Genital Malformations in Children With VACTERL - Has Time Come to Include "G" in the Acronym?

BACKGROUND: Genital malformations are frequently diagnosed in patients with VACTERL, but are currently not included in the acronym. This study aimed to analyze the frequency of genital anomalies in patients with esophageal atresia (EA) and/or anorectal malformation (ARM), with a subgroup analysis of children fulfilling the VACTERL criteria. METHOD: This was a cross-sectional retrospective analysis of two prospectively collected registries of patients operated on for ARM and EA between 2012 and 2022 at a specialized national center. Children were screened routinely for malformations according to the VACTERL acronym. RESULTS: A total of 174 children were included in the study. VACTERL was diagnosed in 60 children (34%), while 114 children (66%) were defined as non-VACTERL. Genital malformations were diagnosed in 38% (23/60) of the children with VACTERL, and in 11% (13/114) of the children without VACTERL (p < 0.001). The presence of genital malformations correlated linearly with the number of diagnosed component features (CFs). In boys with VACTERL, the most common genital malformation was undescended testes present in 10/27 (21%) compared to 1/71 (1%) in non-VACTERL boys (p < 0.001). Müllerian duct anomalies were found in 26% of girls with VACTERL vs. 7% in non-VACTERL girls (p < 0.05). CONCLUSION: There was a higher frequency of genital malformations in patients with VACTERL emphasizing the importance of genital assessment for these patients. We propose VACTERL-G as an extension of the current acronym aiming to reduce the risk of long-term morbidity due to delayed diagnosis of reproductive anomalies.

Orchidopexy for undescended testis-rate and predictors of re-ascent.

PURPOSE: This study aimed to investigate the rate of re-ascent requiring re-operation after primary orchidopexy and to investigate eventual differences between the inguinal and scrotal approach as well as other potential predictors for re-ascent. METHODS: A retrospective cohort study of children treated for undescended testis (UDT) with orchidopexy between 2018 and 2022 was conducted. The primary outcome was re-ascent requiring re-operation, and the secondary outcome was atrophy rate. Independent variables were age, underlying conditions, side, surgical approach, operation time, bilaterality, congenital/ascended UDT, presence of scrotal hypoplasia, presence of a patent processus vaginalis, division of external oblique, and suture of the testis. Univariate and logistic regression were used to evaluate differences between groups and risk for re-ascent. RESULTS: A total of 662 testes in 554 patients were included. Re-operation occurred in 6% (7% with inguinal approach, 3% with scrotal approach, p = 0.04). Re-operation was associated with younger age, congenital UDT, and inguinal approach, but neither of these variables remained significant in multivariate analyses. Atrophy occurred in one testis. CONCLUSION: The rate of re-ascent was 6% and the atrophy rate was 0.15%. A larger study may find predictors for re-ascent but with very low absolute risk. The lower rate of re-ascent with the scrotal approach is probably due to selection bias.

National survey of physicians in Swedish child health centres finds insecurity and unawareness regarding management of undescended testicles.

AIM: To investigate underlying factors for previously reported shortcomings in child health centres' (CHC) referral process of boys with undescended testicles. METHODS: A total of 386 physicians working at Swedish CHCs were surveyed regarding their knowledge about undescended testicles and their clinical management. Multivariate regression analyses were performed to identify risk factors of non-adherence to guidelines and self-reported lack of clinical skills. RESULTS: The overall knowledge of the health benefits of undescended testicle surgery was high (89%), while two-thirds were unaware of surgery being recommended <1 year of age. One-fifth of respondents had never received guidance on examination techniques. Male gender (adjusted odds ratio [aOR] 0.51, 95% confidence interval [95% CI] 0.31-0.86), education in paediatrics (aOR 0.37, 95% CI 0.18-0.76) and more experience (aOR 0.02, 95% CI 0.01-0.09) significantly decreased the risk of unfamiliarity with examinations. More experience decreased the risk of stating the incorrect indications for undescended testicle surgery (aOR 0.17, 95% CI 0.03-0.95) and finding examinations difficult (aOR 0.22, 95% CI 0.07-0.72). Medical education outside Nordic countries was a risk factor for unawareness of guidelines (aOR 2.06, 95% CI 1.21-3.51). CONCLUSION: The knowledge and confidence level of the study population varied widely. The results indicate a need for further theoretical and practical education among Swedish CHC physicians.

