Preselection of robust radiomic features does not improve outcome modelling in non-small cell lung cancer based on clinical routine FDG-PET imaging.

BACKGROUND: Radiomics is a promising tool for identifying imaging-based biomarkers. Radiomics-based models are often trained on single-institution datasets; however, multi-centre imaging datasets are preferred for external generalizability owing to the influence of inter-institutional scanning differences and acquisition settings. The study aim was to determine the value of preselection of robust radiomic features in routine clinical positron emission tomography (PET) images to predict clinical outcomes in locally advanced non-small cell lung cancer (NSCLC). METHODS: A total of 1404 primary tumour radiomic features were extracted from pre-treatment [18F]fluorodeoxyglucose (FDG)-PET scans of stage IIIA/N2 or IIIB NSCLC patients using a training cohort (n = 79; prospective Swiss multi-centre randomized phase III trial SAKK 16/00; 16 centres) and an internal validation cohort (n = 31; single centre). Robustness studies investigating delineation variation, attenuation correction and motion were performed (intraclass correlation coefficient threshold > 0.9). Two 12-/24-month event-free survival (EFS) and overall survival (OS) logistic regression models were trained using standardized imaging: (1) with robust features alone and (2) with all available features. Models were then validated using fivefold cross-validation, and validation on a separate single-centre dataset. Model performance was assessed using area under the receiver operating characteristic curve (AUC). RESULTS: Robustness studies identified 179 stable features (13%), with 25% stable features for 3D versus 4D acquisition, 31% for attenuation correction and 78% for delineation. Univariable analysis found no significant robust features predicting 12-/24-month EFS and 12-month OS (p value > 0.076). Prognostic models without robust preselection performed well for 12-month EFS in training (AUC = 0.73) and validation (AUC = 0.74). Patient stratification into two risk groups based on 12-month EFS was significant for training (p value = 0.02) and validation cohorts (p value = 0.03). CONCLUSIONS: A PET-based radiomics model using a standardized, multi-centre dataset to predict EFS in locally advanced NSCLC was successfully established and validated with good performance. Prediction models with robust feature preselection were unsuccessful, indicating the need for a standardized imaging protocol.

Comparison of robust to standardized CT radiomics models to predict overall survival for non-small cell lung cancer patients.

BACKGROUND: Radiomics is a promising tool for the identification of new prognostic biomarkers. Radiomic features can be affected by different scanning protocols, often present in retrospective and prospective clinical data. We compared a computed tomography (CT) radiomics model based on a large but highly heterogeneous multicentric image dataset with robust feature pre-selection to a model based on a smaller but standardized image dataset without pre-selection. MATERIALS AND METHODS: Primary tumor radiomics was extracted from pre-treatment CTs of IIIA/N2/IIIB NSCLC patients from a prospective Swiss multicentric randomized trial (npatient  = 124, ninstitution  = 14, SAKK 16/00) and a validation dataset (npatient  = 31, ninstitution  = 1). Four robustness studies investigating inter-observer delineation variation, motion, convolution kernel, and contrast were conducted to identify robust features using an intraclass correlation coefficient threshold >0.9. Two 12-months overall survival (OS) logistic regression models were trained: (a) on the entire multicentric heterogeneous dataset but with robust feature pre-selection (MCR) and (b) on a smaller standardized subset using all features (STD). Both models were validated on the validation dataset acquired with similar reconstruction parameters as the STD dataset. The model performances were compared using the DeLong test. RESULTS: In total, 113 stable features were identified (nshape  = 8, nintensity  = 0, ntexture  = 7, nwavelet  = 98). The convolution kernel had the strongest influence on the feature robustness (<20% stable features). The final models of MCR and STD consisted of one and two features respectively. Both features of the STD model were identified as non-robust. MCR did not show performance significantly different from STD on the validation cohort (AUC [95%CI] = 0.72 [0.48-0.95] and 0.79 [0.63-0.95], p = 0.59). CONCLUSION: Prognostic OS CT radiomics model for NSCLC based on a heterogeneous multicentric imaging dataset with robust feature pre-selection performed equally well as a model on a standardized dataset.

