The 8th Edition TNM Stage Reclassification of T4 Non-Small Cell Lung Cancer: A Granular Examination of Short and Long-Term Outcomes.

INTRODUCTION: Whilst the American Joint Committee on Cancer 7th edition (AJCC7) classified pT4 non-small-cell lung cancers (NSCLC) as those with extra-pulmonary invasion, the revised 8th edition (AJCC8) included tumors > 7cm regardless of extra-pleural spread. We examined perioperative and long-term outcomes of classical T4 definitions with patients whose tumors were greater than 7cm without extra-pulmonary invasion. MATERIALS AND METHODS: A retrospective single center cohort study was performed. All consecutive patients with pT4 lesions between 2011 and 2018 were identified based on either the AJCC7 or AJCC8 classification. Clinicopathological variables were extracted and compared in a univariate manner. A multivariate Cox regression analysis was performed to assess factors associated with overall survival. RESULTS: Forty patients were allocated to AJCC7 and 118 to AJCC8. Patients in the former were more likely to have positive lymph nodes, synchronous metastasis, multifocal disease and lymphovascular invasion. AJCC7 patients were more likely to undergo pneumonectomy despite significantly more being treated with neoadjuvant therapy. Ninety-day mortality was higher in the AJCC7 group. There was no difference in long-term overall survival. On multivariate analysis male gender, squamous cell histology and increasing tumor size were associated with an increased risk of death. CONCLUSION: Although long-term outcomes were similar, the heterogenicity within the AJCC8 classification emphasizes the need to contextualize the perioperative outcomes for patients with pT4 NSCLC. These data are important for future iterations of the TNM classification in view of emerging neoadjuvant options for patients with cT4 operable NSCLC.

Genotyping and Cytology Triage of High-Risk HPV DNA Positive Women for Detection of Cervical High-Grade Lesions.

OBJECTIVE: A demonstration project of primary human papillomavirus (HPV) testing was initiated in 2011 among more than 23,000 women attending routine cervical cancer screening. We examined the additional diagnostic performance of HPV genotyping for detecting disease in women with abnormal cytology. METHODS: Women aged 30 to 65 years were originally screened for HPV using Hybrid Capture II test. Women with positive results were triaged using conventional cytology, and those with atypical squamous cells of undetermined significance or worse (≥ASC-US) were referred to colposcopy. We retrospectively genotyped (Roche cobas 4800 HPV system [Roche Molecular Systems Inc, Pleasanton, CA]) cervical specimens that were HPV + with Hybrid Capture II test and extracted women's medical history postbaseline screening. We calculated positive predictive values (PPVs) and 95% confidence intervals (CIs) of triage tests to detect histologically confirmed cervical intraepithelial neoplasia of grade 2 or worse (CIN2 + ) within the first year of follow-up among women positive for HPV16, HPV18, and HPV16 and/or HPV18 as well as among those negative for HPVs 16 and 18. RESULTS: Of 1,396 HPV-positive women, 1,092 (78%) were classified as normal, 136 (10%) had CIN1, 80 (6%) had CIN2, 81 (6%) had CIN3, and 7 women had cancer throughout the entire follow-up period. Seventy CIN2 + cases were detected within the first year of follow-up. The PPV for detecting CIN2 + was 20.9% (63/239; 95% CI = 16.4-25.9) for ASC-US + cytology. In women with ASC-US + , PPVs were 31.2% (24/77; 95% CI = 21.1-42.7) for HPV16 + , 27.8% (5/18; 95% CI = 9.7-53.5) for HPV18 + , 30.8% (28/91; 95% CI = 21.5-41.3) for HPV16 + and/or HPV18 + women, and 16.6% (35/211; 95% CI = 11.8-22.3) in women testing negative for HPVs 16 and 18. CONCLUSION: Partial genotyping as an additional triage strategy to cytology can markedly improve clinical diagnostic performance.

Endoscopic Submucosal Dissection for Upper Gastrointestinal Neoplasia-a North American Perspective.

