Intestinal Perforation

The nSOFA components and scoring paradigms were modeled after the adult SOFA.^{12 (link),13 (link)} The nSOFA uses only objective and available clinical standard-of-care data to provide an operational definition of organ dysfunction that facilitates mortality risk stratification among VLBW infants with unequivocal LOI (bacteremia or intestinal perforation).^{14 (link)} The nSOFA uses categorical scores (total score range from 0 [best] to 15 [worst]) to objectively describe dynamic changes in (1) receipt of mechanical ventilation and oxygen to maintain a physiologic peripheral saturation (score range, 0-8); (2) inotropic or vasoactive drug support, including the use of corticosteroids for presumed adrenal insufficiency or catecholamine-resistant shock (score range, 0-4); and (3) the presence and severity of thrombocytopenia based on the most recent platelet measure (score range, 0-3) (Table 1; eAppendix in the Supplement).
The nSOFA score was validated in an independent, single-center cohort of infants with LOI.^{14 (link)} In this multicenter, retrospective study to determine the generalizability of the nSOFA, each center identified qualifying infants and calculated the nSOFA score at 9 discrete time points, including and surrounding the LOI episode, using a web-based calculator and data from the electronic health records. The time the blood sample was drawn from the patient represented time 0 (T0). The time points that preceded (T minus 48 hours [T-48], T-24, T-12, and T-6) and followed (T plus 6 hours [T6], T12, T24, and T48) the infection evaluation were based on the progression of organ dysfunction in previous studies.^{14 (link),15 (link)}

All patients over the age of 18 with colon cancer in UICC stages I and II who underwent a resection of the tumor at the Medical University of Innsbruck, Department of Visceral, Transplant, and Thoracic Surgery between 2007 and 2016 were evaluated for this retrospective study. Patients with rectal cancer were excluded because of the rather complex multimodal treatment (e.g., neoadjuvant radiochemotherapy, ostomy creation, and reversal) and the higher risk of local recurrence, to create a patient collective as homogenous as possible. Patients who received adjuvant chemotherapy (recommended by the interdisciplinary tumor-board despite UICC stages I or II due to additional risk factors such as bowel perforation, high grading 3/4, positive vascular-, lymphangio-, or perineural-status) were excluded. Further exclusion criteria were endoscopic resection, R1- or R2- resection, and mucinous carcinoma. Figure 1 shows the flowchart of included and excluded patients.Fig. 1

Flowchart of the included and excluded patients. VTT, Visceral, Transplant, and Thoracic Surgery; UICC, Union internationale contre le cancer; CRC, colorectal cancer; DF, disease free

The surveillance time was 5 years, according to the follow-up protocol at the Medical University of Innsbruck, Department of Visceral, Transplant, and Thoracic Surgery, based on the recommendations of NCCN (National Comprehensive Cancer Network), ESMO (European Society for Medical Oncology), and ACO ASSO (Austrian Society for Surgical Oncology) (Table 1).Table 1

The surveillance protocol at the Medical University of Innsbruck, Department of Visceral, Transplant, and Thoracic Surgery based on the recommendations of NCCN (National Comprehensive Cancer Network), ESMO (European Society for Medical Oncology), and ACO ASSO (Austrian Society for Surgical Oncology)

	1st year				2nd year				3rd year				4th year				5th year
Months	3	6	9	12	15	18	21	24	27	30	33	36	39	42	45	48	51	54	57	60
CEA	x	x	x	x	x	x	x	x	-	x	-	x	-	x	-	x	-	x	-	x
Clinical examination	x	x	x	x	x	x	x	x	-	x	-	x	-	x	-	x	-	x	-	x
Colonoscopy	(xa)	-	-	x	-	-	-	-	-	-	-	-	-	-	-	Xb	-	-	-	-
CT scan	-	-	-	x	-	-	-	x	-	-	-	x	-	-	-	x	-	-	-	x

In case of curative treatment of distant metastases, CT scans are repeated in 6-monthly intervals during the first 2 years, and the surveillance period is prolonged for further 5 years

CEA carcinoembryonic antigen, CT computed tomography

^aIf not performed preoperatively

^bIf normal findings are to be repeated regularly according to national screening protocols

Data were collected from medical reports, operative reports, anesthesia protocols, and histopathological findings, by using electronic health records (Klinisches Informationssystem, KIS, Powerchart, Cerner). Demographic variables were age and gender. Clinical variables included the physical status classification system ASA (American Society of Anesthesiologists), surgical resection, histopathology evaluation, and the TNM classification. Outcome variables included surveillance drop-out, 5-year disease-free survival (DFS), and 5-year overall survival (OS). Recurrence was defined as clear radiological or endoscopic suspicion with or without histological proof. Tumor recurrence was divided into local recurrence and metastases (e.g., liver or lung metastases). Additionally, metachronous colorectal cancer was documented. Finally, the therapeutic approach of recurrence was analyzed.
Statistical analyses were performed with the software SPSS (IBM SPSS Statistics 20; International Business Machines Corporation; Armonk, New York, USA). The Kaplan–Meier method was used to calculate the DFS and OS.
The local ethics committee approved the study (Votum 1437/2021).

In this nested case-control study, we selected 24 preterm infants of less than 30 weeks gestation born at Texas Children’s Hospital-Pavilion for Women (Houston, TX, United States of America). Subjects were enrolled between September 2015 and August 2019. Fecal samples were collected by the subject’s bedside nurse into sterile fecal collection containers, stored at 4°C, and transferred within 48 h into aliquots of 0.5 mL by research study personnel and stored at −80°C until analysis.
Subjects were selected from two larger observational prospective cohort studies involving preterm infants. Both studies collected serial stool samples to be used for microbiome analysis. Studies were approved by the Institutional Review Board at Baylor College of Medicine (protocols H-36828 and H-43075). All study procedures were in accordance with the ethical standards of Baylor College of Medicine. Written parental informed consent was provided for each infant enrolled in each study. Eligible study participants from Study 1^{66 (link)} included premature infants born at < 1500 g with no barriers to enteral milk feedings enrolled within the first 72 h of life. Exclusion criteria included anomalies or birth defects that precluded enteral feeding, severe perinatal hypoxia, or < 50% projected survival based on the National Institute of Child Health and Human Development Neonatal Research Network Extremely Preterm Birth Outcome Data calculator. For Study 2, eligible study participants included premature infants born between 24 and 34 weeks GA, birth weight ≤ 1250 g, and enrolled within the first 72 h of life. Infants were excluded for > 1250 g birth weight, low likelihood of survival, major congenital anomalies or clinically significant congenital heart disease, intestinal perforation, Bell’s Stage 2 or greater NEC, early transfer to another institution, or failure to achieve full enteral feedings by 28 days of life.
Cholestasis was defined by a serum conjugated bilirubin level ≥ 1 mg/dL and > 20% of the total bilirubin at any point during hospital admission. Elevated conjugated bilirubin represents impaired bile formation or flow.^{9 (link)} All neonates were screened within the first 48 h of life and again as clinically indicated (e.g., concerns for sepsis or new-onset jaundice). Each cholestatic infant was matched to a control (non-cholestatic) infant with emphasis on matching by birthweight, sex, delivery by Cesarean section, antibiotic exposure, % of feeds mother’s milk, and multiple fecal samples obtained. Anthropometrics were obtained at birth and approximately 36 weeks PMA by a trained research nurse. Growth velocities (weight, length, and head circumference) were calculated from birth to approximately 36 weeks PMA. The timing of patient fecal sampling, serum conjugated bilirubin measurements, antibiotic use, and UDCA treatment (if applicable) are shown in Supplementary Figures S1 and S2.