Background Minimally invasive Ivor Lewis esophagectomy (MIE) is gaining popularity for the treatment of esophageal cancer. However, as it is a technically demanding operation, a learning curve should ...be defined to guide training and allow implementation at institutions not currently using this technique. Study Design Our study included a retrospective series of the first 80 consecutive patients undergoing MIE by a single surgeon with advanced training in minimally invasive esophageal surgery in independent practice at a high-volume tertiary center. Patients were stratified into 2 groups of 40 patients, with chronological order defining early and late experiences. Primary end points included conversion to open procedure, surgical time, blood loss, chest drainage duration, time to oral intake, hospital stay, postoperative morbidity, and mortality. The cumulative sum methodology was used and analyzed by visually inspecting the plots. Results Conversion to open procedure occurred in 2 (5%) patients in the early group and none in the late group (p = 0.49). Comparing early vs late experience, mean surgical time was 364 vs 316 minutes (p < 0.01), estimated blood loss was 205 vs 176 mL (p = 0.14), median hospital stay was 7 vs 6 days (p < 0.01), and morbidity was observed in 16 (40%) and 14 (35%) patients (p = 0.82), respectively. There were no anastomotic leaks or 30-day mortality. Cumulative sum plots showed decreasing surgical time after patient 54 (plateau after patient 31), decreasing chest tube duration after patients 38 and 33, sooner oral intake after patient 35, and decreased hospital stay after patient 33. Conclusions Improved operative and perioperative parameters for MIE were observed in the last 40 patients when compared with the first 40 patients. A reasonable learning curve for MIE would require the operation and perioperative care of 35 to 40 patients.
The native extracellular matrix (ECM) outlines the architecture of organs and tissues. It provides a unique niche of composition and form, which serves as a foundational scaffold that supports ...organ-specific cell types and enables normal organ function. Here we describe a standard process for pressure-controlled perfusion decellularization of whole organs for generating acellular 3D scaffolds with preserved ECM protein content, architecture and perfusable vascular conduits. By applying antegrade perfusion of detergents and subsequent washes to arterial vasculature at low physiological pressures, successful decellularization of complex organs (i.e., hearts, lungs and kidneys) can be performed. By using appropriate modifications, pressure-controlled perfusion decellularization can be achieved in small-animal experimental models (rat organs, 4-5 d) and scaled to clinically relevant models (porcine and human organs, 12-14 d). Combining the unique structural and biochemical properties of native acellular scaffolds with subsequent recellularization techniques offers a novel platform for organ engineering and regeneration, for experimentation ex vivo and potential clinical application in vivo.
Bioengineered lungs produced from patient-derived cells may one day provide an alternative to donor lungs for transplantation therapy. Here we report the regeneration of functional pulmonary ...vasculature by repopulating the vascular compartment of decellularized rat and human lung scaffolds with human cells, including endothelial and perivascular cells derived from induced pluripotent stem cells. We describe improved methods for delivering cells into the lung scaffold and for maturing newly formed endothelium through co-seeding of endothelial and perivascular cells and a two-phase culture protocol. Using these methods we achieved ∼75% endothelial coverage in the rat lung scaffold relative to that of native lung. The regenerated endothelium showed reduced vascular resistance and improved barrier function over the course of in vitro culture and remained patent for 3 days after orthotopic transplantation in rats. Finally, we scaled our approach to the human lung lobe and achieved efficient cell delivery, maintenance of cell viability and establishment of perfusable vascular lumens.
There is a large unmet need for a simple, accurate, noninvasive, quantitative, and high-resolution imaging modality to detect lung fibrosis at early stage and to monitor disease progression. ...Overexpression of collagen is a hallmark of organ fibrosis. Here, we describe the optimization of a collagen-targeted PET probe for staging pulmonary fibrosis.
