A pilocytic astrocytoma with novel ATG16L1::NTRK2 fusion responsive to larotrectinib: a case report with genomic and functional analysis.

The outcome of pilocytic astrocytoma (PA) depends heavily on the success of surgery. In cases where surgery alone is not curative, genetic analysis can be used to identify treatment targets for precision medicine. Here, we report a pediatric PA case that underwent incomplete surgical resection due to the tumor location. Clinical routine analyses demonstrated that the tumor did not carry any BRAF alteration. After postoperative surveillance, according to the low-grade glioma (LGG) protocol, recurrent tumor progressions resulted in multiple chemotherapy regimens. Screening formalin-fixed paraffin-embedded tumor material using an open-ended RNA sequencing panel revealed a novel in-frame autophagy related 16 like 1-neurotrophic receptor tyrosine kinase 2 (ATG16L1::NTRK2) fusion gene. The NTRK2 rearrangement was subsequently confirmed by fluorescent in situ hybridization on tumor tissue sections. Functional validation was performed by in vitro transient transfection of HEK293 cells and showed the ATG16L1::TRKB fusion protein to activate both the mitogen-activated protein kinase pathway and the phosphoinositide 3-kinase oncogenic pathways through increased phosphorylation of extracellular signal-regulated kinase, AKT, and S6. As a result of the identification of the NTRK fusion, the patient was enrolled in a phase I/II clinical trial of the highly selective TRK inhibitor larotrectinib. The patient responded well without significant side effects, and 8 months after the start of treatment, the contrast-enhancing tumor lesions were no longer detectable, consistent with a complete response as per Response Assessment in Neuro-Oncology (RANO) criteria. Presently, after 22 months of treatment, the patient's complete remission is sustained. Our findings highlight the importance of screening for other oncogenic drivers in BRAF-negative LGGs since rare fusion genes may serve as targets for precision oncology therapy.

Hyperthermic intraperitoneal chemotherapy (HIPEC) as another treatment modality for desmoplastic round cell tumour patients: first paediatric experience from UK.

We present the first young paediatric patient with desmoplastic small round cell tumour (DSRCT) treated in UK with hyperthermic intraperitoneal chemotherapy (HIPEC). A 7-year-old girl was diagnosed with abdominal DSRCT with peritoneal and liver metastases. After six cycles of chemotherapy she obtained a partial response, including almost complete resolution of the two liver metastases. It was decided to pursue cytoreductive surgery (CRS) combined with HIPEC, a procedure commonly performed in adults, but seldom in a child. The surgery was macroscopically complete and the HIPEC uncomplicated. She continued treatment without delays, including whole abdomino-pelvic radiotherapy and maintenance chemotherapy (cyclophosphamide/vinorelbine for 12 months). She is currently in complete remission 4 months after end of treatment and 26 months after diagnosis. HIPEC was made possible by successful collaboration between multiple teams. CRS-HIPEC proved to be safe and feasible and could be offered to other children with diagnoses of peritoneal malignancies across the UK.

Use of angiotensin II receptor blockers and the risk of acute pancreatitis: a nested case-control study.

BACKGROUND: There is no specific treatment against acute pancreatitis (AP). A protective effect by angiotensin II receptor blockers (ARB) on AP has been suggested experimentally, but clinical evidence is scarce. METHODS: We conducted a population-based case-control study using The Health Improvement Network in the United Kingdom, comprising about 167,000 hypertensive patients in the study period 1996-2005. In multivariate logistic regression analysis, odds ratios were calculated with 95% confidence intervals (CI). Adjustments included sex, age, calendar year, body mass index, tobacco smoking, alcohol, general practitioner visits per year, and various antihypertensive medications with regard to exposure to ARB, and risk of AP. RESULTS: Among 633,281 person-years at risk, 265 new cases of AP were identified. Current users of ARB had a 37% statistically non-significant reduced risk of developing AP as compared to non-users (OR 0.63, 95% CI 0.38-1.02). No clear association was found between use of other antihypertensive drugs and risk of AP. CONCLUSION: Our study adds some support to previous experimental findings. Use of ARB might be associated with a reduced risk of AP. More research is needed to elucidate the potential role of ARB in the development of AP in the clinical setting.

Intestinal failure after necrotising enterocolitis: incidence and risk factors in a Swedish population-based longitudinal study.

BACKGROUND AND OBJECTIVE: Paediatric intestinal failure (IF) is a disease entity characterised by gut insufficiency often related to short bowel syndrome. It is commonly caused by surgical removal of a large section of the small intestine in association with necrotising enterocolitis (NEC), which usually affects premature infants. This study investigated the incidence and risk of IF in preterm infants with or without NEC. DESIGN: A matched cohort study to investigate the incidence and risk factors for IF in a population-based setting in Sweden from 1987 to 2009 using the Swedish Patient Register. PARTICIPANTS: Infants with a diagnosis of NEC (n=720) were matched for gestational age and year of birth with reference individuals without NEC (n=3656). The study cohort was censored at death, IF or at end of follow-up (2 years of age). We calculated HRs with 95%CIs for IF using Cox regression, adjusting for pertinent perinatal factors. RESULTS: IF was 15 times more common in the infants with NEC compared with the reference infants (HR=7.2, with 95% CI 3.7 to 14.0). Other risk factors for IF were small for gestational age, extreme preterm birth and abdominal surgery. Neonatal mortality in infants with NEC decreased from 20.6% in 1987-1993 to 10.4% in 2007-2009. CONCLUSION: IF was more common in the infants with NEC but was also linked to extreme preterm birth, a history of abdominal surgery and small for gestational age. IF was more common at the end of the study period, indicating that it increases when more preterm infants with NEC survive the neonatal period.