A Role for NF-κB in Organ Specific Cancer and Cancer Stem Cells

Kaltschmidt C, Banz-Jansen C, Benhidjeb T, et al. A Role for NF-κB in Organ Specific Cancer and Cancer Stem Cells. Cancers. 2019;11(5): 655.Cancer stem cells (CSCs) account for tumor initiation, invasiveness, metastasis, and recurrence in a broad range of human cancers. Although being a key player in cancer development and progression by stimulating proliferation and metastasis and preventing apoptosis, the role of the transcription factor NF-κB in cancer stem cells is still underestimated. In the present review, we will evaluate the role of NF-κB in CSCs of glioblastoma multiforme, ovarian cancer, multiple myeloma, lung cancer, colon cancer, prostate cancer, as well as cancer of the bone. Next to summarizing current knowledge regarding the presence and contribution of CSCs to the respective types of cancer, we will emphasize NF-κB-mediated signaling pathways directly involved in maintaining characteristics of cancer stem cells associated to tumor progression. Here, we will also focus on the status of NF-κB-activity predominantly in CSC populations and the tumor mass. Genetic alterations leading to NF-κB activity in glioblastoma, ependymoma, and multiple myeloma will be discussed

Irinotecan and temozolomide in combination with dasatinib and rapamycin versus irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma (RIST-rNB-2011): a multicentre, open-label, randomised, controlled, phase 2 trial

Background Neuroblastoma is the most common extracranial solid tumour in children. Relapsed or refractory neuroblastoma is associated with a poor outcome. We assessed the combination of irinotecan–temozolomide and dasatinib–rapamycin (RIST) in patients with relapsed or refractory neuroblastoma. Methods The multicentre, open-label, randomised, controlled, phase 2, RIST-rNB-2011 trial recruited from 40 paediatric oncology centres in Germany and Austria. Patients aged 1–25 years with high-risk relapsed (defined as recurrence of all stage IV and MYCN amplification stages, after response to treatment) or refractory (progressive disease during primary treatment) neuroblastoma, with Lansky and Karnofsky performance status at least 50%, were assigned (1:1) to RIST (RIST group) or irinotecan–temozolomide (control group) by block randomisation, stratified by MYCN status. We compared RIST (oral rapamycin [loading 3 mg/m2 on day 1, maintenance 1 mg/m2 on days 2–4] and oral dasatinib [2 mg/kg per day] for 4 days with 3 days off, followed by intravenous irinotecan [50 mg/m2 per day] and oral temozolomide [150 mg/m2 per day] for 5 days with 2 days off; one course each of rapamycin–dasatinib and irinotecan–temozolomide for four cycles over 8 weeks, then two courses of rapamycin–dasatinib followed by one course of irinotecan–temozolomide for 12 weeks) with irinotecan–temozolomide alone (with identical dosing as experimental group). The primary endpoint of progression-free survival was analysed in all eligible patients who received at least one course of therapy. The safety population consisted of all patients who received at least one course of therapy and had at least one post-baseline safety assessment. This trial is registered at ClinicalTrials.gov, NCT01467986, and is closed to accrual. Findings Between Aug 26, 2013, and Sept 21, 2020, 129 patients were randomly assigned to the RIST group (n=63) or control group (n=66). Median age was 5·4 years (IQR 3·7–8·1). 124 patients (78 [63%] male and 46 [37%] female) were included in the efficacy analysis. At a median follow-up of 72 months (IQR 31–88), the median progression-free survival was 11 months (95% CI 7–17) in the RIST group and 5 months (2–8) in the control group (hazard ratio 0·62, one-sided 90% CI 0·81; p=0·019). Median progression-free survival in patients with amplified MYCN (n=48) was 6 months (95% CI 4–24) in the RIST group versus 2 months (2–5) in the control group (HR 0·45 [95% CI 0·24-0·84], p=0·012); median progression-free survival in patients without amplified MYCN (n=76) was 14 months (95% CI 9–7) in the RIST group versus 8 months (4–15) in the control group (HR 0·84 [95% CI 0·51–1·38], p=0·49). The most common grade 3 or worse adverse events were neutropenia (54 [81%] of 67 patients given RIST vs 49 [82%] of 60 patients given control), thrombocytopenia (45 [67%] vs 41 [68%]), and anaemia (39 [58%] vs 38 [63%]). Nine serious treatment-related adverse events were reported (five patients given control and four patients given RIST). There were no treatment-related deaths in the control group and one in the RIST group (multiorgan failure). Interpretation RIST-rNB-2011 demonstrated that targeting of MYCN-amplified relapsed or refractory neuroblastoma with a pathway-directed metronomic combination of a multkinase inhibitor and an mTOR inhibitor can improve progression-free survival and overall survival. This exclusive efficacy in MYCN-amplified, relapsed neuroblastoma warrants further investigation in the first-line setting

