbidity and mortality in infants without extensive comorbidities during and just after elective laparoscopic procedures seem limited, indicating that the advantages of performing elective laparoscopic OTC for infants with cancer at high risk of gonadal damage may outweigh the anesthetic and surgical risks of laparoscopic surgery in this age group.

A Dutch paediatric palliative care guideline: a systematic review and evidence-based recommendations for symptom treatment.

BACKGROUND: Children with life-threatening and life-limiting conditions can experience high levels of suffering due to multiple distressing symptoms that result in poor quality of life and increase risk of long-term distress in their family members. High quality symptom treatment is needed for all these children and their families, even more so at the end-of-life. In this paper, we provide evidence-based recommendations for symptom treatment in paediatric palliative patients to optimize care. METHODS: A multidisciplinary panel of 56 experts in paediatric palliative care and nine (bereaved) parents was established to develop recommendations on symptom treatment in paediatric palliative care including anxiety and depression, delirium, dyspnoea, haematological symptoms, coughing, skin complaints, nausea and vomiting, neurological symptoms, pain, death rattle, fatigue, paediatric palliative sedation and forgoing hydration and nutrition. Recommendations were based on evidence from a systematic literature search, additional literature sources (such as guidelines), clinical expertise, and patient and family values. We used the GRADE methodology for appraisal of evidence. Parents were included in the guideline panel to ensure the representation of patient and family values. RESULTS: We included a total of 18 studies that reported on the effects of specific (non) pharmacological interventions to treat symptoms in paediatric palliative care. A few of these interventions showed significant improvement in symptom relief. This evidence could only (partly) answer eight out of 27 clinical questions. We included 29 guidelines and two textbooks as additional literature to deal with lack of evidence. In total, we formulated 221 recommendations on symptom treatment in paediatric palliative care based on evidence, additional literature, clinical expertise, and patient and family values. CONCLUSION: Even though available evidence on symptom-related paediatric palliative care interventions has increased, there still is a paucity of evidence in paediatric palliative care. We urge for international multidisciplinary multi-institutional collaboration to perform high-quality research and contribute to the optimization of symptom relief in palliative care for all children worldwide.

Anesthesia Depresses Cerebrovascular Reactivity to Acetazolamide in Pediatric Moyamoya Vasculopathy.

Measurements of cerebrovascular reactivity (CVR) are essential for treatment decisions in moyamoya vasculopathy (MMV). Since MMV patients are often young or cognitively impaired, anesthesia is commonly used to limit motion artifacts. Our aim was to investigate the effect of anesthesia on the CVR in pediatric MMV. We compared the CVR with multidelay-ASL and BOLD MRI, using acetazolamide as a vascular stimulus, in all awake and anesthesia pediatric MMV scans at our institution. Since a heterogeneity in disease and treatment influences the CVR, we focused on the (unaffected) cerebellum. Ten awake and nine anesthetized patients were included. The post-acetazolamide CBF and ASL-CVR were significantly lower in anesthesia patients (47.1 ± 15.4 vs. 61.4 ± 12.1, p = 0.04; 12.3 ± 8.4 vs. 23.7 ± 12.2 mL/100 g/min, p = 0.03, respectively). The final BOLD-CVR increase (0.39 ± 0.58 vs. 3.6 ± 1.2% BOLD-change (mean/SD), p < 0.0001), maximum slope of increase (0.0050 ± 0.0040%/s vs. 0.017 ± 0.0059%, p < 0.0001), and time to maximum BOLD-increase (~463 ± 136 and ~697 ± 144 s, p = 0.0028) were all significantly lower in the anesthesia group. We conclude that the response to acetazolamide is distinctively different between awake and anesthetized MMV patients, and we hypothesize that these findings can also apply to other diseases and methods of measuring CVR under anesthesia. Considering that treatment decisions heavily depend on CVR status, caution is warranted when assessing CVR under anesthesia.

Feasibility of quantitative sensory testing in juvenile idiopathic arthritis.