Mapping of referral patterns for undescended testes - Risk factors for referral of children with normal testes.

BACKGROUND: Accurate referral of boys with suspected undescended testes (UDT) is of importance to preserve fertility and reduce risk of future testicular cancer. While late referral is well studied, there is less knowledge about incorrect referrals, hence, referral of boys with normal testes. OBJECTIVE: To evaluate the proportion of UDT referrals that did not lead to surgery or follow-up, and to assess risk factors for referral of boys with normal testes. STUDY DESIGN: All UDT referrals to a tertiary center of pediatric surgery during 2019-2020 were retrospectively assessed. Only children with suspected UDT in the referral (not suspected retractile testicles) were included. Primary outcome was normal testes at examination by a pediatric urologist. Independent variables were age, season, region of residence, referring care unit, referrer's educational level, referrer's findings, and ultrasound result. Risk factors for not needing surgery/follow-up were assessed with logistic regression and presented as adjusted odds ratios with a 95% confidence interval (aOR, [95% CI]). RESULTS: A total of 378 out of 740 included boys (51.1%) had normal testes. Patients >4 years (aOR 0,53, 95% CI [0,30-0,94]), referrals from pediatric clinics (aOR 0.27, 95% CI [0.14-0.51]) or surgery clinics (aOR 0.06, 95% CI [0.01-0.38]) had lower risk of normal testes. Boys referred during spring (aOR 1.80, 95% CI [1.06-3.05]), by a non-specialist physician (aOR 1.58, 95% CI [1.01-2.48]) or referrer's description of bilateral UDT (aOR 2.34, 95% CI [1.58-3.45]), or retractile testes (aOR 6.99, 95% CI [3.61-13.55]) had higher risk of not needing surgery/follow-up. None of the referred boys that had normal testes had been re-admitted at the end of this study (October 2022). DISCUSSION: Over 50% of boys referred for UDT had normal testes. This is higher or equal to previous reports. Efforts to reduce this rate should in our setting probably be directed towards well-child centers and training in examination of testicles. The main limitation of this study is the retrospective design and the rather short follow-up time, which however should have very modest effect on the main findings. CONCLUSION: Over 50% of boys referred for UDT have normal testes. A national survey regarding the management and examination of boys testicles has been launched and directed at well-child centers to further evaluate the findings of the current study.

Brachytherapy for Pediatric Patients at Gustave Roussy Cancer Campus: A Model of International Cooperation for Highly Specialized Treatments.

PURPOSE: Childhood cancer is rare, and treatment is frequently associated with long-term morbidity. Disparities in survival and long-term side effects encourage the establishment of networks to increase access to complex organ-conservative strategies, such as brachytherapy. We report our experience of an international cooperation model in childhood cancers. METHODS AND MATERIALS: We examined the outcome of all children referred to our center from national or international networks to be treated according to a multimodal organ-conservative approach, including brachytherapy. RESULTS: We identified 305 patients whose median age at diagnosis was 2.2 years (range, 1.4 months to 17.2 years). Among these patients, 99 (32.4%) were treated between 2015 and 2020; 172 (56.4%) were referred from national centers; and 133 (43.6%) were international patients from 31 countries (mainly Europe). Also, 263 patients were referred for primary treatment and 42 patients were referred for salvage treatment. Genitourinary tumors were the most frequent sites, with 56.4% bladder/prostate rhabdomyosarcoma and 28.5% gynecologic tumors. In addition to brachytherapy, local treatment consisted of partial tumor resection in 207 patients (67.9%), and 39 patients (13%) had additional external radiation therapy. Median follow-up was 58 months (range, 1 month to 48 years), 93 months for national patients, and 37 months for international patients (P < .0001). Five-year local control, disease-free survival, and overall survival rates were 90.8% (95% confidence interval [CI], 87.3%-94.4%), 84.4% (95% CI, 80.1%-89.0%), and 93.3% (95% CI, 90.1%-96.5%), respectively. Patients referred for salvage treatment had poorer disease-free survival (P < .01). Implementation of image guided pulse-dose-rate brachytherapy was associated with better local control among patients with rhabdomyosarcoma referred for primary treatment (hazard ratio, 9.72; 95% CI, 1.24-71.0). At last follow-up, 16.7% patients had long-term severe treatment-related complications, and 2 patients (0.7%) had developed second malignancy. CONCLUSIONS: This retrospective series shows the feasibility of a multinational referral network for brachytherapy allowing high patient numbers in rare pediatric cancers. High local control probability and acceptable late severe complication probability could be achieved despite very challenging situations. This cooperation model could serve as a basis for generating international reference networks for high-tech radiation such as brachytherapy to increase treatment care opportunities and cure probability.