Six peptides were synthesized, conjugated to a copper chelator, and radiolabeled with
Cu. The collagen affinity of each probe was measured in a plate-based assay. The pharmacokinetics and metabolic stability of the probes were studied in healthy rats. The capacity of these probes to detect and stage pulmonary fibrosis in vivo was assessed in a mouse model of bleomycin-induced fibrosis using PET imaging.
All probes exhibited affinities in the low micromolar range (1.6 μM < Kd < 14.6 μM) and had rapid blood clearance. The probes showed 2- to 8-fold-greater uptake in the lungs of bleomycin-treated mice than sham-treated mice, whereas the distribution in other organs was similar between bleomycin-treated and sham mice. The probe
Cu-CBP7 showed the highest uptake in fibrotic lungs and the highest target-to-background ratios. The superiority of
Cu-CBP7 was traced to a much higher metabolic stability compared with the other probes. The specificity of
Cu-CBP7 for collagen was confirmed by comparison with a nonbinding isomer.
Cu-CBP7 is a promising candidate for in vivo imaging of pulmonary fibrosis.
As worldwide life expectancy rises, the number of candidates for surgical treatment of esophageal cancer over 70 years will increase. This study aims to examine outcomes after esophagectomy in ...elderly patients.
This study is a retrospective review of 474 patients undergoing esophagectomy for cancer during 2002 to 2011. A total of 334 (70.5%) patients were less than 70 years old (group A), 124 (26.2%) 70 to 79 years (group B), and 16 (3.4%) 80 years or greater (group C). We analyzed the effect of age on outcome variables including overall and disease specific survival.
Major morbidity was observed to occur in 115 (35.6%) patients of group A, 58 (47.9%) of group B, and 10 (62.5%) of group C (p = 0.010). Mortality, both 30-day and 90-day was observed in 2 (0.6%) and 7 (2.2%) of group A, 4 (3.2%) and 7 (6.1%) of group B, and 1 (6.3%) and 2 (14.3%) of group C, respectively (p = 0.032 and p = 0.013). Anastomotic leak was observed in 16 (4.8%) patients of group A, 6 (4.8%) of group B, and 0 (0%) of group C (p = 0.685). Anastomotic stricture (defined by the need for ≥ 2 dilations) was observed in 76 (22.8%) of group A, 13 (10.5%) of group B, and 1 (6.3%) of group C (p = 0.005). Five-year overall and disease specific survival was 64.8% and 72.4% for group A, 41.7% and 53.4% for group B, 49.2% and 49.2% for group C patients (p = 0.0006), respectively.
Esophagectomy should be carefully considered in patients 70 to 79 years old and can be justified with low mortality. Outcomes in octogenarians are worse suggesting esophagectomy be considered on a case by case basis. Stricture rate is inversely associated to age.
Patients suffering from end-stage organ failure requiring organ transplantation face donor organ shortage and adverse effect of chronic immunosuppression. Recent progress in the field of organ ...bioengineering based on decellularized organ scaffolds and patient-derived cells holds great promise to address these issues.
Perfusion-decellularization is the most consistent method to obtain decellularized whole-organ scaffolds to serve as a platform for organ bioengineering. Important advances have occurred in organ bioengineering using decellularized scaffolds in small animal models. However, the function exhibited by bioengineered organs has been rudimentary. Pluripotent stem cells seem to hold promise as the ideal regenerative cells to be used with this approach but the techniques to effectively and reliably manipulate their fate are still to be discovered. Finally, this technology needs to be scaled up to human size to be of clinical relevance.
The search for alternatives to allogeneic organ transplantation continues. Important milestones have been achieved in organ bioengineering with the use of decellularized scaffolds. However, many challenges remain on the way to producing an autologous, fully functional organ that can be transplanted similar to a donor organ.
Pulmonary fibrosis is scarring of the lungs that can arise from radiation injury, drug toxicity, environmental or genetic causes, and for unknown reasons idiopathic pulmonary fibrosis (IPF). ...Overexpression of collagen is a hallmark of organ fibrosis. We describe a peptide-based positron emission tomography (PET) probe (
Ga-CBP8) that targets collagen type I. We evaluated
Ga-CBP8 in vivo in the bleomycin-induced mouse model of pulmonary fibrosis.