Health-related quality of life in neonates and infants: a conceptual framework.

PURPOSE: With reduced mortality of neonatal conditions, health-related quality of life (HRQOL) has become an important clinical outcome. However, since the meaning of HRQOL in dependent, non-autonomous infants and neonates remains largely undefined, HRQOL measurement and economic evaluation are limited due to the lack of age-specific methodology. The objective was to construct a conceptual framework of neonatal and infant HRQOL (NIHRQOL) which identifies factors relevant to the neonate and infant, their relationship with each other and the caregiving environment. METHODS: Using qualitative methods, a concept was developed based on in-depth analysis of verbatim records of two focus groups (6 caregivers, 6 healthcare providers) and five interviews with caregivers of chronically ill neonates/infants (n = 2), and healthcare professionals of a pediatric tertiary healthcare center (n = 3). Two analysts independently performed thematic analysis using an inductive and contextual approach. RESULTS: The majority of participants regarded NIHRQOL as an individual entity, which was closely related and strongly influenced by caregivers and family. It may be gauged by the perceived degree of effort required to achieve expected normalcy in everyday life for the neonate/infant and its family. The importance of individual HRQOL factors is developmental stage-dependent. CONCLUSION: Neonatal and infant HRQOL is a multidimensional, multilayered and interconnected concept, where the child's needs contribute most directly, and the caregiver's and society's ability to meet those needs characterize the interdependence between the child and its caregiving environment. Developmental stage-specific HRQOL instruments for premature and mature neonates, and infants are warranted to allow for valid HRQOL measurement.

Repeat irradiation for children with supratentorial high-grade glioma.

BACKGROUND: There are very few studies about the role of repeat irradiation (RT2) for children with recurrent supratentorial high-grade glioma (HGG). It was the aim of this study to assess the effectiveness and safety of RT2 in this population. PROCEDURE: This was a retrospective cohort study of 40 children age 18 years and under with recurrent supratentorial HGG who had received at least one course of RT. In-field reirradiation volumes included focal or whole brain RT, with doses ranging from 30 to 54 Gy. The primary endpoint was overall survival (OS) from the first day of RT2. RESULTS: Fourteen patients underwent RT2. The median survival of these patients was 6.5 months. Patients with ≥12 months elapsed time between RT1 and RT2 experienced longer OS than patients who had < 12 months (P = 0.009). There was no difference in OS between patients with or without germline mutations (e.g., Lynch, Li-Fraumeni, or constitutional mismatch-repair deficiency, P = 0.20). Ten patients received RT2 that overlapped with RT1 volumes for locally recurrent disease. Of this group, 80% experienced clinical benefit from in-field RT2, defined as clinical/radiologic response or stable disease. Ninety-three percent completed the prescribed course of RT2, with one patient developing grade 3 radiation necrosis four months after RT2. When compared with 26 patients who were not offered reirradiation, those selected for RT2 had improved median survival from the time of first disease progression (9.4 vs 3.8 months, P = 0.005). CONCLUSIONS: Reirradiation for children with recurrent supratentorial HGG is a safe, effective treatment that provides short-term disease control.

Toxic shock syndrome in paediatric thermal injuries: A case series and systematic literature review.

