Treatment intensity affects immune reconstitution even after childhood cancer not treated with hematopoietic stem cell transplantation.

BACKGROUND: Only a few previous studies examine immune system recovery after completed cancer treatment. AIMS: The aim of this study was to analyze immune reconstitution after childhood cancer therapy in a non-hematopoietic stem cell transplantation setting. METHODS AND RESULTS: We analyzed children (N = 79) who received chemotherapy with/without irradiation for cancer diagnosed between 2014 and 2019 at Turku University Hospital, Finland. We retrospectively collected data on baseline parameters and post-treatment immunological recovery, namely neutrophil and lymphocyte counts, IgG levels, CD19, CD4 and natural killer cell counts. Immunological parameters were followed until their normalization. Treatment intensity was stratified according to the Intensity of Treatment Rating Scale (ITR-3). We analyzed the effects of treatment intensity on normalization of immunological parameters across the entire treatment range. Treatment intensity had a major effect on immune system recovery after completion of treatment. Most patients had normal immunological parameters 1-4 months post-treatment both in high- and low-intensity treatment groups, but patients classified in the high-intensity group had low parameters more often than patients in the low-intensity group. CONCLUSION: Our data suggest a fast recovery of studied immunological parameters after the majority of current pediatric oncologic treatments. Treatment for high-risk acute lymphoblastic leukemia, acute myeloid leukemia, medulloblastoma, and mature B-cell lymphoma was associated with prolonged recovery times for a substantial proportion of cases. High treatment intensity was associated with prolonged immunological recovery.

A previous champagne tap reduces the probability of traumatic lumbar puncture in the following procedure.

A cerebrospinal fluid (CSF) sample containing no red blood cells (RBC), colloquially known as a champagne tap, is an ideal outcome of a lumbar puncture (LP). In this pseudoprospective study of 2573 patients aged from 0 days to 95 years, we examined in four different age categories (neonates and infants, children and adolescents, adults, and older adults) whether a champagne tap in the patient's first LP procedure and a shorter time than 1 week between the two successive procedures are independently associated with fewer blood-contaminated CSF samples (traumatic LP) in the following procedure. One out of five CSF samples from the patient's first LP procedures were RBC-free on average, varying from about 9% in neonates and infants to about 36% in children and adolescents. The mean incidence of champagne taps was 19.5%. According to binary logistic regression, a champagne tap in the previous LP procedure significantly determined whether the following procedure was not blood-contaminated. The odds of traumatic LP were halved or even reduced tenfold after a champagne tap. Less than a week between the two successive procedures, in turn, multiplied the odds of traumatic LP in the latter even more than tenfold. A champagne tap was not significantly associated with traumatic LP in the following procedure among pediatric patients. If the patient's condition or therapy plan permits and the blood contamination can compromise the reliability of the CSF-based analysis and consequent diagnosis, postponing the LP procedure by several days is advisable to improve the odds of receiving a high-quality CSF sample.

Success and complications in lumbar punctures of pediatric patients with leukemia: a study protocol for a randomized clinical crossover trial of a bioimpedance needle system versus conventional procedure.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed in children. At present, the long-term survival from pediatric ALL is well over 90%. However, the probability of event-free survival is reduced if the lumbar puncture (LP) procedures at the beginning of the patient's intrathecal therapy cause blood leakage into the spinal canal and blast cells contaminate the cerebrospinal fluid. According to the literature, such traumatic LP procedures concern one out of five pediatric patients with ALL. Recently, a novel medical device measuring the tissue bioimpedance at the tip of a spinal needle was found feasible in pediatric patients with ALL. The LP procedure was successful at the first attempt in 80% of procedures, and the incidence of traumatic LPs was then 11%. The purpose of the present study is to compare the bioimpedance spinal needle system with the standard clinical practice resting on a conventional spinal needle and investigate its efficacy in clinical practice. METHODS: The study is a multicenter, randomized, two-arm crossover noninferiority trial of pediatric hemato-oncology patients that will be conducted within the usual clinical workflow. Patients' LP procedures will be performed alternately either with the IQ-Tip system (study arm A) or a conventional Quincke-type 22G spinal needle (study arm B). For each enrolled patient, the order of procedures is randomly assigned either as ABAB or BABA. The total number of LP procedures will be at least 300, and the number of procedures per patient between two and four. After each study LP procedure, the performance will be recorded immediately, and 1-week diary-based and 4-week record-based follow-ups on symptoms, complications, and adverse events will be conducted thereafter. The main outcomes are the incidence of traumatic LP, first puncture success rate, and incidence of post-dural puncture headache. DISCUSSION: The present study will provide sound scientific evidence on the clinical benefit, performance, and safety of the novel bioimpedance spinal needle compared with the standard clinical practice of using conventional spinal needles in the LP procedures of pediatric patients with leukemia. TRIAL REGISTRATION: ISRCTN ISRCTN16161453. Registered on 8 July 2022.