Sex and age differences in lower urinary tract dysfunction in healthy children.

AIM: Information about healthy children's urinary tract symptoms is scarce but would be helpful in children with congenital urinary tract conditions. The aim of this study was to develop and evaluate a Lower Urinary Tract Dysfunction (LUTD) questionnaire. METHODS: A 15-item questionnaire based on definitions by the International Children's Continence Society (ICCS) about urinary tract function, was given to children 4-15 years old with no gastrointestinal or urinary tract conditions. The study was approved ethically. RESULTS: The response rate was 82% (311/377), 50% (n = 155) were girls. Children were of the age groups 3.5-7 years (n = 136), 8-12 years (n = 127), and 13-15 years (n = 48). More girls than boys reported urinary tract infections (20% vs 3%, p < 0.001), while prevalences of incontinence and enuresis were equivalent in both sexes. In the youngest age group, enuresis was the most frequently reported symptom (11%), then daytime incontinence (10%). The older children more frequently reported previous urinary tract infections (12% and 17% in respective groups) and daytime incontinence (9% and 6%, respectively). CONCLUSION: A LUTD questionnaire is developed and evaluated within this study. Daytime urinary incontinence is the overall most common lower urinary tract symptom and girls report infections more frequently than boys.

Patient-Reported Outcomes of Bladder and Bowel Control in Children with Spina Bifida.

BACKGROUND: The primary aim was to describe patient-reported morbidity from neurogenic bladder and bowel dysfunction in a cohort of children with spina bifida. The secondary aim was to describe the overall surgical burden in these children. METHODS: Children with meningocele or myelomeningocele, born between 2000-2016, and followed by a tertiary spina bifida center were evaluated in a cross-sectional cohort study using data from charts and a prospective national follow-up program. RESULTS: In the group of 62 patients, clean intermittent catheterization (CIC) was used by 47 (76%) of the patients, and anticholinergic treatment was used by 36 (58%). More than one third of the patients reported inadequate results with daily urinary leakage. Laxatives and enema were used regularly by 45 (73%) and 39 (63%) patients, respectively. Inadequate results were reported by seven (11%) patients. One or more urogenital or gastrointestinal operations had been performed in 26 (42%) patients, with a total of 109 procedures overall. CONCLUSIONS: Despite substantial bowel and bladder management, a significant portion of children suffered from inadequate results concerning bladder and bowel control. Many surgeries were performed in a defined group of the children. Prospective, long-term studies can evaluate if more aggressive medical and/or surgical management could increase bowel and bladder control.

Resolution of hydronephrosis after pyeloplasty in children.

BACKGROUND: There is still a lack of knowledge regarding the natural course of resolution of hydronephrosis after pyeloplasty, and no consensus exists on how resolution of hydronephrosis is defined or when resolution is expected to occur. OBJECTIVE: To determine when resolution of hydronephrosis occurs following pyeloplasty, by type of obstruction and by surgical approach. METHODS: This retrospective study included 125 children age <15 years treated with pyeloplasty and followed for two years with repeated ultrasound and MAG3 scan. Children with single kidneys, bilateral disease, and without hydronephrosis were excluded. Children with re-interventions were excluded in the evaluation of hydronephrosis but not in terms of success rate. Outcomes time to resolution of hydronephrosis (Anterior-Posterior diameter (APD) <10 mm or >50% reduction of APD) and 2-year success rate. Exposure was surgical approach and type of obstruction (intrinsic/extrinsic). Survival analysis was performed, adjusting for age, gender, year, laterality, preoperative renal function on MAG3, calyces dilatation and APD in the multivariable analysis. RESULTS: At 12 months and 24 months follow-up, 90% and 93% had reached resolution, respectively. All children with persistent dilatation had improved drainage and stable or improved function on MAG3. There was no difference in time to resolution of hydronephrosis between open versus robotic-assisted laparoscopic surgery (adjusted HR 0.90, [0.54-1.52], p = 0.70), nor between different types of obstruction (aHR 0.84 [0.53-1.34], p = 0.47). Eight children had re-intervention, all identified within 3 months after primary surgery, and four had a postoperative drop on MAG3, giving a total success rate of 91% (121/135). DISCUSSION: The vast majority of cases resolve and do so within 12 months from surgery. Since the improvement of hydronephrosis seems small between the first and second year after surgery, the value of follow-up beyond 12 months could be questioned. Based on the present study and previous literature we would recommend that children with persisting dilatation should continue their follow-up with ultrasound beyond 12 months. Children with complete resolution of their hydronephrosis at 12 months do not likely benefit from further follow-up. The same follow-up protocol should be applied, regardless of whether the obstruction is intrinsic or extrinsic in nature, or the surgery is performed with open or robotic-assisted approach. Overall, the definition of resolution of hydronephrosis varies in the literature and have impact on the results and may compromise comparisons. CONCLUSION: Surgical approach or type of obstruction does not seem to affect time to resolution of hydronephrosis after pyeloplasty in children. Follow-up with ultrasound beyond 12 months does not seem to benefit children with complete resolution.

