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

Possible modification of BRSK1 on the risk of alkylating chemotherapy-related reduced ovarian function

STUDY QUESTION: Do genetic variations in the DNA damage response pathway modify the adverse effect of alkylating agents on ovarian function in female childhood cancer survivors (CCS)? SUMMARY ANSWER: Female CCS carrying a common BR serine/threonine kinase 1 (BRSK1) gene variant appear to be at 2.5-fold increased odds of reduced ovarian function after treatment with high doses of alkylating chemotherapy. WHAT IS KNOWN ALREADY: Female CCS show large inter-individual variability in the impact of DNA-damaging alkylating chemotherapy, given as treatment of childhood cancer, on adult ovarian function. Genetic variants in DNA repair genes affecting ovarian function might explain this variability. STUDY DESIGN, SIZE, DURATION: CCS for the discovery cohort were identified from the Dutch Childhood Oncology Group (DCOG) LATER VEVO-study, a multi-centre retrospective cohort study evaluating fertility, ovarian reserve and risk of premature menopause among adult female 5-year survivors of childhood cancer. Female 5-year CCS, diagnosed with cancer and treated with chemotherapy before the age of 25 years, and aged 18 years or older at time of study were enrolled in the current study. Results from the discovery Dutch DCOG-LATER VEVO cohort (n = 285) were validated in the pan-European PanCareLIFE (n =465) and the USA-based St. Jude Lifetime Cohort (n = 391). PARTICIPANTS/MATERIALS, SETTING, METHODS: To evaluate ovarian function, anti-Miillerian hormone (AMH) levels were assessed in both the discovery cohort and the replication cohorts. Using additive genetic models in linear and logistic regression, five genetic variants involved in DNA damage response were analysed in relation to cyclophosphamide equivalent dose (CED) score and their impact on ovarian function. Results were then examined using fixed-effect meta-analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Meta-analysis across the three independent cohorts showed a significant interaction effect (P= 3.0 x 10(-4)) between rs11668344 of BRSK 1 (allele frequency = 0.34) among CCS treated with high-dose alkylating agents (CED score >= 8000 mg/m(2)), resulting in a 2.5-fold increased odds of a reduced ovarian function (lowest AMH tertile) for CCS carrying one G allele compared to CCS without this allele (odds ratio genotype AA: 2.01 vs AG: 5.00). LIMITATIONS, REASONS FOR CAUTION: While low AMH levels can also identify poor responders in assisted reproductive technology, it needs to be emphasized that AMH remains a surrogate marker of ovarian function. WIDER IMPLICATIONS OF THE FINDINGS: Further research, validating our findings and identifying additional risk contributing genetic variants, may enable individualized counselling regarding treatment-related risks and necessity of fertility preservation procedures in girls with cancer

Association of candidate pharmacogenetic markers with platinum-induced ototoxicity: PanCareLIFE dataset

Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The PanCareLIFE cross-sectional cohort study evaluated the genetic associations in a large pan-European population and assessed the diagnostic accuracy of the genetic markers. 1,112 pediatric cancer survivors who had provided biomaterial for genotyping were screened for participation in the pharmacogenetic association study. 900 participants qualified for inclusion. Based on the assessment of original audiograms, patients were assigned to three phenotype categories: no, minor, and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1, and ACYP2) were genotyped. The genotype and phenotype data represent a resource for conducting meta-analyses to derive a more precise pooled estimate of the effects of genes on the risk of hearing loss due to platinum treatment

Genetic determinants of ototoxicity during and after childhood cancer treatment: Protocol for the pancarelife study