Ga-CBP8 showed high specificity for pulmonary fibrosis and high target/background ratios in diseased animals. The lung PET signal and lung
Ga-CBP8 uptake (quantified ex vivo) correlated linearly (
= 0.80) with the amount of lung collagen in mice with fibrosis. We further demonstrated that the
Ga-CBP8 probe could be used to monitor response to treatment in a second mouse model of pulmonary fibrosis associated with vascular leak. Ex vivo analysis of lung tissue from patients with IPF supported the animal findings. These studies indicate that
Ga-CBP8 is a promising candidate for noninvasive imaging of human pulmonary fibrosis.
Neoadjuvant therapy is integral in the treatment of locally advanced esophageal cancer. Despite increasing acceptance of minimally invasive approaches to esophagectomy, there remain concerns about ...the safety and oncologic soundness after neoadjuvant therapy. We examined outcomes in patients undergoing open and minimally invasive (MIE) Ivor Lewis esophagectomy after neoadjuvant therapy.
This was a retrospective series of 130 consecutive patients with esophageal cancer undergoing Ivor Lewis esophagectomy with curative intention after neoadjuvant therapy at a tertiary academic center (2008 to 2012).
An open procedure was performed in 74 patients (56.9%), and 56 (43.1%) underwent MIE after neoadjuvant therapy. MIE patients had shorter median intensive care unit (p = 0.002) and hospital lengths of stay (p < 0.0001). The incidence of postoperative complications was similar (open: 54.8% vs MIE: 41.1%, p = 0.155). However, observed respiratory complications were significantly reduced after MIE (8.9%) compared with open (29.7%; p = 0.004). Anastomotic leak rates were similar (open: 1.4% vs. MIE: 0%, p = 1.00). Mortality at 30 and 90 days was comparable (open: 2.7% and 4.1% vs MIE: 0% and 1.8%, p = 0.506 and p = 0.634, respectively). Complete resection rates and the number of collected lymph nodes was similar. Overall survival rates at 5 years were similar (open: 61% vs MIE: 50%, p = 0.933). MIE was not a significant predictor of overall survival (hazard ratio, 1.07; 95% confidence interval, 0.61 to 1.87; p = 0.810).
MIE proves its safety after neoadjuvant therapy because it leads to faster progression during the early postoperative period while reducing pulmonary complications. Open and MIE approaches appear equivalent with regards to perioperative oncologic outcomes after neoadjuvant therapy. Long-term outcomes need further validation.
Abstract Bio-engineered organs for transplantation may ultimately provide a personalized solution for end-stage organ failure, without the risk of rejection. Building upon the process of whole organ ...perfusion decellularization, we aimed to develop novel, translational methods for the recellularization and regeneration of transplantable lung constructs. We first isolated a proliferative KRT5+ TP63+ basal epithelial stem cell population from human lung tissue and demonstrated expansion capacity in conventional 2D culture. We then repopulated acellular rat scaffolds in ex vivo whole organ culture and observed continued cell proliferation, in combination with primary pulmonary endothelial cells. To show clinical scalability, and to test the regenerative capacity of the basal cell population in a human context, we then recellularized and cultured isolated human lung scaffolds under biomimetic conditions. Analysis of the regenerated tissue constructs confirmed cell viability and sustained metabolic activity over 7 days of culture. Tissue analysis revealed extensive recellularization with organized tissue architecture and morphology, and preserved basal epithelial cell phenotype. The recellularized lung constructs displayed dynamic compliance and rudimentary gas exchange capacity. Our results underline the regenerative potential of patient-derived human airway stem cells in lung tissue engineering. We anticipate these advances to have clinically relevant implications for whole lung bioengineering and ex vivo organ repair.
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