OBJECTIVES: Organ-sparing endoscopic submucosal dissection (ESD) is an acceptable treatment strategy for superficial neoplastic lesions of the esophagus and stomach. The adoption of this technique has lagged in North America compared with Asia, and we sought to report on our experiences with ESD for upper GI neoplasia. METHODS: A prospectively entered database of all patients undergoing endoscopic resection of esophageal and gastric neoplasia at McGill University from 2009 to 2019 was queried for those who received ESD. RESULTS: A total of 103 consecutive ESDs were identified from 2009 to 2019. Seventy-one (69%) patients were male and the median age was 72 (range: 38-90). Sixty-one (59%) cases were esophageal and 42 (41%) gastric. Forty-nine (48%) were performed in the endoscopy suite under local sedation only. Perforation occurred in 9 patients (7 esophageal and 2 stomach), of which 3 required operative repair. Histology was principally invasive carcinoma (79, 77%), with 17 (16%) dysplastic lesions (e.g., HGD), 1 (1%) neuroendocrine tumor, and 7 (7%) benign lesions. En bloc resection was achieved in 90 (87%), and the complete resection rate was 74 (72%), with 51 (50%) of procedures fulfilling the criteria for curative resection. At medium of 23-month (2-199) follow-up of these 51 curative resections, one case of recurrent carcinoma was found at follow-up and was managed with repeat endoscopic resection. Non-curative ESDs were found 45 (R1 resection = 29: risk of lymph node metastasis = 16), 21 had active surveillance, and 24 were resected. CONCLUSION: ESD is a viable, effective, and safe therapeutic and staging modality for superficial lesions of the stomach and esophagus.

Feasibility analysis for the development of a video-assisted thoracoscopic (VATS) lobectomy 23-hour recovery pathway.

Background: Video-assisted thoracoscopic (VATS) lobectomy has been demonstrated to offer several benefits over open surgery. The purpose of this study was to assess the feasibility and safety of an ultra-fast-track 23-hour recovery pathway for VATS lobectomy. Methods: A prospectively maintained institutional database was queried for patients who underwent VATS lobectomy from 2006 to 2016 at the McGill University Health Centre in Montreal, Quebec, and data were supplemented with focused chart review. Patients discharged with a length of stay (LOS) of 23 hours or less were compared with those with an LOS of 2 days or more. Logistic regression was performed to identify predictors of LOS of 23 hours or less. Results: Two hundred and five patients were included in the study. Perioperative 30-day mortality for our cohort was 0% and the major complication rate was 8.3%. The median LOS was 3 days (interquartile range [IQR] 2-4 d). Thirty-four patients were discharged within 23 hours and none of them required readmission; 171 patients were discharged on postoperative day 2 or later and 9 of them (5.3%) required readmission (p = 0.36). The proportion of patients discharged within 23 hours increased in 2016 compared with previous years (25.8% v. 12.0%, p = 0.05). Patients discharged within 23 hours had shorter chest tube duration (odds ratio [OR] 0.20, 95% confidence interval [CI] 0.09-0.46, p < 0.001), lower clinical stage disease (stages II-III v. stage I OR 0.07, 95% CI 0.01-0.52, p = 0.011), lower pathologic stage lesions (stages II-III v. stage I OR 0.26, 95% CI 0.07-0.91, p = 0.035), fewer surgical complications (OR 0.04, 95% CI 0.01-0.30, p = 0.002) and shorter operative time (surgery duration > 120 min OR 0.42, 95% CI 0.18-0.95, p = 0.04). Our exploratory prediction modelling showed that chest tube duration, clinical stage and surgeon were the most influential predictors of discharge within 23 hours. Conclusion: The only preoperative factors that predicted shorter LOS in our cohort were clinical stage and surgeon. A significant proportion of patients can be discharged safely by adopting a VATS lobectomy 23-hour enhanced recovery pathway.