BACKGROUND: Toxic shock syndrome (TSS) is a rare, but potentially life-threatening complication of thermal injuries in children. The study objective was to systematically review the literature on paediatric TSS after burns or scalds, and describe our experience with this condition in Switzerland. METHODS: All tertiary paediatric healthcare centres managing burns and scalds in Switzerland were inquired. A systematic literature review was performed using EMBASE (1947-2016), MEDLINE (1946-2016), Web of Science (1900-2016) and Google Scholar in October 2016. Data on patient characteristics, symptoms, laboratory parameters, management and outcome were extracted from paper and electronic patient charts. Descriptive statistics were performed. RESULTS: The literature review revealed 25 articles describing 59 cases observed in 10 countries (UK, USA, Hungary, Austria, Sweden, Denmark, Israel, Japan, Spain, Switzerland) from 1985 to 2016. The patient age ranged from 8 months to 8 years at the time point of TSS-diagnosis. The injured total body surface area ranged from <1% to 41%. Forty-one patients suffered from scalds, 6 from burns and in 12 cases the type of injury was not specified. The TSS-diagnosis was made 1-7days after thermal injury. Nineteen children underwent admission to the Intensive Care Unit. Six children died from TSS. In Switzerland, we identified 11 consecutive cases between 07/2001 and 06/2011 (median age 15 months, range 9 months-14 years; 9 male, 2 female; 3 burns, 8 scalds; 7% median total body surface area (TBSA), range 2-30%). Diagnosis of TSS was made on day 5 after injury in median (range 3-34 days). Eight of eleven patients received intensive care. Survivors (10/11) suffered no long-term sequelae besides scars. One 13-month old boy died 3days after a 7%-TBSA scald. CONCLUSIONS: Toxic shock syndrome is an important complication of paediatric burns in Switzerland and several other countries world-wide. Diagnosis and management remain challenging. Awareness among treating clinicians is crucial for a favourable outcome.

Change of Outcomes in Pediatric Intestinal Failure: Use of Time-Series Analysis to Assess the Evolution of an Intestinal Rehabilitation Program.

BACKGROUND: The clinical picture of pediatric intestinal failure has changed over the past 15 years, while effectiveness evolving treatment options remains unclear. This study explored evolution in care and quantified independent effects of new treatment options. STUDY DESIGN: Consecutive patients (n = 196) with neonatal or infantile intestinal failure, born between July 1996 and December 2011, were derived from an intestinal rehabilitation program (IRP) patient registry. Change over time was analyzed using multivariable Box-Jenkins method-based autoregressive integrative moving average models (ARIMA), robust linear regression, and nonparametric trend analysis. Four systematically introduced treatment options (IRP, serial transverse enteroplasty, omega-3 lipid emulsions, and ethanol locks) were evaluated. Analyses were adjusted for patient characteristics and disease severity. The primary outcome was disease-specific mortality from liver failure and sepsis. Secondary outcomes included parenteral nutrition weaning, transplantations, catheter complications, and liver disease. RESULTS: Patient characteristics remained unchanged over time, except for decreasing small bowel length (-0.5%/quarter; 95% CI -0.85, -0.16) and ICU admission time (-0.6 days/quarter; 95% CI -1.03, -0.18). Disease-specific mortality diminished significantly over time (-0.02 deaths/quarter; 95% CI -0.03, -0.01) by IRP and omega-3 lipids introduction (-0.6 deaths/quarter each, 95% CI -1.23, -0.02 and -0.77, -0.45, respectively). Serial transverse enteroplasty and ethanol locks had no significant impact. Parenteral nutrition weaning and transplantations remained unchanged, while catheter sepsis and complication rates decreased by 0.3 episodes/1,000 catheter-days each (95% CI -0.43, -0.2 and -0.45, -0.24, respectively). CONCLUSIONS: Introduction of IRP and omega-3 lipids independently decreased disease-specific mortality. For the first time, time series analysis was applied to evaluate effectiveness of treatment options in intestinal rehabilitation.

De novo epidermal regeneration using human eccrine sweat gland cells: higher competence of secretory over absorptive cells.

In our previous work, we showed that human sweat gland-derived epithelial cells represent an alternative source of keratinocytes to grow a near normal autologous epidermis. The role of subtypes of sweat gland cells in epidermal regeneration and maintenance remained unclear. In this study, we compare the regenerative potential of both secretory and absorptive sweat gland cell subpopulations. We demonstrate the superiority of secretory over absorptive cells in forming a new epidermis on two levels: first, the proliferative and colony-forming efficiencies in vitro are significantly higher for secretory cells (SCs), and second, SCs show a higher frequency of successful epidermis formation as well as an increase in the thickness of the formed epidermis in the in vitro and in vivo functional analyses using a 3D dermo-epidermal skin model. However, the ability of forming functional skin substitutes is not limited to SCs, which supports the hypothesis that multiple subtypes of sweat gland epithelial cells hold regenerative properties, while the existence and exact localization of a keratinocyte stem cell population in the human eccrine sweat gland remain elusive.