[Diagnosis and treatment of phimosis delegated to trained assistant nurses]. / Diagnostik och behandling av fimos hos pojkar kan delegeras.

Phimosis in boys is a common condition. In the majority of cases it is physiological without symptoms. Symptomatic phimosis can often be treated successfully with local steroid cream - only a minority of patients need surgery.  This study concludes that diagnosis, information to patients and guardians, initiation and follow-up of local steroid treatment can successfully, and safely, be delegated to trained assistant nurses.

Health-related quality of life and scar satisfaction in a cohort of children operated on for sacrococcygeal teratoma.

AIM: The aims of this study were to evaluate health-related quality of life (HRQoL) in children with sacrococcygeal teratoma and to explore the effect of the scar on physical, emotional and behavioral aspects. METHODS: A cohort of children operated on for sacrococcygeal teratoma between 2000 and 2013 at Lund University Hospital, Sweden, and their parents were interviewed. HRQoL was evaluated with PedsQL, and scar satisfaction was estimated through Patient Observer Scar Assessment Score (POSA). RESULTS: All eligible children (n = 17) were included (100% response rate). Median age was 7.3 years (range 3.5-16.0). Mean total PedsQL score was 92.3 (range 72.0 to 99.0). Patients with comorbidity scored lower (87.5) than those without (95.0) (p < 0.05). Pain during sitting down was reported by two (20%) patients, and itching was reported by another two patients (20%) aged > 8 years. No children reported that they avoided situations due to the scar, and most (80% of children and 90% of parents) reported absent or only mild negative emotions when considering the scar. CONCLUSION: Children with sacrococcygeal teratoma had a good overall HRQoL, but comorbidity reduced the outcome. A few children reported scar-related impact on physical, behavioral and emotional aspects.

Urinary tract anomalies and urinary tract dysfunction in children with Hirschsprung disease-Is follow-up indicated?

BACKGROUND/PURPOSE: Urinary tract function in children with Hirschsprung disease (HD) is rarely considered. AIM: to evaluate the prevalence of urinary tract anomalies and dysfunction in children with HD compared to controls. METHODS: This was an observational cross sectional case-control study. Children with HD who underwent transanal endorectal pull-through technique (TERPT) from 2005 to 2017 were invited to participate. Ultrasound of the urinary tract was performed postoperatively. Children >4 years were asked to answer a urinary tract function questionnaire. Controls were age-matched healthy children. Ethical approval was obtained. RESULTS: Seventy two children with HD and TERPT were included. Ultrasound was performed in 58 children (83%) post-TERPT. Ten anomalies were diagnosed in six children (10%). Structural anomalies included abnormal kidney size (7%), renal agenesis (2%), prominent calyces (2%) and renal pelvis anomaly (25). Probable acquired anomalies included hydronephrosis (2%), hydroureter (2%) and parenchymal damage (2%). One child had a prior nephrectomy owing to a Wilms' tumor. All 37 children >4 years (27 boys and 10 girls), median aged 8 years (range 4-12), answered the questionnaire as did 284 healthy controls (144 boys and 140 girls). Boys with HD reported a higher frequency of enuresis: 65% versus 9% (p = 0.001) and urinary tract infections: 18% versus 3% (p = 0.012). Girls with HD reported enuresis more frequently (60%) than healthy girls (7%) (p = 0.001). Children with HD with constipation reported enuresis more frequently (p = 0.038). CONCLUSIONS: Urinary tract anomalies and dysfunction deserve attention in the follow-up of children with HD. We suggest screening for urinary tract anomalies and urinary tract symptoms in follow-up of children with HD. TYPE OF STUDY: Treatment study. LEVEL: III.