A novel homozygous mutation in the Glycerol-3-Phosphate Dehydrogenase 1 gene combined with a heterozygous mutation in the Glucokinase Regulator gene associated with hyperglycaemia, hypertriglyceridaemia and non-alcoholic fatty liver in a 17 year old woman

Avrami G, Drasdo M, Neuber S, Jorch N, Hamelmann E. A novel homozygous mutation in the Glycerol-3-Phosphate Dehydrogenase 1 gene combined with a heterozygous mutation in the Glucokinase Regulator gene associated with hyperglycaemia, hypertriglyceridaemia and non-alcoholic fatty liver in a 17 year old woman. Hormone Research in Paediatrics . 2022;95(SUPPL 2):181

Predictors of transient congenital primary hypothyroidism: data from the German registry for congenital hypothyroidism (AQUAPE “HypoDok”)

Neonatal screening for congenital primary hypothyroidism (CH) may not distinguish between transient (TCH) and permanent dysfunction (PCH), causing potential overtreatment and concerns in affected families. To specify the indication for interruption of therapy, we analysed the German registry 'HypoDok' for infants with CH, which oversees 1625 patients from 49 participating centres in Germany and Austria from 1997 until today. A total of 357 patients with a thyroid gland in loco typico were identified and retrospectively grouped according to cessation (TCH, n = 24) or continuation (PCH, n = 333) of L-thyroxine (L-

Long-Term Occupational Consequences for Families of Children With Type 1 Diabetes: The Mothers Take the Burden

Dehn-Hindenberg A, Saßmann H, Berndt V, et al. Long-Term Occupational Consequences for Families of Children With Type 1 Diabetes: The Mothers Take the Burden. Diabetes Care. 2021: dc210740.OBJECTIVE: To investigate the occupational and financial consequences for parents following the onset of type 1 diabetes in their child.; RESEARCH DESIGN AND METHODS: A questionnaire assessing occupational and financial situations before and in the first year after the onset of diabetes was distributed to all families with a child ≤14 years of age at diagnosis with a diabetes duration of at least 12 months in nine German pediatric diabetes centers.; RESULTS: Data of 1,144 children (mean age at diagnosis 6.7 [3.6] years; 46.5% female) and their families were obtained. Mothers' occupational status reflected in paid working hours was significantly reduced in the first year after their child's diabetes diagnosis (P < 0.001). Overall, 15.1% of mothers stopped working, and 11.5% reduced working hours. Mothers of preschool children were particularly affected. Fathers' working status hardly changed (P = 0.75). Nearly half of the families (46.4%) reported moderate to severe financial losses. Compared with an earlier similar study in 2003, significant negative occupational consequences for mothers and financial burden on families remained unchanged in 2018 (P = 0.59 and 0.31, respectively).; CONCLUSIONS: Mothers of young children with newly diagnosed diabetes experienced negative consequences in their occupational situation. This inequality for mothers can have long-term negative consequences for their mental health and future economic situation. There is an urgent need for action to reduce the burden on families and to provide professional, social, and regulatory support, especially for mothers of young children with diabetes. © 2021 by the American Diabetes Association

Diabetes care in pediatric refugees from Africa or Middle East - experiences from Germany and Austria based on real-world data from the DPV registry.

Prinz N, Konrad K, Brack C, et al. Diabetes care in pediatric refugees from Africa or Middle East - experiences from Germany and Austria based on real-world data from the DPV registry. European journal of endocrinology. 2019;181(1):31-38.OBJECTIVE: With increasing migration to Europe, diabetes diagnosis and treatment of refugees became challenging. To describe current experience with pediatric refugees in Germany and Austria.; DESIGN AND METHODS: 43,137 patients (<21 years) with type 1 diabetes from the diabetes patient follow-up registry (DPV) were studied, and divided by refugee status into patients born in Middle East (n=365) or Africa (n=175) and native patients (child and parents born in Germany/Austria; G/A: n=42,597). Groups were compared using multivariable regression adjusted for age, sex and diabetes duration (SAS 9.4). In refugees the first year after arrival was studied, and for native children the most recent year of care.; RESULTS: After adjustment, HbA1c was highest in refugees (ME vs. AFR vs. G/A: 72.3±1.0 vs. 75.0±1.4 vs. 66.0±0.1 mmol/mol, each p<0.001) and microalbuminuria (9.9 vs 13.6 vs. 6.5%, each p<0.05) was more prevalent. African children experienced severe hypoglycemia (17.8±4.3 vs. 25.4±8.7 vs. 11.5±0.3 per 100 patient years) significantly more often, whereas hypoglycemia with coma (5.1±1.1 vs. 4.1±1.6 vs. 2.6±0.1 per 100 patient years) and retinopathy (2.1 vs. n/a vs. 0.2%) were significantly more common in children from Middle East compared to natives. Insulin pumps were used in a markedly larger proportion of native patients (7.4 vs. 13.2 vs. 43.0%, each p<0.001).; CONCLUSIONS: A relevant number of pediatric refugees with type 1 diabetes are treated in German/Austrian diabetes clinics. Refugee children, parents and caregivers are faced with several problems in diabetes therapy and outcome that should be addressed more intensively by pediatric diabetes teams