Late surgical outcomes among congenital diaphragmatic hernia (CDH) patients: why long-term follow-up with surgeons is recommended.

BACKGROUND: CDH patients experience multi-system morbidity. Despite apparent health, late childhood complications do occur. We reviewed the long-term surgical morbidity of our CDH patients to determine whether protracted clinical surveillance is warranted. METHODS: A single-institution retrospective chart review of all CDH survivors treated from 1999 to 2011 who are followed at our CDH multidisciplinary clinic was performed. Descriptive and statistical analyses were performed to show risk of surgical complications over time. RESULTS: A total of 187 CDH patients were treated with 160 surviving to discharge (86%). Primary repair was performed in 115 (73%), and 42 (27%) underwent patch repair. CDH recurrence occurred in 23 (15%) at a median time of 0.7 (range 0-8.5) years (65% asymptomatic). Seventy percent of recurrences occurred before 2 years and 17% after 4 years. Bowel obstruction occurred in 12 (8%) at a median time of 0.7 (range 0.2-7.2) years post-repair, and chest deformity occurred in 13 (8%) at a median of 5 (range 1.1-6.8) years. For patch repairs, scoliosis occurred in 4 (10%) patients at a median age of 3 (range 0.6-5) years. CONCLUSION: Surgical complications in CDH survivors are common, can occur many years later, and are frequently asymptomatic. Long-term surveillance of CDH patients is recommended for early identification and treatment of complications.

The impact of multi-disciplinary intestinal rehabilitation programs on the outcome of pediatric patients with intestinal failure: a systematic review and meta-analysis.

BACKGROUND: Pediatric intestinal failure (IF) is a complex clinical problem requiring coordinated multi-disciplinary care. Our objective was to review the evidence for the benefit of intestinal rehabilitation programs (IRP) in pediatric IF patients. METHODS: A systematic review was performed on Medline (1950-2012), Pubmed (1966-2012), and Embase (1980-2012) conference proceedings and trial registries. The terms short bowel syndrome, intestinal rehabilitation, intestinal failure, patient care teams, and multi-disciplinary teams were used. Fifteen independent studies were included. Three studies that were cohort studies, including a comparison group, were included in a meta-analysis. RESULTS: Compared to historical controls (n=103), implementation of an IRP (n=130) resulted in a reduction in septic episodes (0.3 vs. 0.5 event/month; p=0.01) and an increase in overall patient survival (22% to 42%). Non-significant improvements were seen in weaning from PN (RR=1.05, 0.88-1.25, p=0.62), incidence of IFALD (RR=0.2, 0-17.25, p=0.48), and relative risk of liver transplantation (3.99, 0.75-21.3, p=0.11). Other outcomes reported included a reduction in calories from parenteral nutrition (100% to 32%-56%), earlier surgical/transplant evaluation, and improved coordination of patient care. CONCLUSION: For pediatric IF patients, IRPs are associated with reduced morbidity and mortality. Standardized clinical practice guidelines are necessary to provide uniform patient care and outcome assessment.

An innovative method of pediatric chest wall reconstruction using Surgisis and swinging rib technique.

PURPOSE: Herein, we describe a new surgical approach for chest wall reconstruction using a native supporting rib and Surgisis. METHODS: A retrospective review of 3 cases from 2 tertiary pediatric health care centers presenting with chest wall defects in the neonatal period was performed. Perioperative data were collected. RESULTS: Two chest wall deformities were diagnosed at birth (Poland syndrome and cleft sternum). One patient was diagnosed prenatally with a mediastinal mass. The first infant had absent ribs 2 through 9. He underwent chest wall reconstruction at 4 weeks of life because of difficulty weaning from ventilation related to paradoxical breathing. The hamartoma of the second asymptomatic patient was removed at 6 weeks. The third patient's V-shaped sternal defect encompassed through the upper two thirds of the sternum and was repaired at 6 months of age with intraoperative transesophageal echocardiogram monitoring. In all cases, Surgisis (collagen matrix) was used as an onlay patch. In 2 cases, a swinging rib acted supportive. Neither patient had intraoperative complications. CONCLUSION: Surgisis is useful in pediatric chest wall reconstruction, particularly in combination with swinging ribs. The capacity for adaptation to the child's growth of this approach is crucial. Short-term safety is shown, but long-term assessment is required.

