Rapid Screening Using Pathomorphologic Interpretation to Detect BRAFV600E Mutation and Microsatellite Instability in Colorectal Cancer.

PURPOSE: Rapid decision-making is essential in precision medicine for initiating molecular targeted therapy for patients with cancer. This study aimed to extract pathomorphologic features that enable the accurate prediction of genetic abnormalities in cancer from hematoxylin and eosin images using deep learning (DL). EXPERIMENTAL DESIGN: A total of 1,657 images (one representative image per patient) of thin formalin-fixed, paraffin-embedded tissue sections from either primary or metastatic tumors with next-generation sequencing-confirmed genetic abnormalities-including BRAFV600E and KRAS mutations, and microsatellite instability high (MSI-H)-that are directly relevant to therapeutic strategies for advanced colorectal cancer were obtained from the nationwide SCRUM-Japan GI-SCREEN project. The images were divided into three groups of 986, 248, and 423 images to create one training and two validation cohorts, respectively. Pathomorphologic feature-prediction DL models were first developed on the basis of pathomorphologic features. Subsequently, gene-prediction DL models were constructed for all possible combinations of pathomorphologic features that enabled the prediction of gene abnormalities based on images filtered by the combination of pathomorphologic feature-prediction models. RESULTS: High accuracies were achieved, with AUCs > 0.90 and 0.80 for 12 and 27, respectively, of 33 analyzed pathomorphologic features, with high AUCs being yielded for both BRAFV600E (0.851 and 0.859) and MSI-H (0.923 and 0.862). CONCLUSIONS: These findings show that novel next-generation pathology methods can predict genetic abnormalities without the need for standard-of-care gene tests, and this novel next-generation pathology method can be applied for colorectal cancer treatment planning in the near future.

Impact of intra- and extrauterine growth on bone mineral density and content in the neonatal period of very-low-birth-weight infants.

BACKGROUND: Very-low-birthweight infants (VLBWIs) are at high risk for suboptimal bone mineral density (BMD) and bone mineral content (BMC). Small-for-gestational-age (SGA) status also causes reduced bone mineralization in full-term infants. However, the impact of intrauterine and postnatal extrauterine growth on BMD and BMC in VLBWIs is inconclusive. METHODS: We retrospectively investigated n=68 VLBWIs, comprising 45 appropriate-for-gestational-age (AGA) and 23 SGA infants who underwent lumbar spine dual-energy X-ray absorptiometry at term-equivalent age. RESULTS: BMD and BMC did not differ between AGA and SGA VLBWIs. Subgroup analyses of infants with birthweight<1000 g vs 1000-1500 g, and GA<27 weeks vs ≥ 27 weeks also showed no differences in BMD and BMC between AGA and SGA infants. In contrast, infants with extrauterine growth restriction (EUGR) showed significantly lower values than those without (BMD: 0.124 ± 0.023 vs 0.141 ± 0.032 g/cm(2), P=0.02; BMC: 0.80 ± 0.26 vs 0.94 ± 0.23 g, P=0.04). There were no differences between AGA and SGA infants with EUGR. However, in the AGA cohort, infants with EUGR showed significantly lower values than those without (BMD: 0.121 ± 0.022; 0.141 ± 0.03 g/cm(2), P=0.02; BMC: 0.73 ± 0.23 vs 0.94 ± 0.23 g, P=0.005). Multiple regression analyses showed GA, weight and head circumference at birth, and weight percentile at term correlated with term BMD. Conversely, only weight percentile at term significantly correlated with term BMC. CONCLUSION: EUGR, rather than IUGR, is a risk factor for reduced BMD and BMC in the neonatal period in VLBWIs.

Nucleated red blood cell counts: an early predictor of brain injury and 2-year outcome in neonates with hypoxic-ischemic encephalopathy in the era of cooling-based treatment.

BACKGROUND: Raised nucleated red blood cell (NRBC) counts in neonates may indicate in utero hypoxia and brain damage. OBJECTIVE: The study aimed to examine the use of NRBC counts as a predictor of brain injury and neurodevelopmental outcomes in neonates with hypoxic-ischemic encephalopathy (HIE) treated under current cooling-based strategy. METHODS: Forty-three neonates with asphyxia between 2004 and 2010 were retrospectively investigated. Twenty neonates with moderate/severe HIE underwent hypothermia (HT), and 23 with mild HIE were treated in normothermia (NT). Neonates were divided into groups according to the presence of cerebral parenchymal lesions on magnetic resonance imaging (MRI) at 2 weeks after birth. All patients were followed-up neurologically for ⩾ 24 months. NRBC counts during the first 3 days were compared between groups. RESULTS: Eleven HT (HT-N) and 21 NT (NT-N) neonates had normal MRI, and 9 HT (HT-L) and 2 NT (NT-L) neonates had parenchymal lesions. NRBC counts, both absolute and /100 white blood cells (WBC) counts, during the first 3 days in HT-L and NT-L were significantly higher than those in HT-N and NT-N, particularly within 6 hours after birth (HT-N: 502 [0-3060]/mm(3) vs HT-L: 2765 [496-6192]; 0 [0-3417] vs NT-L: 4384 [3978-4789], median [range]). Neonates with /100 white blood cells ⩾ 6/mm(3) and absolute NRBC counts ⩾ 1324/mm(3) within 6 hours of birth had high risks of abnormal MRIs and 2-year outcomes. CONCLUSIONS: NRBC counts can predict brain injury and neurological outcomes in cooled and non-cooled asphyxiated neonates.