Incidence of traumatic lumbar punctures in adults: the impact of a patient's first procedure.

INTRODUCTION: Lumbar puncture (LP) is a widely used diagnostic method in patients of all ages. Blood-contaminated cerebrospinal fluid samples are frequent and may compromise diagnostic accuracy. OBJECTIVES: We determined age-specific incidences of traumatic LPs (TLPs) in adults and examined factors that accounted for the incidence of TLPs. METHODS: Erythrocyte count data from 15,812 LP procedures (2,404 were performed twice) were collected from hospital records of patients aged from 18 to 104 years. The incidence of TLPs in a patient's second LP procedure was evaluated with logistic regression analysis using the first LP, the time between the procedures and age as predictors. RESULTS: The incidence of TLP in the second procedure was at least double that in the first procedure. If the first procedure was traumatic, the odds ratio of a TLP in the second procedure was 7-40-fold. One day between the successive procedures was associated with an over 10-fold odds ratio increase of TLP, and a week was still 4-8-fold odds ratio increase. Age was also associated with the incidence of TLP. CONCLUSIONS: Two factors (a week or less between a patient's two LP procedures or a traumatic first LP) multiply the odds of the second procedure being traumatic and contribute to whether a patient's following LP procedure is successful.

Inflammatory biomarkers after an exercise intervention in childhood acute lymphoblastic leukemia survivors.

Cancer survivors show increased risk for non-communicable diseases and chronic low-grade inflammation characterizes the development of such diseases. We investigated inflammatory plasma protein profiles of survivors of childhood acute lymphoblastic leukemia (ALL) in comparison to healthy controls and after an intervention with a home-based exercise program. Survivors of childhood ALL aged 16-30 years (n = 21) with a median age at diagnosis 4.9 (1.6-12.9) years and a median time of 15.9 years from diagnosis, and sex- and age-matched healthy controls (n = 21) were studied. Stored plasma samples were analyzed with Olink's 92-protein-wide Inflammation panel in 21 ALL long-term survivors at baseline, after a previous 16-week home-based exercise intervention (n = 17) and in 21 age- and sex-matched controls at baseline. Protein expression levels were compared between the groups. Inflammatory protein levels did not differ between the survivors and controls at baseline. Significantly reduced levels after the intervention were found in 11 proteins related to either vascular inflammation, insulin resistance, or both: tumor necrosis factor superfamily member 14 (TNFSF14), oncostatin M (OSM), monocyte chemoattractant protein 1 (MCP-1), MCP-2, fibroblast growth factor 21 (FGF-21), chemokine (C-C motif) ligand 4 (CCL4), transforming growth factor alpha (TGF-α), tumor necrosis factor-related apoptosis-inducing ligand 10 (TRAIL), adenosine deaminase (ADA), chemokine (C-X-C motif) ligand 6 (CXCL6), and latency-associated peptide transforming growth factor beta 1 (LAP TGF-ß1). The ALL survivors were not significantly more affected by inflammation than controls at baseline. The survivors' 16-week exercise intervention led to significant reduction in inflammatory protein levels. Physical exercise should be promoted for survivors of childhood cancer.

A survey on thromboprophylaxis and coagulation assessment in children and young adults with acute lymphoblastic leukaemia (ALL) in the Nordic and Baltic countries: Different practices of assessment and management.