OBJECTIVE: Juvenile Idiopathic Arthritis (JIA) is a childhood-rheumatic disease with pain as a major early complaint, and in 10-17% pain remains a major symptom. Very few data exist on sensory threshold changes at the knee in JIA, a location in which inflammation often manifests. We determined whether JIA is associated with sensory threshold changes at the knee by using Quantitative Sensory Testing (QST) and established reference values at the knee of children. METHODS: Sixteen patients with JIA aged 9-18 years with one affected knee and a patient-reported pain by Visual Analog Scale (VAS) > 10 on a 0-100 scale, and 16 healthy controls completed the study and were included for the analysis. QST was assessed in compliance with the German Research Network on Neuropathic Pain (DFNS) standard. Disease severity was determined using Juvenile Disease Activity Score (JADAS. Perceived pain was assessed with a visual analogue scale(0-100). Feasibility of QST was tested in patients aged 6-9. RESULTS: Under the age of 9, QST testing showed not to be feasible in 3 out of 5 JIA patients. Patients with JIA aged 9 and older reported an average VAS pain score of 54.3. QST identified a significant reduction in pressure pain threshold (PPT) and increase in cold detection threshold (CDT) compared to healthy controls. PPT is reduced in both the affected and the unaffected knee, CDT is reduced in the unaffected knee, not the affected knee. CONCLUSION: In a Dutch cohort of Patients with JIA, QST is only feasible from 9 years and up. Also, sensory threshold changes at the knee are restricted to pressure pain and cold detection thresholds in Patients with JIA. PERSPECTIVE: This article shows that in a Dutch population, the extensive QST protocol is only feasible in the age group from 9 years and older, and a reduced set of QST tests containing at least pressure pain thresholds and cold detection thresholds could prove to be better suited to the pediatric setting with arthritis.

Reducing pain in children with cancer at home: a feasibility study of the KLIK pain monitor app.

PURPOSE: This study assessed adherence to, feasibility of, and barriers and facilitators of implementation of an app developed to monitor and follow-up with pain in children with cancer at home. METHODS: Children (8-18 years) receiving cancer treatment (all diagnoses) or their parents (of children aged 0-7 years) used the KLIK Pain Monitor app for 3 weeks. Pain was assessed twice daily using an 11-point numeric rating scale (NRS-11) (ranging from 0 to 10). Healthcare professionals (HCP's) from the hospital's Pediatric Pain Service were instructed to follow-up with clinically significant pain scores (≥ 4) within 120 min (scores 4-6) or 30 min (scores 7-10). Adherence, feasibility, and implementation outcomes were assessed using questionnaires, app log data, and interviews. RESULTS: Twenty-seven children (M age = 7.3 years, 51.8% male) and six HCP's participated. Sixty-three percent (N = 17) of families used the app on a daily basis during three weeks, and 18.5% (N = 5) reported pain scores twice daily during that time (family adherence). Twelve out of 27 children (44.4%) reported a clinically significant pain score at least once. In 70% (14/20) of clinically significant pain scores, HCP's followed-up with families within the set timeframe (HCP adherence). Outcomes reveal feasibility for the majority of app functions (i.e., positive evaluation by ≥ 70% families/HCP's), and non-feasible aspects could be resolved. Identified barriers and facilitators were used to improve future implementation efforts. CONCLUSION: Use of the KLIK Pain Monitor app seems feasible. Future research will determine its effectiveness in reducing pain in children with cancer at home.

Prospective 3-arm study on pain and epithelial healing after corneal crosslinking.