Patient-Derived Xenograft Models Reveal Intratumor Heterogeneity and Temporal Stability in Neuroblastoma.

Patient-derived xenografts (PDX) and the Avatar, a single PDX mirroring an individual patient, are emerging tools in preclinical cancer research. However, the consequences of intratumor heterogeneity for PDX modeling of biomarkers, target identification, and treatment decisions remain underexplored. In this study, we undertook serial passaging and comprehensive molecular analysis of neuroblastoma orthotopic PDXs, which revealed strong intrinsic genetic, transcriptional, and phenotypic stability for more than 2 years. The PDXs showed preserved neuroblastoma-associated gene signatures that correlated with poor clinical outcome in a large cohort of patients with neuroblastoma. Furthermore, we captured spatial intratumor heterogeneity using ten PDXs from a single high-risk patient tumor. We observed diverse growth rates, transcriptional, proteomic, and phosphoproteomic profiles. PDX-derived transcriptional profiles were associated with diverse clinical characteristics in patients with high-risk neuroblastoma. These data suggest that high-risk neuroblastoma contains elements of both temporal stability and spatial intratumor heterogeneity, the latter of which complicates clinical translation of personalized PDX-Avatar studies into preclinical cancer research.Significance: These findings underpin the complexity of PDX modeling as a means to advance translational applications against neuroblastoma. Cancer Res; 78(20); 5958-69. ©2018 AACR.

Four evolutionary trajectories underlie genetic intratumoral variation in childhood cancer.

A major challenge to personalized oncology is that driver mutations vary among cancer cells inhabiting the same tumor. Whether this reflects principally disparate patterns of Darwinian evolution in different tumor regions has remained unexplored1-5. We mapped the prevalence of genetically distinct clones over 250 regions in 54 childhood cancers. This showed that primary tumors can simultaneously follow up to four evolutionary trajectories over different anatomic areas. The most common pattern consists of subclones with very few mutations confined to a single tumor region. The second most common is a stable coexistence, over vast areas, of clones characterized by changes in chromosome numbers. This is contrasted by a third, less frequent, pattern where a clone with driver mutations or structural chromosome rearrangements emerges through a clonal sweep to dominate an anatomical region. The fourth and rarest pattern is the local emergence of a myriad of clones with TP53 inactivation. Death from disease was limited to tumors exhibiting the two last, most dynamic patterns.

Long-Term Outcome of Sacrococcygeal Teratoma: A Controlled Cohort Study of Urinary Tract and Bowel Dysfunction and Predictors of Poor Outcome.

OBJECTIVE: To evaluate urinary tract and bowel function in children with sacrococcygeal teratoma, compare the findings with healthy children, and assess predictors of poor outcome. STUDY DESIGN: This was a controlled cohort study of all patients operated for sacrococcygeal teratoma at a tertiary pediatric surgery center, 2000-2013. Urinary and bowel function were compared with healthy control patients matched for age and sex. Perioperative and histopathologic risk factors were analyzed. RESULTS: In total, 17 patients with sacrococcygeal teratoma and 85 healthy control patients were included in the study. Patients with sacrococcygeal teratoma more often were reported to have uncontrolled voiding (12% vs 0%, P < .01), difficulty in bladder emptying (24% vs 0%, P < .001), and pyelonephritis (18% vs 1%, P < .05). Constipation was more common in patients with sacrococcygeal teratoma (47 % vs 14%, P < .05), but the overall bowel function score was equal in the 2 groups. Children with large tumors and immature histology were more likely to have a dysfunctional outcome (P < .05). CONCLUSIONS: Uncontrolled voiding, difficulty in bladder emptying, pyelonephritis, and constipation were more common in patients with sacrococcygeal teratoma than in healthy children. Dysfunctional outcome was more prevalent in children with large and immature teratomas.

Diagnosis, Symptoms, and Outcomes of Hirschsprung's Disease from the Perspective of Gender.