Five-year outcomes after serial transverse enteroplasty in children with short bowel syndrome.

AIM: The aim of this study is to report 5-year outcomes in patients who have received serial transverse enteroplasty (STEP) using clinical and biochemical assessments of intestinal function. METHODS: Thirty-one STEP procedures have been performed at our institution. Twelve patients who received STEP before January 2005 were analyzed. Clinical and biochemical outcomes were performed pre-STEP and post-STEP on an annual basis. Paired t tests were used to compare post-STEP outcomes to pre-STEP values (P < .05 was significant). MAIN RESULTS: There were 12 patients (3 females; median age, 5.5 months). Serial transverse enteroplasty resulted in mean increase in length of dilated bowel segment of 89% ± 26% and increase in total small bowel length of 46% ± 40%. Two patients received liver-intestinal transplants post-STEP (at 4 and 5 months), and 2 patients died of liver failure at 3 and 8 months. The remaining 8 of 12 patients all show stable intestinal absorptive capacity (data not shown). Of 8 patients, 7 were weaned off parenteral nutrition by 4 years. No patient has required repeat STEP or bowel tapering. Two patients developed staple line leak, and 1 patient developed gastrointestinal bleed from staple line ulcers. CONCLUSION: This report represents the largest series of STEP patients followed up beyond 5 years. Long-term clinical, biochemical, and radiologic outcomes appear to be robust.

Ethanol locks to prevent catheter-related bloodstream infections in parenteral nutrition: a meta-analysis.

OBJECTIVE: Patients with pediatric intestinal failure (IF) depend on parenteral nutrition for growth and survival, but are at risk for complications, such as catheter-related bloodstream infections (CRBSIs). CRBSI prevention is crucial, as sepsis is an important cause of IF-associated liver disease and mortality. We aim to estimate the pooled effectiveness and safety of ethanol locks (ELs) in comparison with heparin locks (HLs) with regard to CRBSI rate and catheter replacements for pediatric IF patients with chronic parenteral nutrition dependence. METHODS: A systematic review without language restriction was performed on Medline (1948-2010), Embase (1980-2010), and conference programs and trial registries up to December 2010. Search terms included "Catheter-Related Infections," "Catheter," "Catheters, Indwelling," "alcohol," "ethanol," and "lock." Two authors identified 4 retrospective studies for the pediatric IF population. Double, independent data extraction using predefined data fields and risk of bias assessment (Newcastle-Ottawa scale) was performed. RESULTS: In comparison with HLs, ELs reduced the CRBSI-rate per 1000 catheter days by 7.67 events and catheter replacements by 5.07. EL therapy decreased the CRBSI rate by 81% and replacements by 72%. One hundred eight to 150 catheter days of EL exposure were necessary to prevent 1 CRBSI and 122 to 689 days of exposure avoided 1 catheter replacement. Adverse events were rare and included thrombotic events. CONCLUSIONS: In pediatric patients with IF, EL is a more effective alternative to HL. Adverse events include thrombotic events.

Costs of prenatal detection of congenital heart disease.