PURPOSE: To investigate the effect of 3 regimes on pain and wound healing after corneal crosslinking (CXL). SETTING: Tertiary academic referral center, Utrecht, the Netherlands. DESIGN: Prospective cohort study. METHODS: Consecutive progressive keratoconus patients who underwent 9 mW/cm epithelium-off CXL were included. Patients received a bandage contact lens (n = 20), occlusive patch (n = 20), or antibiotic ointment (n = 20) after treatment. Pain scores and quality of life, measured by the McGill Pain Questionnaire and Visual Analogue Scale (VAS), were analyzed. Epithelial healing after 2 days, correlations between pain and psychological factors that influence pain perception (depression anxiety stress score and pain catastrophizing score), and oral pain medication were evaluated. RESULTS: Sixty eyes of 52 patients were analyzed. On average, patients experienced considerable pain after CXL (median VAS score 6.2, range 0 to 10). The postoperative regimen did not significantly affect pain scores, although the antibiotic ointment group reported a higher VAS score (median VAS score 7.2 vs 6.7 and 6.0; P = .57). Occlusive patching showed a trend to quicker resolution of epithelial defects (85% completely healed vs 65% with lenses and 70% with antibiotic ointment; P = .43). Correlations with pain-modulating psychological factors were weak (R < 0.3) and not significant. The use of pain medication corresponded poorly to the prescribed use. CONCLUSION: This study demonstrated clinical equivalence of 3 regimes in combating postoperative pain after routine CXL. Wound healing appeared quicker in the occlusive patch group and therefore might be the best standard of care after CXL. The clinical tradition of using bandage contact lenses should be reevaluated.

Treatment-Related Toxicities During Anti-GD2 Immunotherapy in High-Risk Neuroblastoma Patients.

The introduction of immunotherapy using an anti-GD2 antibody (dinutuximab, ch14.18) has significantly improved survival rates for high-risk neuroblastoma patients. However, this improvement in survival is accompanied by a substantial immunotherapy-related toxicity burden. The primary objective of this study was to describe treatment-related toxicities during immunotherapy with dinutuximab, IL-2, GM-CSF, and isotretinoin. A retrospective, single center analysis of immunotherapy-related toxicities was performed in twenty-six consecutive high-risk neuroblastoma patients who received immunotherapy as maintenance therapy in the Princess Máxima Center (Utrecht, Netherlands). Toxicities were recorded and graded according to the CTCAE. Particular attention was drawn to pain and fever management and toxicities leading to dose modifications of dinutuximab and IL-2. Twenty-three patients (88%) completed all six courses of immunotherapy. Disease progression, isotretinoin-associated liver toxicity, and catheter-related infection in combination with peripheral neuropathy were reasons for immunotherapy discontinuation. The most common grade ≥3 toxicities for courses 1-5, respectively, were pain, catheter-related infections, and fever. In total, 310 grade ≥3 toxicities were recorded in 124 courses. Thirty-three grade 4 toxicities in 19/26 patients and no grade 5 toxicities (death) were seen. Fifty-nine percent of grade ≥3 toxicities were recorded in the two courses with IL-2. Catheter-related bloodstream infections were identified in 81% of patients. Four of these episodes led to intensive care admission followed by full recovery (grade 4).

How sugars protect proteins in the solid state and during drying (review): Mechanisms of stabilization in relation to stress conditions.

This review aims to provide an overview of current knowledge on stabilization of proteins by sugars in the solid state in relation to stress conditions commonly encountered during drying and storage. First protein degradation mechanisms in the solid state (i.e. physical and chemical degradation routes) and traditional theories regarding protein stabilization (vitrification and water replacement hypotheses) will be briefly discussed. Secondly, refinements to these theories, such as theories focusing on local mobility and protein-sugar packing density, are reviewed in relationship to the traditional theories and their analogies are discussed. The last section relates these mechanistic insights to the stress conditions against which these sugars are used to provide protection (i.e. drying, temperature, and moisture). In summary sugars should be able to adequately form interactions with the protein during drying, thereby maintaining it in its native conformation and reducing both local and global mobility during storage. Generally smaller sugars (disaccharides) are better at forming these interactions and reducing local mobility as they are less inhibited by steric hindrance, whilst larger sugars can reduce global mobility more efficiently. The principles outlined here can aid in choosing a suitable sugar as stabilizer depending on the protein, formulation and storage condition-specific dominant route of degradation.

Influence of Miscibility of Protein-Sugar Lyophilizates on Their Storage Stability.