Understanding Daily, Emotional, and Physical Burdens and Needs of Parents Caring for Children with Type 1 Diabetes

Aims. To investigate (1) daily, emotional, and physical caregiving burdens in parents of children with type 1 diabetes, (2) the sociodemographic and clinical predictors of three burdens, and (3) support measures that parents wish to receive. Methods. The study was a multicenter cross-sectional survey conducted in nine German pediatric diabetes centers. A questionnaire assessing three types of burdens and wishes for support was distributed to parents with a child with type 1 diabetes visiting one of the pediatric centers for a routine check-up. Results. Data from 1,107 parents (83% mothers) were analyzed. Parents reported significantly higher emotional burdens compared to daily and physical burdens (p<0.0001). Mothers felt more burdened than fathers did. Parents of younger children reported higher daily and physical burdens compared to the parents of older children, and similarly, parents of technology users reported higher daily and physical burdens compared to the parents of nontechnology users. However, emotional burdens did not differ in both comparisons. Other demographic factors (i.e., parent’s age, migration status, and single-parent family status) predicted high levels of daily or physical burdens, but only HbA1c level and the parent’s gender (mother) predicted a high emotional burden. Independent of the level of burden, 78% of parents wanted additional diabetes training. Conclusion. Despite parents reporting high emotional burdens in connection with diabetes care, HbA1c and the gender of the reporting parent were the only risk factors. As the child gets older, parents’ daily and physical distress decrease but not the emotional burden. Diabetes training including regularly offered booster sessions as well as low-threshold interventions for mental health issues and practical self-care skills is recommended to provide continuous support for parents

The long-term impact of in vitro drug sensitivity on risk stratification and treatment outcome in acute lymphoblastic leukemia of childhood (CoALL 06-97)

Background In a study of childhood acute lymphoblastic leukemia (CoALL 06-97 study), the in vitro sensitivityof the patients' cells to prednisolone, vincristine and asparaginase was introduced as anew additional risk parameter for treatment stratification. In parallel in vivo treatment responsewas assessed by determining the presence and extent of minimal residual disease in a subset ofpatients (n=224). Here we report the long-term impact of in vitro sensitivity-based risk stratificationaccording to survival and compare the results of in vitro sensitivity with in vivo response. Design and Methods Patients with a sensitive in vitro profile were treated with a reduced intensity protocol (n=167)whereas patients defined as low risk according to conventional parameters but with a resistantin vitro profile were given intensified therapy (n=47). Results At a median follow-up of 6.8 years event-free survival was 0.80±0.03 for patients with a sensitiveprofile, 0.73±0.03 for those with an intermediate profile and 0.67±0.08 for those with aresistant profile (P=0.015). Overall, the treatment results of the cases stratified according to invitro sensitivity were similar to those of the historical control group stratified based on conventionalrisk factors. Minimal residual disease at the end of induction was a strong predictor ofoutcome in B-precursor and T-cell acute lymphoblastic leukemia. There was no correlationbetween in vitro and in vivo treatment response in B-precursor leukemia (Spearman's r=0.13;P=0.15) in contrast to T-cell acute lymphoblastic leukemia (Spearman's r=0.63; P<0.001) Conclusions A moderate reduction in treatment intensity for patients with a sensitive in vitro profile waspossible without jeopardizing treatment outcome. However, in vitro drug testing was affectedby a decrease in risk predictive power over time and was not correlated with in vivo assessmentof minimal residual disease in B-precursor acute lymphoblastic leukemia. It was, therefore,abandoned in favor of the assessment of in vivo response in subsequent CoALL trials