Patients undergoing treatment for acute lymphoblastic leukaemia (ALL) are at risk of coagulopathy, especially thromboembolism. We conducted a survey on practices in the assessment and management of coagulopathy during the new ALLTogether protocol in 29 (17 paediatric, 12 adult) Nordic and Baltic cancer centres. While 92% of adult centres used thromboprophylaxis with low-molecular-weight heparin, no paediatric centre did. Almost all providers performed baseline coagulation studies, but only 59% continued the assessment. Fibrinogen replacement was conducted in 59%, and antithrombin replacement in 28% of the centres. The survey highlights the need for guidelines in the management of coagulopathy during ALL therapy.

Bioimpedance spinal needle provides high success and low complication rate in lumbar punctures of pediatric patients with acute lymphoblastic leukemia.

In this prospective single-arm study of 50 pediatric patients with acute lymphoblastic leukemia (ALL), we evaluated the clinical performance of a novel bioimpedance spinal needle system in 152 intrathecal treatment lumbar punctures (LP) of these patients. The system detects in real-time when the needle tip reaches the cerebrospinal fluid (CSF) in the spinal canal. The success was defined as getting a CSF sample and/or administering the intrathecal treatment with one needle insertion. Incidence of traumatic LP (TLP) was defined as ≥ 10 erythrocytes/µL of CSF. Post-procedural complications were monitored with a one-week diary and one-month register follow-up. The success of the first attempt was 79.5%, with the CSF detection sensitivity of 86.1%. The incidence of TLP was 17.3%. A successful first attempt was associated with a significantly lower incidence of TLP (10% vs 40%, p = 0.0015). During the week after the procedure, the incidence of post-dural puncture headache was 6%. During the follow-up, no major complications were observed. In conclusion, the novel bioimpedance spinal needle system achieved a high success rate and low incidence of TLP and other complications in pediatric patients with ALL in a real-world clinical setting, indicating clinical utility for this system in pediatric hemato-oncology.

Bisphosphonate treatment in children with acute lymphoblastic leukemia and osteonecrosis - radiological and clinical findings in a national cohort.

Background: Osteonecrosis (ON) is a recognized complication of childhood ALL, but its optimal management remains unestablished. This study evaluated the effect of bisphosphonate (BP) treatment on the evolution of ON lesions in childhood ALL.Material and Methods: We included a national cohort of ALL patients diagnosed with symptomatic ON before 18 years of age and treated with BPs (N = 10; five males). Patients were followed both clinically and with serial MRIs. ON lesions were graded according to the Niinimäki classification.Results: The 10 patients had a total of 55 ON lesions. The median age was 13.3 years at ALL diagnosis and 14.8 years at ON diagnosis. Four patients had received HSCT before the ON diagnosis. BPs used were pamidronate (N = 7), alendronate (N = 2) and ibandronate (N = 1). The duration of BP treatment varied between 4 months and 4 years. In 4/10 patients, BP treatment was given during the chemotherapy. BPs were well-tolerated, with no severe complications or changes in kidney function. At the end of follow up 13/55 (24%) ON lesions were completely healed both clinically and radiographically; all these lesions were originally graded 3 or less. In contrast, ON lesions originally classified as grade 5 (joint destruction; N = 4) remained at grade 5. All grade 5 hip joint lesions needed surgical treatment. During BP treatment, the pain was relieved in 7/10 patients. At the end of follow-up, none of the patients reported severe or frequent pain.Conclusion: BP treatment was safe and seemed effective in relieving ON-induced pain in childhood ALL. After articular collapse (grade 5) lesions did not improve with BP treatment. Randomized controlled studies are needed to further elucidate the role of BPs in childhood ALL-associated ON.

Use of electronic patient data storage for evaluating and setting the risk category of late effects in childhood cancer survivors.