For sugars to act as successful stabilizers of proteins during lyophilization and subsequent storage, they need to have several characteristics. One of them is that they need to be able to form interactions with the protein and for that miscibility is essential. To evaluate the influence of protein-sugar miscibility on protein storage stability, model protein IgG was lyophilized in the presence of various sugars of different molecular weight. By comparing solid-state nuclear magnetic resonance spectroscopy relaxation times of both protein and sugar on two different timescales, i.e., (1)H T1 and (1)H T1ρ, miscibility of the two components was established on a 2-5- and a 20-50-nm length scale, respectively, and related to protein storage stability. Smaller sugars showed better miscibility with IgG, and the tendency of IgG to aggregate during storage was lower for smaller sugars. The largest sugar performed worst and was phase separated on both length scales. Additionally, shorter protein (1)H T1 relaxation times correlated with higher aggregation rates during storage. The enzyme-linked immunosorbent assay (ELISA) assay showed overlapping effects of aggregation and chemical degradation and did not correspond as well with the miscibility. Because of the small scale at which miscibility was determined (2-5 nm) and the size of the protein domains (∼2.5 × 2.5 × 5 nm), the miscibility data give an indirect measure of interaction between protein and sugar. This reduced interaction could be the result of steric hindrance, providing a possible explanation as to why smaller sugars show better miscibility and storage stability with the protein.

In-line near infrared spectroscopy during freeze-drying as a tool to measure efficiency of hydrogen bond formation between protein and sugar, predictive of protein storage stability.

Sugars are often used as stabilizers of protein formulations during freeze-drying. However, not all sugars are equally suitable for this purpose. Using in-line near-infrared spectroscopy during freeze-drying, it is shown here that hydrogen bond formation during freeze-drying, under secondary drying conditions in particular, can be related to the preservation of the functionality and structure of proteins during storage. The disaccharide trehalose was best capable of forming hydrogen bonds with the model protein, lactate dehydrogenase, thereby stabilizing it, followed by the molecularly flexible oligosaccharide inulin 4kDa. The molecularly rigid oligo- and polysaccharides dextran 5kDa and 70kDa, respectively, formed the least amount of hydrogen bonds and provided least stabilization of the protein. It is concluded that smaller and molecularly more flexible sugars are less affected by steric hindrance, allowing them to form more hydrogen bonds with the protein, thereby stabilizing it better.

Inulin, a flexible oligosaccharide. II: Review of its pharmaceutical applications.

Inulin is a flexible oligosaccharide which has been used primarily in food for decades. Recently new applications in the pharmaceutical arena were described. In a previous review (Mensink et al. (2015). Carbohydrate Polymers, 130, 405) we described the physicochemical characteristics of inulin, characteristics which make inulin a highly versatile substance. Here, we review its pharmaceutical applications. Applications of inulin that are addressed are stabilization of proteins, modified drug delivery (dissolution rate enhancement and drug targeting), and lastly physiological and disease-modifying effects of inulin. Further uses of inulin include colon specific drug administration and stabilizing and adjuvating vaccine formulations. Overall, the uses of inulin in the pharmaceutical area are very diverse and research is still continuing, particularly with chemically modified inulins. It is therefore likely that even more applications will be found for this flexible oligosaccharide.

Inulin, a flexible oligosaccharide I: Review of its physicochemical characteristics.

Inulin, a fructan-type polysaccharide, consists of (2→1) linked ß-d-fructosyl residues (n=2-60), usually with an (1↔2) α-d-glucose end group. The applications of inulin and its hydrolyzed form oligofructose (n=2-10) are diverse. It is widely used in food industry to modify texture, replace fat or as low-calorie sweetener. Additionally, it has several applications in other fields like the pharmaceutical arena. Most notably it is used as a diagnostic agent for kidney function and as a protein stabilizer. This work reviews the physicochemical characteristics of inulin that make it such a versatile substance. Topics that are addressed include morphology (crystal morphology, crystal structure, structure in solution); solubility; rheology (viscosity, hydrodynamic shape, gelling); thermal characteristics and physical stability (glass transition temperature, vapor sorption, melting temperature) and chemical stability. When using inulin, the degree of polymerization and processing history should be taken into account, as they have a large impact on physicochemical behavior of inulin.