Background: Survival rates after childhood cancer now reach nearly 80% in developed countries. However, treatments that lead to survival and cure can cause serious adverse effects with lifelong negative impacts on survivor quality of life. Hearing impairment is a common adverse effect in children treated with cisplatin-based chemotherapy or cranial radiotherapy. Ototoxicity can extend from high-tone hearing impairment to involvement of speech frequencies. Hearing impairment can impede speech and language and neurocognitive development. Although treatment-related risk factors for hearing loss following childhood cancer treatment have been identified, the individual variability in toxicity of adverse effects after similar treatment between childhood cancer patients suggests a role for genetic susceptibility. Currently, 12 candidate gene approach studies have been performed to identify polymorphisms predisposing to platinum-induced ototoxicity in children being treated for cancer. However, results were inconsistent and most studies were underpowered and/or lacked replication. Objective: We describe the design of the PanCareLIFE consortium's work packages that address the genetic susceptibility of platinum-induced ototoxicity. Methods: As a part of the PanCareLIFE study within the framework of the PanCare consortium, we addressed genetic susceptibility of treatment-induced ototoxicity during and after childhood cancer treatment in a large European cohort by a candidate gene approach and a genome-wide association screening. Results: This study included 1124 survivors treated with cisplatin, carboplatin, or cranial radiotherapy for childhood cancer, resulting in the largest clinical European cohort assembled for this late effect to date. Within this large cohort we defined a group of 598 cisplatin-treated childhood cancer patients not confounded by cranial radiotherapy. The PanCareLIFE initiative provided, for the first time, a unique opportunity to confirm already identified determinants for hearing impairment during childhood cancer using a candidate gene approach and set up the first international genome-wide association study of cisplatin-induced direct ototoxicity in childhood cancer patients to identify novel allelic variants. Results will be validated in an independent replication cohort. Patient recruitment started in January 2015 and final inclusion was October 2017. We are currently performing the analyses and the first results are expected by the end of 2019 or the beginning of 2020. Conclusions: Genetic factors identified as part of this pan-European project, PanCareLIFE, may contribute to future risk prediction models that can be incorporated in future clinical trials of platinum-based therapies for cancer and may help with the development of prevention strategies

Interindividual variation in ovarian reserve after gonadotoxic treatment in female childhood cancer survivors - a genome-wide association study: results from PanCareLIFE

Objective: To discover new variants associated with low ovarian reserve after gonadotoxic treatment among adult female childhood cancer survivors using a genome-wide association study approach. Design: Genome-wide association study. Setting: Not applicable. Patients: A discovery cohort of adult female childhood cancer survivors from the pan-European PanCareLIFE cohort (n = 743; median age: 25.8 years), excluding those who received bilateral ovarian irradiation, bilateral oophorectomy, central nervous system or total body irradiation, or stem cell transplantation. Replication was attempted in the US-based St. Jude Lifetime Cohort (n = 391; median age: 31.3 years). Exposure: Female childhood cancer survivors are at risk of therapy-related gonadal impairment. Alkylating agents are well-established risk factors, and the interindividual variability in gonadotoxicity may be explained by genetic polymorphisms. Data were collected in real-life conditions, and cyclophosphamide equivalent doses were used to quantify alkylation agent exposure. Main Outcome Measure: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function, and the findings were combined in a meta-analysis. Results: Three genome-wide significant (0.01 if not genome-wide significant), and biologic relevance, 15 single nucleotide polymorphisms were selected for replication. None of the single nucleotide polymorphisms were statistically significantly associated with AMH levels. A meta-analysis indicated that rs78861946 was associated with borderline genome-wide statistical significance (reference/effect allele: C/T; effect allele frequency: 0.04, beta (SE): −0.484 (0.091). Conclusion: This study found no genetic variants associated with a lower ovarian reserve after gonadotoxic treatment because the findings of this genome-wide association study were not statistically significant replicated in the replication cohort. Suggestive evidence for the potential importance of 1 variant is briefly discussed, but the lack of statistical significance calls for larger cohort sizes. Because the population of childhood cancer survivors is increasing, large-scale and systematic research is needed to identify genetic variants that could aid predictive risk models of gonadotoxicity as well as fertility preservation options for childhood cancer survivors

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

The Association of Handgrip Strength and Type 2 Diabetes Mellitus in Six Ethnic Groups: An Analysis of the HELIUS Study