Contexte: Il a été démontré que la lobectomie par chirurgie thoracique vidéoassistée (CTVA) offre plusieurs avantages comparativement à la chirurgie ouverte. La présente étude avait pour but d'évaluer la faisabilité et la sûreté d'un protocole de récupération ultrarapide en 23 heures pour la lobectomie par CTVA. Méthodes: Nous avons extrait d'une base de données d'établissement maintenue de manière prospective des données sur les patients ayant subi une lobectomie par CTVA entre 2006 et 2016 au Centre universitaire de santé McGill à Montréal (Québec), complétées par un examen ciblé des dossiers. Les patients ayant reçu leur congé après une hospitalisation de 23 heures ou moins ont été comparés à ceux dont l'hospitalisation avait duré 2 jours ou plus. Nous avons ensuite mis en évidence les facteurs prédictifs d'une hospitalisation de 23 heures ou moins par une analyse de régression logistique. Résultats: Deux cent cinq patients ont été inclus dans l'étude. La mortalité périopératoire dans les 30 jours suivant l'intervention était de 0 % dans notre cohorte, et le taux de complications majeures était de 8,3 %. La durée d'hospitalisation médiane était de 3 jours (écart interquartile [EI] 2 à 4 jours). Trente-quatre patients ont reçu leur congé dans les 23 heures suivant l'intervention, et aucun n'a dû être réhospitalisé; comparativement, 171 patients ont reçu leur congé au deuxième jour ou après, et 9 d'entre eux (5,3 %) ont dû être réhospitalisés (p = 0,36). Le pourcentage de patients ayant reçu leur congé dans les 23 heures a augmenté en 2016 par rapport aux années précédentes (25,8 % c. 12,0 %, p = 0,05). Les patients au congé dans les 23 heures conservaient leur drain thoracique moins longtemps (rapport de cotes [RC] 0,20, intervalle de confiance [IC] de 95 % 0,09 à 0,46, p < 0,001); leur stade clinique était moins élevé (stades II à III c. stade I ­ RC 0,07, IC de 95 % 0,01 à 0,52, p = 0,011); le stade pathologique de leurs lésions était plus faible (stades II à III c. stade I ­ RC 0,26, IC de 95 % 0,07 à 0,91, p = 0,035); ils avaient moins de complications chirurgicales (RC 0,04, IC de 95 % 0,01 à 0,30, p = 0,002); et la durée de leur intervention était plus courte (durée de la chirurgie > 120 minutes ­ RC 0,42, IC de 95 % 0,18 à 0,95, p = 0,04). Notre modèle prédictif exploratoire a montré que le délai avant le retrait du drain thoracique, le stade clinique et le chirurgien était les facteurs prédictifs les plus importants du congé dans les 23 heures. Conclusion: Les seuls facteurs préopératoires permettant de prédire une hospitalisation plus courte dans notre cohorte étaient le stade clinique et le chirurgien. Un pourcentage important des patients peuvent recevoir leur congé sans danger si on suit un protocole de récupération optimisée en 23 heures après une lobectomie par CTVA.

Comparison of Dor and Nissen fundoplication after laparoscopic paraesophageal hernia repair.

BACKGROUND: Fundoplication is performed routinely during laparoscopic repairs of a paraesophageal hernia, but the degree of fundoplication remains controversial. The purpose of this study is to assess postoperative dysphagia and reflux after a Dor versus a Nissen fundoplication in patients undergoing laparoscopic repair of giant paraesophageal hernias. METHODS: We performed a retrospective cohort study of all patients undergoing laparoscopic repair of giant paraesophageal hernias with Nissen or Dor fundoplication between January 2012 and December 2017 at a high-volume center, excluding revisional and emergency cases. Primary outcomes were reflux and dysphagia at 1 and 6 months. Severe dysphagia was defined as intolerance to liquids. Balanced cohorts were created using coarsened exact matching. RESULTS: A total of 106 patients were included, and 87 were matched (Dor = 48, Nissen = 58). Baseline characteristics were well balanced between matched groups. Mean follow-up duration was 17.7 months (standard deviation 16.4). The incidence of severe dysphagia at 1 month was less in the Dor group (0 of 48 vs 8 of 58, P = .02) with similar reflux symptoms. There was no difference in severe dysphagia and reflux symptoms at 6 months and at the latest visit. CONCLUSION: Dor fundoplication is associated with less severe, early postoperative dysphagia. Future studies assessing the relative importance of dysphagia and reflux on quality of life should be conducted to tailor the operative technique and optimize patient satisfaction.

Sentinel Lymph Node Sampling for Early Gastric Cancer-Preliminary Results of A North American Prospective Study.

INTRODUCTION: Although endoscopic resection for early gastric cancer is well established, anatomical resection with regional lymphadenectomy is recommended for lesions at high risk for occult lymph node metastasis (e.g., lymphovascular invasion, poor grade, and deep submucosal invasion). However, 75-95% high-risk early gastric cancer (HR-EGC) patients ultimately have node-negative disease and could potentially have undergone organ-sparing resection. Due to the inadequacy of standard modalities to reliably rule out nodal metastases in HR-EGC patients, sentinel lymph node (SLN) sampling was developed in Asia with promising results. However, the applicability of this technique in the West has been brought into question due to potential differences in tumor histology and body habitus. This prospective study aimed to test SLN sampling for North American EGC patients. METHODS: All patients with biopsy-confirmed T0-2 N0-1 M0 gastric adenocarcinoma at the Montreal General Hospital-McGill University Health Centre were eligible for enrollment. Esophageal and GEJ cancers were excluded due to the high rate of intrathoracic lymph node involvement. Peritumoral submucosal injection with T99 radiocolloid was performed endoscopically 24-30 h prior to surgery. Methylene blue dye injection was performed after induction of anesthesia. SLN basins were identified as those having > 10% of baseline tumor radiation signal or blue color, or both. After basins were individually removed, standard laparoscopic anatomical resection was then performed with D2 lymphadenectomy. ( ClinicalTrials.gov identifier: NCT03049345). Data are presented as median (interquartile range). RESULTS: From July 2016-April 2018, 253 patients with esophagogastric adenocarcinoma were evaluated. Of these, 10 met inclusion criteria (90% male, age 66(30) years). Subtotal gastrectomy was performed in nine patients (90%) and length of stay was 4 (2) days. At least one SLN basin was identified in nine cases (90%). The median #SLN basins identified was 2(2) with a median of 5(5) total SLNs retrieved per patient. In the one case for which no SLN basins were identified, only blue dye injection was used, whereas SLNs were identified in all cases using the dual tracer method. Final T-stage was pT1b/T2 in four (40%), pT1a in two (20%), and Tx in four (40%). Two patients (20%) had lymph node metastases on final pathological analysis, both of which were identified by SLN sampling (accuracy 100%; false negative rate 0%). No adverse events related to SLN retrieval were identified. CONCLUSIONS: This study represents the first prospective feasibility evaluation of sentinel lymph node sampling for early gastric cancer in North America with promising preliminary results. The dual tracer method was superior to single agent blue dye in identifying sentinel nodal basins. Considerable further study is necessary to verify the safety and utility of SLN mapping in North American patients with early gastric adenocarcinoma.