Predictors of neurological outcome in cooled neonates.

BACKGROUND: We define clinical predictors of neurological outcome in neonates with hypoxic-ischemic encephalopathy undergoing hypothermia therapy. METHODS: Twenty-one neonates who underwent selective head cooling between 2004 and 2010 and were followed neurologically for ≥ 24 months were investigated retrospectively. Patients were divided according to the neurological outcome at 2 years of age into group A (n = 11), patients with normal neurological function, and group B (n = 10), patients with neurological disabilities (n = 9) or those who died (n = 1). Predictors were determined by χ(2) and Mann-Whitney U-tests, anova, Spearman rank correlations and receiver-operator curves. RESULTS: Group B showed higher average blood lactate levels during the first day, particularly at 24 h of life; lower day-3 cerebral blood flow resistance index; higher maximum dobutamine dose used; higher rate of thiamylal sodium used; more severe background electroencephalogram suppression during the first week (group A: 11/11 cases ≤ grade 3; group B: 7/9 cases at grade 4-5) and higher rate of cerebral lesions on magnetic resonance imaging in the second week (group A: 1/11 case; group B: 9/10 cases) than group A. The most useful predictor of poor prognosis was cerebral parenchymal lesions on magnetic resonance imaging with 90%, 90% and 90% of sensitivity, specificity and accuracy, followed by week-1 background electroencephalogram ≥ grade 4 with 70%, 100% and 85% and day-3 cerebral blood flow resistance index < 0.46 with 71%, 88% and 80%, respectively. CONCLUSIONS: Prediction of post-cooling neurological outcome could be improved substantially by evaluating multiple factors.

Low-dose vasopressin infusion therapy for refractory hypotension in ELBW infants.

BACKGROUND: Severe hypotension in infants, especially in preterm infants, is associated with poor neurological outcome and high mortality. In adults, low-dose vasopressin (arginine vasopressin: AVP) infusion therapy has been effective for treating hypotension that is refractory to vasopressors and inotropes. METHODS: The effects of AVP infusion therapy for refractory hypotension were retrospectively evaluated in extremely low-birthweight infants. Between January 2002 and November 2005, 22 infants with refractory hypotension treated with low-dose AVP infusion were reviewed. The average birthweight was 658 g (+/-142 g), and the average gestational age was 24.9 weeks (+/-1.4). The changes in blood pressure, urinary output, and other parameters in response to AVP therapy were analyzed in all the infants. RESULTS: After AVP infusion, systolic blood pressure increased from 30 mmHg to 43 mmHg (P < 0.0001), and the diastolic pressure increased from 15 mmHg to 24 mmHg (P < 0.0001). The urine output dramatically increased from 1.5 mL/kg per h to 4.0 mL/kg per h (P < 0.0001). AVP infusion, however, was not effective in four of the 22 patients (18%). The sodium concentration in the serum decreased mildly after administration. In six patients the serum sodium concentration decreased below 130 mEq/L. Severe mitral regurgitation was observed in two patients. Three infants showed a transient decrease in the platelet count during AVP infusion. CONCLUSIONS: Low-dose AVP therapy should be considered as rescue therapy when high-dose catecholamine therapy and/or steroid administration do not produce sufficient increase in the blood pressure. Further investigations are required to prove the efficacy and safety of AVP infusion therapy in preterm infants.

Iopamidol enema treatment for meconium obstruction of prematurity in extremely low-birth weight infants: a safe and effective method.

BACKGROUND/PURPOSE: Meconium obstruction of prematurity (MO) often occurs in extremely low-birth weight (ELBW) infants, and its treatment is quite a challenge for neonatologists. We attempted to establish a method of primary treatment for MO of prematurity in ELBW infants. METHODS: An iopamidol enema with 50 cm H(2)O static pressure was performed as the primary treatment. This procedure is safe and effective and we recommend this as the first treatment for MO in ELBW infants. RESULTS: The procedure was performed 50 times in 23 infants and no complications occurred. Out of 23 patients, 20 (88%) improved, but the other 3 did not. In the failure group, the procedure was performed on a significantly later date and the mortality rate was higher (12.5 vs. 67%). CONCLUSIONS: This procedure is safe and effective. We recommend this as the first treatment for MO in ELBW infants.