A Role for Tumor Volume Assessment in Resectable Esophageal Cancer.

BACKGROUND: Esophageal cancer has a poor prognosis, and many patients undergoing surgery have a low chance of cure. Imaging studies suggest that tumor volume is prognostic. The study aimed to evaluate pathological tumor volume (PTV) as a prognostic variable in esophageal cancer. METHODS: This single-center cohort study included 283 patients who underwent esophageal cancer resections between 2000 and 2012. PTVs were obtained from pathological measurements using a validated volume formula. The prognostic value of PTV was analyzed using multivariable regression models, adjusting for age, tumor grade, tumor (T) stage, nodal stage, lymphovascular invasion, resection margin, resection type, and chemotherapy response, which provided hazard ratios (HRs) with 95 % confidence intervals (CIs). Primary outcomes were time to death and time to recurrence. Secondary outcomes were margin involvement and lymph node positivity. Correlation analysis was performed between imaging and PTVs. RESULTS: On unadjusted analysis, increasing PTV was associated with worse overall mortality (HR 2.30, 95 % CI 1.41-3.73) and disease recurrence (HR 1.87, 95 % CI 1.14-3.07). Adjusted analysis demonstrated worse overall mortality with increasing PTV but reached significance in only one subgroup (HR 1.70, 95 % CI 1.09-2.38). PTV was an independent predictor of margin involvement (OR 2.28, 95 % CI 1.02-5.13) and lymph node-positive status (OR 2.77, 95 % CI 1.23-6.28). Correlation analyses demonstrated significant positive correlation between computed tomography (CT) software and formula tumor volumes (r = 0.927, p < 0.0001), CT and positron emission tomography tumor volumes (r = 0.547, p < 0.0001), and CT and PTVs (r = 0.310, p < 0.001). CONCLUSIONS: Tumor volume may predict survival, margin status, and lymph node positivity after surgery for esophageal cancer.

Single-cell guided prenatal derivation of primary fetal epithelial organoids from human amniotic and tracheal fluids.

Isolation of tissue-specific fetal stem cells and derivation of primary organoids is limited to samples obtained from termination of pregnancies, hampering prenatal investigation of fetal development and congenital diseases. Therefore, new patient-specific in vitro models are needed. To this aim, isolation and expansion of fetal stem cells during pregnancy, without the need for tissue samples or reprogramming, would be advantageous. Amniotic fluid (AF) is a source of cells from multiple developing organs. Using single-cell analysis, we characterized the cellular identities present in human AF. We identified and isolated viable epithelial stem/progenitor cells of fetal gastrointestinal, renal and pulmonary origin. Upon culture, these cells formed clonal epithelial organoids, manifesting small intestine, kidney tubule and lung identity. AF organoids exhibit transcriptomic, protein expression and functional features of their tissue of origin. With relevance for prenatal disease modeling, we derived lung organoids from AF and tracheal fluid cells of congenital diaphragmatic hernia fetuses, recapitulating some features of the disease. AF organoids are derived in a timeline compatible with prenatal intervention, potentially allowing investigation of therapeutic tools and regenerative medicine strategies personalized to the fetus at clinically relevant developmental stages.

Bioengineering human intestinal mucosal grafts using patient-derived organoids, fibroblasts and scaffolds.

Tissue engineering is an interdisciplinary field that combines stem cells and matrices to form functional constructs that can be used to repair damaged tissues or regenerate whole organs. Tissue stem cells can be expanded and functionally differentiated to form 'mini-organs' resembling native tissue architecture and function. The choice of the scaffold is also pivotal to successful tissue reconstruction. Scaffolds may be broadly classified into synthetic or biological depending upon the purpose of the engineered organ. Bioengineered intestinal grafts represent a potential source of transplantable tissue for patients with intestinal failure, a condition resulting from extensive anatomical and functional loss of small intestine and therefore digestive and absorptive capacity. Prior strategies in intestinal bioengineering have predominantly used either murine or pluripotent cells and synthetic or decellularized rodent scaffolds, thus limiting their translation. Microscale models of human intestinal epithelium on shaped hydrogels and synthetic scaffolds are more physiological, but their regenerative potential is limited by scale. Here we present a protocol for bioengineering human intestinal grafts using patient-derived materials in a bioreactor culture system. This includes the isolation, expansion and biobanking of patient-derived intestinal organoids and fibroblasts, the generation of decellularized human intestinal scaffolds from native human tissue and providing a system for recellularization to form transplantable grafts. The duration of this protocol is 12 weeks, and it can be completed by scientists with prior experience of organoid culture. The resulting engineered mucosal grafts comprise physiological intestinal epithelium, matrix and surrounding niche, offering a valuable tool for both regenerative medicine and the study of human gastrointestinal diseases.

Building gut from scratch - progress and update of intestinal tissue engineering.