Blue-light filtering alters angiogenic signaling in human retinal pigmented epithelial cells culture model.

BACKGROUND: Light exposure and more specifically the spectrum of blue light contribute to the oxidative stress in Age-related macular degeneration (AMD). The purpose of the study was to establish whether blue light filtering could modify proangiogenic signaling produced by retinal pigmented epithelial (RPE) cells under different conditions simulating risk factors for AMD. METHODS: Three experiments were carried out in order to expose ARPE-19 cells to white light for 48 h with and without blue light-blocking filters (BLF) in different conditions. In each experiment one group was exposed to light with no BLF protection, a second group was exposed to light with BLF protection, and a control group was not exposed to light. The ARPE-19 cells used in each experiment prior to light exposure were cultured for 24 h as follows: Experiment 1) Normoxia, Experiment 2) Hypoxia, and Experiment 3) Lutein supplemented media in normoxia. The media of all groups was harvested after light exposure for sandwich ELISA-based assays to quantify 10 pro-angiogenic cytokines. RESULTS: A significant decrease in angiogenin secretion levels and a significant increase in bFGF were observed following light exposure, compared to dark conditions, in both normoxia and hypoxia conditions. With the addition of a blue light-blocking filter in normoxia, a significant increase in angiogenin levels was observed. Although statistical significance was not achieved, blue light filters reduce light-induced secretion of bFGF and VEGF to near normal levels. This trend is also observed when ARPE-19 cells are grown under hypoxic conditions and when pre-treated with lutein prior to exposure to experimental conditions. CONCLUSIONS: Following light exposure, there is a decrease in angiogenin secretion by ARPE-19 cells, which was abrogated with a blue light - blocking filter. Our findings support the position that blue light filtering affects the secretion of angiogenic factors by retinal pigmented epithelial cells under normoxic, hypoxic, and lutein-pretreated conditions in a similar manner.

Overexpression of CD109 in the Epidermis Differentially Regulates ALK1 Versus ALK5 Signaling and Modulates Extracellular Matrix Synthesis in the Skin.

Transforming growth factor-ß (TGF-ß) is a multifunctional growth factor involved in many physiological processes including wound healing and inflammation. Excessive TGF-ß signaling in the skin has been implicated in fibrotic skin disorders such as keloids and scleroderma. We previously identified CD109 as a TGF-ß co-receptor and inhibitor of TGF-ß signaling and have shown that transgenic mice overexpressing CD109 in the epidermis display decreased scarring. In certain cell types, in addition to the canonical type I receptor, ALK5, which activates Smad2/3, TGF-ß can signal through another type I receptor, ALK1, which activates Smad1/5. Here we demonstrate that ALK1 is expressed and co-localizes with CD109 in mouse keratinocytes and that mice overexpressing CD109 in the epidermis display enhanced ALK1-Smad1/5 signaling but decreased ALK5-Smad2/3 signaling, TGF-ß expression, and extracellular matrix production in the skin when compared with wild-type littermates. Furthermore, treatment with conditioned media from isolated keratinocytes or epidermal explants from CD109 transgenic mouse skin leads to a decrease in extracellular matrix production in mouse skin fibroblasts. Taken together, our findings suggest that CD109 differentially regulates TGF-ß-induced ALK1-Smad1/5 versus ALK5-Smad2/3 pathways, leading to decreased extracellular matrix production in the skin and that epidermal CD109 expression regulates dermal function through a paracrine mechanism.