BACKGROUND: Many of the late effects of cancer treatment in childhood may occur even decades after the treatment, and only a minority of the survivors remain as healthy as their peers. Providing appropriate long-term care for childhood cancer survivors after transition to primary health care is a challenge. Both survivors and primary care providers need information on potential late effects. The lack of a systematic late effect follow-up plan may lead to excessive use of health care services or delayed intervention. While manual compilation of individual follow-up plans is time consuming for experienced clinicians, electronic algorithms may be feasible. PROCEDURE: In Finland, international guidelines for determining the risk of late effects have been implemented. Nationally, Turku University Hospital was asked with developing an automatized system for calculating the risk of late effects, based on electronic patient records saved in the hospital data lake. An electronic algorithm that uses details from exposure-based health screening guidelines published by the Children's Oncology Group was created. The results were compared with those manually extracted by an experienced clinician. RESULTS: Significant concordance between the manual and algorithm-based risk classification was found. A total of 355 patients received a classification using the algorithm, and 325 of those matched with the manual categorization, producing a Cohen's coefficient of 0.91 (95% confidence interval 0.88-0.95). CONCLUSION: Automated algorithms can be used to categorize childhood cancer survivors efficiently and reliably into late effect risk groups. This further enables automatized compilation of appropriate individual late effect follow-up plan for all survivors.

Mode of delivery - effects on gut microbiota and humoral immunity.

BACKGROUND: The rate of caesarean deliveries has increased 10-fold worldwide during the past decades. OBJECTIVE: To evaluate differences in the establishment of gut microbiota in infants born by vaginal or caesarean delivery and its impact on mucosal immunity. METHODS: Altogether, 165 consecutive children, prospectively followed from birth at our clinic in Turku, Finland, were gathered; 141 (85%) were born by vaginal delivery and 24 (15%) by caesarean section. Blood was drawn at physician visits for indirect evaluation of mucosal immunity by ELISPOT assay. Faecal samples were obtained for determination of the gut microbiota by fluorescence in situ hybridization of bacterial cells. RESULTS: Infants delivered by caesarean section harboured fewer bifidobacteria at an early age and were shown to mount a stronger humoral immune response. At 1 month of age, the total gut bacterial cell counts per 1 g faeces were higher in vaginally delivered infants (9.9 x 10(9), 95% CI 7.9 x 10(9)-1.2 x 10(10)) as compared to caesarean section delivered (3.1 x 10(9), 95% CI 1.1 x 10(9)-8.6 x 10(9)) (p = 0.001). This distinction was mainly due to the greater number of bifidobacteria in vaginally delivered infants (1.9 x 10(9), 95% CI 6.3 x 10(8)-5.6 x 10(9) vs. 1.5 x 10(6), 95% CI 4.1 x 10(2)-5.7 x 10(9), respectively) (p = 0.001). During the first year of life, the total number of IgA-, IgG- and IgM-secreting cells was lower (p = 0.03, p = 0.02, p = 0.11, respectively) in infants born by vaginal delivery than in those born by caesarean section, possibly reflecting excessive antigen exposure across the vulnerable gut barrier. CONCLUSIONS: Our findings demonstrate that the mode of delivery may have, possibly via gut microbiota development, significant effects on immunological functions in the infant (http://www.clinicaltrials.gov/ct/gui/show/NCT00167700).

How practice meets guidelines: evaluation of nutrition counselling in Finnish well-women and well-baby clinics.

AIM: To assess the current practices of nutrition counselling given by nurses in well-women (WW) and well-baby (WB) clinics in Finland. DESIGN: A semi-structured questionnaire was distributed to nurses and their clients in clinics nationwide. MAIN OUTCOME MEASURES: The source and the quality of nutrition counselling and specific conditions including allergic diseases and vitamin D supplementation. RESULTS: The clinics constituted the most important source of information for the clients. Personal counselling was highly appreciated. However, 83% of pregnant women reported having received dietary counselling, which deviates from the figure reported by nurses (99%, p=0.0003). Counselling concerning allergies was targeted to reduce the risk of infant allergy by means of elimination diets. In contrast to the report of the nurses (60% in WW and 18% in WB clinics), only 16% (p<0.0001) of the pregnant and 7% (p=0.022) of the breastfeeding women reported that they had been advised to use vitamin D supplements during the winter season. CONCLUSION: This study calls for co-operation between scientists, governmental policy makers and healthcare professionals to ensure a continuous chain of information, applicable to nutrition counselling, from scientific data to everyday practice.