Does time to theater matter in simple gastroschisis?

Objective: A recent publication has suggested that expedited time to theater in gastroschisis results in higher rates of primary closure and decreases the length of stay (LOS). This study primarily aims to assess the impact of time to first management of neonates with gastroschisis on the LOS. Methods: Neonates admitted between August 2013 and August 2020 with gastroschisis were included. Data were collected retrospectively, and neonates with complex gastroschisis were excluded. Variables including gestation, birth weight, time of first management, primary/delayed closure and use of patch were evaluated as possible confounding variables. The outcome measures were time to full feeds, time on parenteral nutrition (PN) and LOS. Univariate and multivariate linear regression analyses were performed. P<0.05 was regarded as significant. Results: Eighty-six neonates were identified, and 16 were then excluded (eight patients with complex gastroschisis, eight patients with time to first management not documented). The median LOS for those who underwent primary closure was 21 days (interquartile range (IQR) =16-29) and for those who underwent silo placement and delayed closure was 59 days (IQR=44-130). The mean time to first management was 473 min (standard deviation (SD) =146 min), with only 20% of these infants being operated on at less than 6 hours of age. Univariate and multivariate analyses demonstrated no relationship between time to first management and LOS (r2=0.00, p=0.82) but did demonstrate a consistent positive association between time to first feed and LOS and delayed closure, resulting in a longer time to full feeds and a longer time on PN. Conclusions: The time to first management was not associated with a change in LOS in these data. Further prospective evaluation of the impact of reducing the time to first feed on the LOS is recommended. Level of evidence: IV.

Malrotation and Fibroblast Growth Factor Receptor-2-Associated Craniosynostosis: An Underrecognized Association and Management Pathway.

INTRODUCTION: Feeding difficulties are common and multifactorial in children with Fibroblast Growth Factor Receptor-2 (FGFR-2) mutations. Intestinal rotation anomalies have been demonstrated to occur more frequently in animals with FGFR-2 mutations. This study aims to describe intestinal rotation anomalies, surgical management, and feeding assistance in children with FGFR-2 mutations who have undergone upper gastrointestinal (UGI) contrast studies. METHODS: Retrospective data were collected of children born between 1988 and 2020 in a UK quaternary craniofacial unit with FGFR-2-associated craniosynostosis. A consultant survey of approach to malrotation was undertaken. RESULTS: Thirty-four children were included, 17 (50%) female. Six (18%) had UGI symptoms, which included bilious vomiting (n=2), nonbilious vomiting (n=5), retching (n=1), feed intolerance (n=3), and failure to thrive (n=3). Nine had a gastrostomy in situ. Intestinal rotation anomalies occurred in 4 (12%) children, 3 of whom underwent a Ladd procedure and two third required gastrojejunal feeding postoperatively. Consultants agreed that all children with FGFR-2 mutation and UGI symptoms should undergo UGI contrast study, as should children requiring a gastrostomy. DISCUSSION: Intestinal rotation anomalies in children with FGFR-2 mutations occur more frequently than the general population. Prompt consideration of UGI contrast in symptomatic children with FGFR-2 mutation is recommended to enable early surgical management of children with malrotation.

Minimizing Enterostomy Complication in Neonates, Lessons Learnt from Three European Tertiary Centres.

INTRODUCTION: Stoma formation in neonates is often a life-saving procedure across a variety of conditions but is still associated with significant morbidity. Tube stoma technique was originally described for short bowel patients, but in selected cases of neonates this approach could prevent the incidence of stoma-related complications. The aim of the study was to evaluate the safety and utility of tube stomas as an alternative to conventional enterostomy in the neonatal population. MATERIAL AND METHODS: A retrospective multicentre analysis of neonates undergoing emergency laparotomy and tube stoma formation between 2005 and 2017 was performed. Tube stoma complications were analysed. The investigation focused on stricture, skin lesion, enteric fistula and prolapse. RESULTS: Thirty-seven neonates underwent tube stoma fashioning during the study period. Tube-stoma complications were limited to three patients (8.1%), with two children (5.4%) requiring additional stoma surgery during the first 30 days because of an enterocutaneous fistula, and one child (2.7%) for bowel stenosis. CONCLUSIONS: In select neonates, such as those with proximal enteric stomas, the tube stoma avoids some of the commonly encountered complications (prolapse, skin excoriation). Further prospective studies are needed to validate these findings in order for us to recommend this technique as superior.

Management and outcome of paediatric testicular tumours - A 20 year experience.