<div><p>We investigated whether ethnic differences in handgrip strength, a marker of poor muscle strength and quality, is a potential cause of ethnic disparities in type 2 diabetes mellitus. We included 2086 Dutch, 2216 South Asian Surinamese, 2084 African Surinamese, 1786 Ghanaian, 2223 Turkish and 2199 Moroccan origin participants from the HELIUS study. We analyzed ethnic differences in handgrip strength, and its association with type 2 diabetes mellitus using logistic regression analyses adjusted for socio-demographic factors, body composition and lifestyle factors. Additionally, we investigated whether handgrip strength explained the ethnic differences in type 2 diabetes mellitus. We found that handgrip strength differed significantly across ethnic groups. After full adjustment, we found an inverse association with type 2 diabetes mellitus (OR 0.95; 95% CI 0.92–0.97) that did not differ substantially between ethnic groups, men and among women, and lean and overweight individuals. The association was not affected by the measure used to define type 2 diabetes mellitus, but was attenuated by exclusion of people with known diabetes. The ethnic differences in type 2 diabetes mellitus were not explained by handgrip strength (e.g. the OR for the South Asian Surinamese vs. Dutch changed from 5.03; 3.69–6.68 to 4.87; 3.57–6.65). In conclusion, we found large ethnic differences in handgrip strength and a consistent association of low handgrip strength with prevalent type 2 diabetes mellitus. This suggests that handgrip strength may be investigated as a target for intervention or a marker to identify people at risk of type 2 diabetes mellitus.</p></div

Ethnic differences in type 2 diabetes mellitus, adjusted for known risk factors and handgrip strength.

<p>OR = odds ratio for type 2 diabetes mellitus determined by a self-reported physician diagnosis, medication use, or a fasting glucose level of ≥7.0 mmol/L (53 mmol/mol); CI = confidence interval</p><p>*Adjusted for age, sex, ethnicity, height and education, BMI, waist circumference, waist-hip ratio, percentage body fat, physical activity score, smoking and alcohol use.</p><p>Ethnic differences in type 2 diabetes mellitus, adjusted for known risk factors and handgrip strength.</p

Characteristics of the study population.

<p>SD = standard deviation; BMI = body mass index; BFP = Body fat percentage measured with bioelectrical impedance [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137739#pone.0137739.ref024" target="_blank">24</a>]; WHR = waist-hip ratio; HGS = handgrip strength, the highest measurement of handgrip strength (in Newton)</p><p>* Highest obtained educational degree: ‘No school’ (never been to school or elementary schooling only), ‘Lower education’ (lower vocational schooling or lower secondary schooling), ‘Intermediate education’ (intermediate vocational schooling or intermediate/higher secondary schooling) or ‘Higher education’ (higher vocational schooling or university)</p><p>† Alcohol use based on the first two questions of the Alcohol Use Disorders Identification Test (AUDIT), classified as ‘Abstinate, ‘Moderate drinking’ (on average a maximum of 2 units alcohol a day, never more than 6 units a day) and ‘Excessive drinking’ (on average more than 2 units alcohol a day or more than 6 units a day)</p><p>‡ Physical activity score (min/week) assessed with the Short Questionnaire to Assess Health-Enhancing Physical Activity (SQUASH)</p><p>§Type 2 diabetes mellitus determined by a self-reported physician diagnosis, medication use or a fasting glucose level of ≥7.0 mmol/L (53 mmol/mol).</p><p>Characteristics of the study population.</p

Oncofertility Perspectives for Girls with Cancer

Infertility is a serious early, as well as late, effect of childhood cancer treatment. If addressed in a timely manner at diagnosis, fertility preservation measures can be taken, preferably before the start of cancer treatment. However, pediatric oncologists might remain reluctant to offer counseling on fertility-preservation methods, although infrastructure to freeze ovarian tissue has become available and is currently considered standard care for pre- and postpubertal girls at high risk of gonadal damage. More importantly, risk factors have been identified for cancer treatment-related impairment of gonadal function, and the first successful pregnancies have been reported after autotransplanted ovarian tissue, which has been harvested from children. Additionally, great progress has been made in the field of ex vivo maturation of oocytes in frozen ovarian tissue, which provides opportunities for those at risk of ovarian micrometastasis. Hence, it is time to counsel girls at risk and make every effort to cryopreserve their ovarian tissue, now more than ever before