Background/Aim. Hirschsprung's disease (HD) has a skewed gender distribution, with a female to male ratio of 1 : 4. This study aims to examine differences between boys and girls with HD regarding preoperative features and postoperative treatment and outcome. Method. The first part of the study was conducted as a retrospective review of all HD patients who underwent transanal endorectal pull-through (TERPT). Pre-, peri-, immediate post-, and first-year postoperative data were collected. The second part was conducted as an observational cross-sectional study by comparing bowel function scores (BFS) determined by structured interviews of patients 4 years old and older. Results. Included were 39 boys and 12 girls. Of these, 25 boys and 9 girls were older than 4 years and participated in the BFS interview. Boys had a higher frequency of hospitalizations during the first postoperative year compared to girls (n = 20 and n = 2, p < 0.05). At long-term follow-up, more boys reported abnormal frequency of defecation, 16 compared to 2 (p < 0.05). There was no difference between genders in terms of preoperative symptoms and overall bowel function later. Conclusion. Boys with HD had more hospitalizations and a higher rate of abnormal frequency of defecation than girls with HD.

Dilations of anastomotic strictures over time after repair of esophageal atresia.

AIM OF THE STUDY: Anastomotic strictures commonly occur in patients undergoing surgery for esophageal atresia (EA). The primary aim of this study was to determine the age distribution of dilation procedures for anastomotic strictures over the patient's childhood after reconstruction of EA. The secondary aim was to evaluate the effect of postoperative proton pump inhibitors (PPIs) on the frequency of dilations. METHODS: This observational study was conducted at a single tertiary center of pediatric surgery. The times that dilations of strictures were performed were assessed during three study periods: 1983-1995, 2001-2009, and 2010-2014. PPIs were not used during the first period, and then, respectively, for 3 and 12 months postoperatively. The indications for dilation were signs of obstruction and/or radiological signs of stricture. PRIMARY RESULTS: A total of 131 children underwent esophageal reconstruction, and of those, 60 (46%) required at least 1 dilation procedure for strictures. There were no differences in the frequencies of dilation procedures between the three study periods (28/66, 18/32 and 14/33, respectively; P = 0.42). The overall median number of dilations per patient was 3 (range 1-21) with no differences between the study periods. The differences between ages at which the first dilation was performed during each study period were significant, as follows: 7, 2, and 8 months, respectively (P = 0.03). Fiftyone percent of all dilation procedures were performed during the first year of life, 16% during the second year, and 33% during years 2-15. Four children (2%) underwent >12 dilations. CONCLUSION: The first year of life was the time of greatest need for dilation of AS after reconstruction of EA; however, dilations were also performed several years later. PPIs did not affect the frequency of dilations during the first year of life.

Prolonged Use of Proton Pump Inhibitors as Stricture Prophylaxis in Infants with Reconstructed Esophageal Atresia.

Introduction Proton pump inhibitors (PPIs) are used as prophylaxis, guarding against anastomotic stricture (AS) in the aftermath of reconstructed esophageal atresia (EA). The incidence of stricture formation was studied in this setting, comparing outcomes of 3- and 12-month PPI prophylactic regimens. Patients and Methods Patient characteristics (gestational age, birth weight, prevalence of chromosomal aberrations, and other malformations), as well as rates of survival, AS formation, and required balloon dilation, were recorded in the following therapeutic subsets: (1) all infants undergoing primary surgical anastomosis for EA in years 2010-2014 and given postoperative PPI prophylaxis for 12 months and (2) all infants similarly treated for EA in years 2001-2009 but given postoperative PPI prophylaxis for 3 months only. Duration of follow-up was 1 year in each group. Results Patient characteristics and survival rates in 12-month (n = 33) and in 3-month (n = 30) treatment groups did not differ significantly. The prevalence of AS was 42%/43% in each group (12 months, 14/33; 3 months, 13/30; p = 1). Median number of dilations required was 3 (range, 1-9) per patient in each group (p = 0.69). Median age at initial dilation was 163 days and 63 days in 12- and 3-month groups, respectively (p = 0.04). Conclusion Development of AS in the first year after reconstruction of EA was not reduced by prolonged PPI prophylaxis (12 vs. 3 months), but initial balloon dilation procedures were performed later in infants who were treated longer.

SERMs have substance-specific effects on bone, and these effects are mediated via ERαAF-1 in female mice.