Little information is available about the transportation costs incurred from the missed prenatal diagnosis of congenital heart disease (CHD). The objectives of the present study were to analyze the costs of emergency transportation related to the postnatal diagnosis of major CHD and to perform a cost/benefit analysis of additional training for ultrasound technicians to study the implications of improved prenatal detection rates. The 1-year costs incurred for emergency transportation of pre- and postnatally diagnosed infants with CHD in Northern California and North Western Nevada were calculated and compared. The prenatal detection rate in our cohort (n = 147) was 30.6%. Infants postnatally diagnosed were 16.5 times more likely (p <0.001) to require emergency transport. The associated emergency transportation costs were US$542,143 in total for all patients with CHD. The mean cost per patient was $389.00 versus $5,143.51 for prenatally and postnatally diagnosed infants, respectively (p <0.001). Assuming an improvement in detection rates after 1-day training for ultrasound technicians, the investment in training cost can be recouped in 1 year if the detection rate increased by 2.4% to 33%. Savings of $6,543,476 would occur within 5 years if the detection rate increased to 50%. In conclusion, CHD diagnosed postnatally results in greater costs related to emergency transportation of ill infants. Improving the prenatal detection rates through improved ultrasound technician training could result in considerable cost savings.

Eosinophilic esophagitis and intermediate esophagitis after tracheoesophageal fistula repair: a case series.

BACKGROUND: Eosinophilic esophagitis (EE) is often missed or underdiagnosed in children, particularly in the setting of reflux disease associated with tracheoesophageal fistula (TEF). Intermediate esophagitis (IE) is a recently described condition, which includes characteristics of gastroesophageal reflux disease and EE but does not present with enough eosinophils on biopsy to diagnose EE. Here we present a case series of EE and IE associated with TEF, and their clinical manifestations. METHODS: A retrospective analysis including clinical presentation, endoscopic and pathologic findings, and treatment of 4 patients with EE and 4 patients with IE who presented between 2003 and 2007 was performed. RESULTS: Male dominance was found equally in both groups (75%), and most patients had a personal history of atopy (87.5%). Food allergies were seen mainly in the EE group (75%). The most frequent primary symptoms in both groups were dysphagia for solids (75%) and for liquids (25%). The median age at diagnosis was 9.8 vs 11.2 years in the EE and IE groups, respectively. On endoscopy, both groups had similar findings including furrows (EE, 75%; IE, 66.6%) and white plaques (EE, 50%; IE, 33.3%). In both groups, almost all patients had basal cell hyperplasia on biopsy (EE, 100%; IE, 75%). Degranulated surface eosinophils (50%) and eosinophilic abscess (25%) were found in the EE group only. Elongated rete papillae were more often seen in EE biopsies (50%) compared with IE biopsies (25%). Peripheral serum eosinophilia was seen in all EE patients and in 33% of the IE patients. The only effective treatment with complete resolution of the symptoms was the topical or systemic application of steroids. CONCLUSIONS: The diagnosis of EE and IE is frequently missed or delayed. Eosinophilic esophagitis should be suspected in reflux disease refractory to conventional treatment, particularly in the setting of TEF. Intermediate esophagitis represents an entity that includes findings of gastroesophageal reflux disease and EE. Endoscopic biopsies are diagnostic for both conditions and allow institution of specific medical treatment.

Lung torsion after tracheoesophageal fistula repair: a case report and review of literature.

Lung torsion is a very rare event that has been described after trauma, spontaneously, and post-thoracic surgery, with only 8 cases reported in the pediatric literature. We present the first case report of lung torsion complicating tracheoesophageal fistula repair. The diagnosis was suggested on chest ultrasonogram and Doppler and confirmed by computed tomographic scans. On exploration, a 90 degree rotation of the right middle and lower lobes in a clockwise direction was found. A complete interlobar fissure and an absent inferior pulmonary ligament were identified as predisposing factors. The lobes were untwisted, and lobar fixation was performed to prevent retorsion. Postoperatively, the patient recovered complete lung function, and the patient's chest radiologic and ultrasonographic examination results normalized. Lung torsion is an extremely uncommon event. It causes clinical deterioration in the face of normal arterial blood gases and requires a high index of suspicion for diagnosis. Resection of the twisted lung or lobe may be unnecessary if diagnosis is made early and vascular occlusion is partial. Patients with complete interlobar fissures may benefit from pulmonary lobe fixation as a prophylaxis against occurrence or recurrence of this complication.