Impact of neoadjuvant therapy on nodal harvest in clinical stage III rectal cancer: Establishing optimum cut-offs by disease response.

INTRODUCTION: A minimum lymph node harvest (LNH) of 12 is the current standard for appropriate nodal staging in resectable rectal cancer. However, the rise of neoadjuvant chemoradiation (NCRT) and total neoadjuvant therapy (TNT) has been associated with decreasing number of LNH. We hypothesize that as tumor response to neoadjuvant therapy increases, the optimum for LNH to achieve appropriate nodal staging should decrease. METHODS: Patients with clinical stage III rectal adenocarcinoma who underwent NCRT/TNT followed by resection were identified from the National Cancer Database. A JoinPoint regression analysis was used to determine the LNH for each tumor regression grade (TRG) category beyond which the rate of positive nodes does not significantly change. RESULTS: Thirteen thousand four hundred and twenty-six patients met inclusion criteria. Of these, 2406 (17.9%) achieved TRG 0 or ypT0 and 8210 (61.2%) achieved ypN0. Collectively, 2043 patients (15.2%) were reported to have a pathologic complete response (ypT0 ypN0). Positive pathologic nodes were found in 15%, 23%, 31%, 54%, and 53% as ypT stage increased from ypT0 to ypT4, respectively. Similarly, ypN+ rates were 15%, 36%, 41%, and 55% in TRG 0-3. No JoinPoint was identified for TRG 0, whereas inflection points were found at 6-10 nodes for TRG1 (p = 0.002) and TRG 2 (p = 0.016), and at 11-15 nodes for TRG 3. CONCLUSION: The benchmark of retrieving 12 nodes in resectable stage III rectal cancer is not consistently achieved after NCRT/TNT. We demonstrate that the LNH requirement to establish accurate pathologic nodal staging can vary depending on the tumor response to neoadjuvant therapies.

Induced organoids derived from patients with ulcerative colitis recapitulate colitic reactivity.

The pathogenesis of ulcerative colitis (UC), a major type of inflammatory bowel disease, remains unknown. No model exists that adequately recapitulates the complexity of clinical UC. Here, we take advantage of induced pluripotent stem cells (iPSCs) to develop an induced human UC-derived organoid (iHUCO) model and compared it with the induced human normal organoid model (iHNO). Notably, iHUCOs recapitulated histological and functional features of primary colitic tissues, including the absence of acidic mucus secretion and aberrant adherens junctions in the epithelial barrier both in vitro and in vivo. We demonstrate that the CXCL8/CXCR1 axis was overexpressed in iHUCO but not in iHNO. As proof-of-principle, we show that inhibition of CXCL8 receptor by the small-molecule non-competitive inhibitor repertaxin attenuated the progression of UC phenotypes in vitro and in vivo. This patient-derived organoid model, containing both epithelial and stromal compartments, will generate new insights into the underlying pathogenesis of UC while offering opportunities to tailor interventions to the individual patient.

A Tissue Engineering Approach to Metastatic Colon Cancer.

Colon cancer remains the third most common cause of cancer in the US, and the third most common cause of cancer death. Worldwide, colon cancer is the second most common cause of cancer and cancer deaths. At least 25% of patients still present with metastatic disease, and at least 25-30% will develop metastatic colon cancer in the course of their disease. While chemotherapy and surgery remain the mainstay of treatment, understanding the fundamental cellular niche and mechanical properties that result in metastases would facilitate both prevention and cure. Advances in biomaterials, novel 3D primary human cells, modelling using microfluidics and the ability to alter the physical environment, now offers a unique opportunity to develop and test impactful treatment.

Organoid Models of Colorectal Pathology: Do They Hold the Key to Personalized Medicine? A Systematic Review.

BACKGROUND: Colorectal cancer and IBD account for a large portion of the practice of colorectal surgery. Historical research models have provided insights into the underlying causes of these diseases but come with many limitations. OBJECTIVE: The aim of this study was to systematically review the literature regarding the advantage of organoid models in modeling benign and malignant colorectal pathology. DATA SOURCES: Sources included PubMed, Ovid-Medline, and Ovid Embase STUDY SELECTION:: Two reviewers completed a systematic review of the literature between January 2006 and January of 2020 for studies related to colon and intestinal organoids. Reviews, commentaries, protocols, and studies not performed in humans or mice were excluded. RESULTS: A total of 73 articles were included. Organoid models of colorectal disease have been rising in popularity to further elucidate the genetic, transcriptomic, and treatment response of these diseases at the individual level. Increasingly complex models utilizing coculture techniques are being rapidly developed that allow in vitro recapitulation of the disease microenvironment. LIMITATIONS: This review is only qualitative, and the lack of well utilized nomenclature in the organoid community may have resulted in the exclusion of articles. CONCLUSIONS: Historical disease models including cell lines, patient-derived tumor xenografts, and animal models have created a strong foundation for our understanding of colorectal pathology. Recent advances in 3-dimensional cell cultures, in the form of patient-derived epithelial organoids and induced human intestinal organoids have opened a new avenue for high-resolution analysis of pathology at the level of an individual patient. Recent research has shown the potential of organoids as a tool for personalized medicine with their ability to retain patient characteristics, including treatment response.