Short bowel syndrome (SBS), a condition defined by insufficient absorptive intestinal epithelium, is a rare disease, with an estimated prevalence up to 0.4 in 10,000 people. However, it has substantial morbidity and mortality for affected patients. The mainstay of treatment in SBS is supportive, in the form of intravenous parenteral nutrition, with the aim of achieving intestinal autonomy. The lack of a definitive curative therapy has led to attempts to harness innate developmental and regenerative mechanisms to engineer neo-intestine as an alternative approach to addressing this unmet clinical need. Exciting advances have been made in the field of intestinal tissue engineering (ITE) over the past decade, making a review in this field timely. In this Review, we discuss the latest advances in the components required to engineer intestinal grafts and summarize the progress of ITE. We also explore some key factors to consider and challenges to overcome when transitioning tissue-engineered intestine towards clinical translation, and provide the future outlook of ITE in therapeutic applications and beyond.

Engineering transplantable jejunal mucosal grafts using patient-derived organoids from children with intestinal failure.

Intestinal failure, following extensive anatomical or functional loss of small intestine, has debilitating long-term consequences for children1. The priority of patient care is to increase the length of functional intestine, particularly the jejunum, to promote nutritional independence2. Here we construct autologous jejunal mucosal grafts using biomaterials from pediatric patients and show that patient-derived organoids can be expanded efficiently in vitro. In parallel, we generate decellularized human intestinal matrix with intact nanotopography, which forms biological scaffolds. Proteomic and Raman spectroscopy analyses reveal highly analogous biochemical profiles of human small intestine and colon scaffolds, indicating that they can be used interchangeably as platforms for intestinal engineering. Indeed, seeding of jejunal organoids onto either type of scaffold reliably reconstructs grafts that exhibit several aspects of physiological jejunal function and that survive to form luminal structures after transplantation into the kidney capsule or subcutaneous pockets of mice for up to 2 weeks. Our findings provide proof-of-concept data for engineering patient-specific jejunal grafts for children with intestinal failure, ultimately aiding in the restoration of nutritional autonomy.

Surgery and paediatric inflammatory bowel disease.

The incidence of paediatric Crohn's disease (CD) and ulcerative colitis (UC) is increasing. Surgical intervention is required during childhood in approximately 25% of children diagnosed with CD, and for 10% of those diagnosed with UC. Although there is evidence that the rate of surgical intervention undertaken in children is decreasing since the introduction of biologic therapy, this may only represent a delay rather than true reversal of the risk of surgery. Surgery for CD is not curative and limited resection is the key principle thus preserving bowel length. For UC, subtotal colectomy is relatively curative; ileo-anal pouch anastomosis can be performed to restore bowel continuity.

The Excised Appendix Tip-To Send or not to Send, That is the Question.

A 9-year-old boy, with previous anorectal malformation and neuropathic bladder and bowel, underwent ileocystoplasty, Monti-Mitrofanoff and appendix antegrade colonic enema procedure. The tip of the macroscopically normal appendix was sent for routine histopathology. Microscopy demonstrated a 5-mm well-differentiated neuroendocrine tumor extending into muscularis propria. K i -67 index was <2%. Due to margin involvement, the appendix conduit and surrounding skin were re-excised and a tube cecostomy was created through a separate incision. Microscopy revealed no residual neuroendocrine tumor, and no further treatment was required.

Primary versus Staged Closure of Exomphalos Major: Cardiac Anomalies Do Not Affect Outcome.

AIM: The objective of the study is to describe management of exomphalos major and investigate the effect of congenital cardiac anomalies. METHODS: A single-center retrospective review (with audit approval) was performed of neonates with exomphalos major (fascial defect ≥ 5cm ± liver herniation) between 2004 and 2014.Demographic and operative data were collected and outcomes compared between infants who had primary or staged closure. Data, median (range), were analyzed appropriately. RESULTS: A total of 22 patients were included, 20 with liver herniation and 1 with pentalogy of Cantrell. Gestational age was 38 (30-40) weeks, birth weight 2.7 (1.4-4.6) kg, and 13 (60%) were male. Two were managed conservatively due to severe comorbidities, 5 underwent primary closure, and 15 had application of Prolene (Ethicon Inc) mesh silo and serial reduction. Five died, including two managed conservatively, none primarily of the exomphalos. Survivors were followed up for 38 months (2-71). Cardiac anomalies were present in 20 (91%) patients: 8 had minor and 12 major anomalies. Twelve (55%) patients had other anomalies. Primary closure was associated with shorter length of stay (13 vs. 85 days, p = 0.02), but infants had similar lengths of intensive care stay, duration of parenteral feeds, and time to full feeds. Infants with cardiac anomalies had shorter times to full closure (28 vs. 62 days, p = 0.03), but other outcomes were similar. CONCLUSION: Infants whose defect can be closed primarily have a shorter length of stay, but other outcomes are similar. Infants with more significant abdominovisceral disproportion are managed with staged closure; the presence of major cardiac anomalies does not affect surgical outcome.

Capsule endoscopy: a dangerous but diagnostic tool.

Current guidelines advocate the use of capsule endoscopy (CE) when gastroscopy and colonoscopy have failed to demonstrate the origin of occult gastrointestinal bleeding. CE has been used successfully in the diagnosis of a variety of conditions such as coeliac disease, polyposis syndromes and small bowel tumours, when routine investigations have failed to yield a diagnosis. In conditions where the diameter of the bowel lumen may be compromised, such as Crohn's disease, CE is contraindicated because of the risk of retention and/or small bowel obstruction. Here we present an unusual case where CE resulted in small bowel obstruction and perforation in a segment of small bowel which had become inflamed secondary to a carcinoid tumour.