The bone-sparing effect of estrogens is mediated primarily via estrogen receptor (ER)α, which stimulates gene transcription through activation function (AF)-1 and AF-2. The role of ERαAF-1 for the estradiol (E2) effects is tissue specific. The selective ER modulators (SERMs) raloxifene (Ral), lasofoxifene (Las), and bazedoxifene (Bza) can be used to treat postmenopausal osteoporosis. They all reduce the risk for vertebral fractures, whereas Las and partly Bza, but not Ral, reduce the risk for nonvertebral fractures. Here, we have compared the tissue specificity of Ral, Las, and Bza and evaluated the role of ERαAF-1 for the effects of these SERMs, with an emphasis on bone parameters. We treated ovariectomized (OVX) wild-type (WT) mice and OVX mice lacking ERαAF-1 (ERαAF-1(0)) with E2, Ral, Las, or Bza. All three SERMs increased trabecular bone mass in the axial skeleton. In the appendicular skeleton, only Las increased the trabecular bone volume/tissue volume and trabecular number, whereas both Ral and Las increased the cortical bone thickness and strength. However, Ral also increased cortical porosity. The three SERMs had only a minor effect on uterine weight. Notably, all evaluated effects of these SERMs were absent in ovx ERαAF-1(0) mice. In conclusion, all SERMs had similar effects on axial bone mass. However, the SERMs had slightly different effects on the appendicular skeleton since only Las increased the trabecular bone mass and only Ral increased the cortical porosity. Importantly, all SERM effects require a functional ERαAF-1 in female mice. These results could lead to development of more specific treatments for osteoporosis.

Neuroblastoma patient-derived orthotopic xenografts reflect the microenvironmental hallmarks of aggressive patient tumours.

Treatment of high-risk childhood neuroblastoma is a clinical challenge which has been hampered by a lack of reliable neuroblastoma mouse models for preclinical drug testing. We have previously established invasive and metastasising patient-derived orthotopic xenografts (PDXs) from high-risk neuroblastomas that retained the genotypes and phenotypes of patient tumours. Given the important role of the tumour microenvironment in tumour progression, metastasis, and treatment responses, here we analysed the tumour microenvironment of five neuroblastoma PDXs in detail. The PDXs resembled their parent tumours and retained important stromal hallmarks of aggressive lesions including rich blood and lymphatic vascularisation, pericyte coverage, high numbers of cancer-associated fibroblasts, tumour-associated macrophages, and extracellular matrix components. Patient-derived tumour endothelial cells occasionally formed blood vessels in PDXs; however, tumour stroma was, overall, of murine origin. Lymphoid cells and lymphatic endothelial cells were found in athymic nude mice but not in NSG mice; thus, the choice of mouse strain dictates tumour microenvironmental components. The murine tumour microenvironment of orthotopic neuroblastoma PDXs reflects important hallmarks of aggressive and metastatic clinical neuroblastomas. Neuroblastoma PDXs are clinically relevant models for preclinical drug testing.

Sacrococcygeal teratoma: A population-based study of incidence and prenatal prognostic factors.

BACKGROUND: Sacrococcygeal teratoma (SCT) is a rare congenital tumor associated with high rates of perinatal mortality and morbidity. This study evaluated the incidence, prenatal detection rate, and early predictors of a complicated outcome following diagnosis of SCT. METHODS: We retrospectively identified all fetuses and newborns diagnosed with SCT in southern Sweden from 2000 to 2013. Prenatal sonograms, charts, and pathology reports were reviewed and analyzed. Each case of SCT was defined as complicated or uncomplicated based on the postnatal outcome. All cases with a fatal outcome or that required cardiac resuscitation during birth or surgery were classified as complicated. RESULTS: The overall incidence of SCT was 1:13,982 (19 children in a cohort of 265,658 live births). A prenatal diagnosis was made in 74% of cases, there were no stillbirths or intrauterine deaths, and the overall mortality rate was 11%. Four cases of SCT (21%) were classified as complicated, and these cases had a significantly larger tumor size at gestational week 20 (P=0.048), had a significantly higher tumor growth rate (P=0.003), and were more often associated with polyhydramnios (P=0.01), and mainly solid/mixed morphology (P=0.001). CONCLUSIONS: The incidence of SCT in southern Sweden was higher than those reported in most previous studies; however, the associated mortality rate was relatively low. Fetuses with large tumors, rapidly growing tumors, and polyhydramnios were more likely to experience a complicated outcome during the postnatal period.