OBJECTIVE: To report a 20-year experience highlighting management and outcome(s) of paediatric testicular tumours. PATIENTS AND METHODS: All males (< 19 years) with an index diagnosis of testicular tumours during the era(s) 1998-2018 in North West England were identified. Data were collected regarding age at diagnosis, disease stage, surgical operations, tumour biology and outcome(s). RESULTS: A total of 34 male patients were identified. Median age at primary diagnosis was 94 months (range: 0-229 months). Eighteen tumours were benign and 16 malignant. Twenty cases (59%) were recorded in pre pubertal children and 14 (41%) in post pubertal males . In the pre pubertal group (0-11 years) - 15 cases of germ cell tumours (unrelated to germ cell neoplasia in situ - non-GCNIS derived) were recorded, including six yolk sac lesions, eight teratomas and one mixed teratoma/yolk sac tumour (pre-pubertal type). Four males with sex cord-stromal tumours included one juvenile granulosa cell tumour, two Sertoli cell tumours and one Leydig cell tumour. One miscellaneous type tumour notably a papillary cyst adenoma was also identified. In the post pubertal male cohort (>12 years) (n = 14) - four non-GCNIS derived tumours were identified (3 epidermoid cysts and one teratoma), eight cases of germ cell tumour derived from germ cell neoplasia in situ (GCNIS derived) included one teratoma, six with mixed germ cell tumours and one embryonal carcinoma. Two males had sex cord stromal tumours: (Leydig cell and granulosa cell biology). Twenty-eight patients underwent high radical inguinal orchidectomy(s) with one male also requiring retroperitoneal surgery to clear distant locoregional disease and a further single case thoracotomy and metastasectomy. Six patients had lesions suitable for 'testicular sparing' surgery. Six patients had metastatic disease at presentation (18%). Overall study survival was 97%. A single fatality occurred in an adolescent male with a mixed GCT harbouring liver, lung and para-aortic disease who died 48 months after initiating treatment. CONCLUSION: We highlight one of the largest study series of paediatric testicular tumours in the UK and Europe. Non-GCNIS derived tumours accounted for the most common tumour biology (56%). Survival for paediatric testicular tumours is reassuringly generally excellent. Delayed presentation however with a malignant testicular tumour may be associated with poor outcome(s).

A Phase I/II Trial of Carfilzomib, Pegylated Liposomal Doxorubicin, and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma.

PURPOSE: Pegylated liposomal doxorubicin (PLD) combined with bortezomib is an effective salvage regimen for relapsed refractory multiple myeloma (RRMM). Carfilzomib, a second-generation proteasome inhibitor, has clinical efficacy even among bortezomib-refractory patients. PATIENTS AND METHODS: We performed a phase I/II trial of carfilzomib, PLD, and dexamethasone (KDD) with the primary endpoints being safety and efficacy (NCT01246063). Twenty-three patients were enrolled in the phase I portion and the MTD of carfilzomib was determined to be 56 mg/m2 (days 1, 2, 8, 9, 15, and 16) when combined with PLD (30 mg/m2 on day 8) and dexamethasone (20 mg on days 1, 2, 8, 9, 15, and 16). Seventeen additional patients were enrolled in the phase II portion. RESULTS: KDD was determined to be well tolerated with the only common grade 3/4 nonhematologic adverse events of infection. Grade 3/4 hematologic toxicity included lymphopenia (63%), thrombocytopenia (40%), anemia (40%), and neutropenia (28%). In the cohort of patients treated at the MTD, where median prior therapies were 2% and 42% were refractory to bortezomib, the overall response rate was 83% (20/24) with 54% (13/24) having a very good partial response or better. The median progression-free survival was 13.7 months (95% CI, 5.0-21.7). CONCLUSIONS: This trial is the first to report outcomes using a triplet regimen of high-dose carfilzomib. KDD was well tolerated and appears efficacious in RRMM. Additional study is needed to more precisely determine patient outcomes with this regimen and its utility compared with other carfilzomib containing salvage regimens.

An orally active reversible inhibitor of cathepsin S inhibits human trans vivo delayed-type hypersensitivity.

Cathepsin S is a major histocompatibility complex (MHC) class II associated invariant chain (Ii) degrading enzyme expressed in antigen presenting cells such as B cells and dendritic cells. This enzyme is essential for MHC class II associated antigen processing and presentation to CD4(+) T cells. Compound I, a selective, reversible and orally bioavailable, inhibitor of cathepsin S, with molecular IC(50)=9 nM, has been recently described. We have tested the effects of compound I in a trans vivo model of delayed-type hypersensitivity. Human peripheral blood mononuclear cells (7-10 x 10(6)) from tetanus-sensitized donors were co-injected with tetanus toxoid (0.25 Lf) into C57Bl/6 mouse footpads. At 24 h, significant footpad swelling (+0.024+/-0.001 cm) characterized by an influx of mouse neutrophils and monocytes was observed. Injection of peripheral blood mononuclear cells alone caused negligible swelling (0.002+/-0.0002 cm). Anti-human MHC class II (HLA-DR, DP, DQ) antibody (5 mg/kg, i.p.) inhibited the swelling 91+/-7%, thus demonstrating a role of human antigen presenting cells in this model. Compound I (10, 30, and 100 mg/kg, p.o.) inhibited the response with an ED50 of approximately 18 mg/kg. Compound III, a less active analogue (molecular IC50>20 microM) had no effect. Furthermore, pretreatment of peripheral blood mononuclear cells with 10 nM compound II, an irreversible inhibitor (molecular IC50=11 nM) inhibited swelling 87+/-4%. These findings support the role of cathepsin S in human delayed-type hypersensitivity. Inhibition of cathepsin S with compound I may be useful in the treatment of human autoimmune diseases like rheumatoid arthritis and multiple sclerosis.