Esophagogastric junction distensibility is greater following Toupet compared to Nissen fundoplication.

BACKGROUND: The goal of antireflux surgery is to create a competent antireflux valve at the esophagogastric junction (EGJ). The two most common types of fundoplications constructed are the 360° Nissen and the 270° Toupet. We sought to determine whether there was a significant difference in distensibility at the EGJ based on fundoplication geometry (full vs. partial). METHODS: This is a retrospective review of prospective data. All subjects underwent laparoscopic fundoplication over a 47-month period for primary GERD or failed fundoplication. An endoluminal functional luminal-imaging probe (EndoFLIP®) was used to assess EGJ distensibility intraoperatively. Minimum esophageal diameter (D min), cross-sectional area (CSA), and distensibility index (DI) were measured at 30- and 40-mL balloon distension volumes prior to abdominal insufflation, after hiatal dissection, and following fundoplication. DI is defined as the narrowest CSA divided by the corresponding pressure expressed in mm2/mmHg. Analysis was conducted to compare distensibility metrics based on the type of fundoplication constructed (Nissen or Toupet). As a secondary outcome, we sought to determine whether there was a difference in distensibility of the EGJ prior to surgery in patients with primary GERD as opposed to those with recurrent GERD after a failed fundoplication. RESULTS: A total of 75 patients underwent fundoplications during the study interval. There were 44 primary and 31 reoperative fundoplications. Nissen fundoplication was constructed in 45 and Toupet in 30. Based on the distensibility index, the EGJ distensibility significantly decreased from prior to surgery to following fundoplication in all patients. Patients undergoing reoperative antireflux surgery had an initial DI at the EGJ similar to that of patients with primary GERD. Following Toupet, the EGJ was significantly more distensible than that after Nissen fundoplication. CONCLUSIONS: Laparoscopic fundoplication results in decreased EGJ distensibility in patients with GERD. The EGJ following partial fundoplication is significantly more distensible than that after a full fundoplication.

Limited Hiatal Dissection Without Fundoplication Results in Comparable Symptomatic Outcomes to Laparoscopic Heller Myotomy with Anterior Fundoplication.

BACKGROUND: Previous randomized controlled trials have demonstrated that partial fundoplication following Heller myotomy results in less pathologic acid exposure to the esophagus when compared to myotomy without fundoplication. Recent studies have questioned the necessity of a fundoplication, especially when a limited hiatal dissection (LHD) is performed and the angle of His is preserved. MATERIALS AND METHODS: This is a retrospective review of prospectively maintained data. All patients underwent primary Heller myotomy for achalasia over a 30-month period. In select patients, an LHD was performed anteriorly. Symptomatic outcomes were assessed up to 2 years postoperation using the Achalasia Severity Questionnaire (ASQ), Gastrointestinal Quality of Life Index (GIQLI), and Gastroesophageal Reflux Disease-Health-Related Quality of Life (GERD-HRQL). RESULTS: A total of 31 patients underwent Heller myotomy during the study interval. The majority of patients underwent Heller myotomy with full hiatal dissection (FHD) (21, 68%). Intraoperative mucosal perforations occurred in 3 (14%) patients undergoing FHD. Patient demographics, surgery details, and baseline symptomatic outcomes did not differ significantly preoperatively. At greater than 1 year postoperation, there was no significant difference between the groups for ASQ, GERD-HRQL, and GIGLI (P = .76, .78, and .33, respectively). CONCLUSIONS: Heller myotomy with LHD and no fundoplication and Heller myotomy with FHD and partial fundoplication result in similar GERD-related quality of life outcomes. Further studies (including pH studies) are necessary to determine if fundoplication is a necessary step in selected patients in whom an LHD is possible.

Intraoperative Assessment of Esophagogastric Junction Distensibility During Laparoscopic Heller Myotomy.

We sought to characterize the changes in esophagogastric junction (EGJ) distensibility during Heller Myotomy with Dor fundoplication using the EndoFLIP device. Intraoperative distensibility measurements on 14 patients undergoing Heller myotomy with Dor fundoplication were conducted over an 18-month period. Minimum esophageal diameter, cross-sectional areas, and distensibility index were measured at 30 and 40 mL catheter volumes before myotomy, postmyotomy, and following Dor fundoplication. Distensibility index is defined as the narrowest cross-sectional area divided by the corresponding pressure expressed in mm/mm Hg. Heller myotomy was found to lead to significant changes in the distensibility characteristics of the EGJ. Minimum esophageal diameter and EGJ distensibility increased significantly with Heller myotomy.