Escape from cell-cell and cell-matrix adhesion dependence underscores disease progression in gastric cancer organoid models.

OBJECTIVE: Cell-cell (CC) and cell-matrix (CM) adhesions are essential for epithelial cell survival, yet dissociation-induced apoptosis is frequently circumvented in malignant cells. DESIGN: We explored CC and CM dependence in 58 gastric cancer (GC) organoids by withdrawing either ROCK inhibitor, matrix or both to evaluate their tumorigenic potential in terms of apoptosis resistance, correlation with oncogenic driver mutations and clinical behaviour. We performed mechanistic studies to determine the role of diffuse-type GC drivers: ARHGAP fusions, RHOA and CDH1, in modulating CC (CCi) or CM (CMi) adhesion independence. RESULTS: 97% of the tumour organoids were CMi, 66% were CCi and 52% were resistant to double withdrawal (CCi/CMi), while normal organoids were neither CMi nor CCi. Clinically, the CCi/CMi phenotype was associated with an infiltrative tumour edge and advanced tumour stage. Moreover, the CCi/CMi transcriptome signature was associated with poor patient survival when applied to three public GC datasets. CCi/CMi and CCi phenotypes were enriched in diffuse-type GC organoids, especially in those with oncogenic driver perturbation of RHO signalling via RHOA mutation or ARHGAP fusions. Inducible knockout of ARHGAP fusions in CCi/CMi tumour organoids led to resensitisation to CC/CM dissociation-induced apoptosis, upregulation of focal adhesion and tight junction genes, partial reversion to a more normal cystic phenotype and inhibited xenograft formation. Normal gastric organoids engineered with CDH1 or RHOA mutations became CMi or CCi, respectively. CONCLUSIONS: The CCi/CMi phenotype has a critical role in malignant transformation and tumour progression, offering new mechanistic information on RHO-ROCK pathway inhibition that contributes to GC pathogenicity.

Risk of hospitalization for upper gastrointestinal bleeding in Helicobacter pylori eradicated patients newly started on warfarin or direct oral anticoagulants: A population-based cohort study.

BACKGROUND: To investigate risks of hospitalization for upper gastrointestinal bleeding (UGIB) in H. pylori-eradicated patients newly started on warfarin or direct oral anti-coagulants (DOACs). METHODS: We identified all patients who had previously received H. pylori eradication therapy or were found to have no H. pylori on endoscopy and were then newly started on warfarin or DOACs from a population-based electronic healthcare database. Primary analysis was the risk of UGIB between warfarin and DOACs users in H. pylori-eradicated patients. Secondary analysis included the UGIB risk between H. pylori-eradicated and H. pylori-negative patients who were newly started on warfarin or DOACs. The hazard ratio (HR) of UGIB was approximated by pooled logistic regression model incorporating the inverse propensity of treatment weightings with time-varying covariables. RESULTS: Among H. pylori-eradicated patients, DOACs had a significantly lower risk of UGIB (HR: 0.26, 95% CI 0.09-0.71) compared with warfarin. In particular, lower UGIB risks with DOACs were observed among older (≥65 years) patients, female, those without a history of UGIB or peptic ulcer, or ischemic heart disease, and non-users of acid-suppressive agents or aspirin. Secondary analysis showed no significant difference in UGIB risk between H. pylori-eradicated and H. pylori-negative patients newly started on warfarin (HR: 0.63,95% CI 0.33-1.19) or DOACs (HR: 1.37, 95% CI 0.45-4.22). CONCLUSIONS: In H. pylori-eradicated patients, new users of DOACs had a significantly lower risk of UGIB than new warfarin users. Furthermore, the risk of UGIB in new warfarin or DOACs users was comparable between H. pylori-eradicated and H. pylori-negative patients.

A Novel Tumor Staging System Incorporating Tumor Regression Grade (TRG) With Lymph Node Status (ypN-Category) Results in Better Prognostication Than ypTNM Stage Groups After Neoadjuvant Therapy for Esophageal Squamous Cell Carcinoma.

OBJECTIVE: This study aims at constructing a staging system incorporating tumor regression grade and ypN-category (TRG-N) in patients with neoadjuvant therapy before esophagectomy. It is hypothesized that this would prognosticate better than the current American Joint Committee on Cancer (AJCC) postneoadjuvant therapy (ypTNM) stage groups. BACKGROUND: Conventional pathological T-category is defined by the depth of invasion, and may lose prognostic relevance after neoadjuvant therapy. TRG defines treatment response by the degree of tumor regression, and when combined with ypN-category may be more prognostic than AJCC postneoadjuvant therapy (ypTNM) stage groups. METHODS: A training cohort of 210 patients with esophageal squamous cell carcinoma and who had had neoadjuvant therapy before esophagectomy were studied. A validation cohort comprised 107 patients from another hospital. Resected esophagi were assessed by ypT-category and TRG, the latter assigned according to the Becker 4-tier system. These categories were grouped with ypN-category into a TRG-N system. Patients' survival was compared between the current AJCC postneoadjuvant therapy (ypTNM) stage groups and this TRG-N system. RESULTS: In the training cohort, 5-year survival rates according to ypTNM stage I, II, IIIA, IIIB, and IVA were 53%, 39.4%, 47%, 18.3%, and 0%, respectively. For TRG-N stages I, II, III, and IV, the respective figures were 59.6%, 43.5%, 23.8%, and 15.6%. TRG-N stage showed better fit in survival than ypTNM stage groups, indicated by lower Akaike Information Criteria (AIC) and Bayesian Information Criterion values. Similar results were found in the validation cohort. Multivariate analysis showed that TRG-N stage ( P =0.02), age ( P =0.006), and sex ( P =0.005) were independent prognostic factors. CONCLUSION: TRG-N stage shows better prognostication than the AJCC postneoadjuvant therapy (ypTNM) stage groups.

Age of eradication and failure rates of clarithromycin-containing triple therapy for Helicobacter pylori: A 15-year population-based study.

BACKGROUND: Failure rates of clarithromycin-containing triple therapy for H. pylori are rising. To determine the trend of failure rates of clarithromycin-containing triple therapy in different age groups in Hong Kong over the past 15 years. MATERIALS AND METHODS: This is a population-based retrospective age-period-cohort study involving all adult H. pylori-infected patients who had received the first course of clarithromycin-containing triple therapy in 2003-2017. Failed eradication was identified by the need of retreatment within 2 years of eradication. Logistic regression model was used to characterize the risk of retreatment. RESULTS: 113,526 H. pylori-infected patients were included. The overall failure rate increased from 4.83% in 2003 to 10.2% in 2016 (p for linear trend <0.001). When stratified by age of eradication, patients 75 years or above had the lowest retreatment rate of 5.11%, which progressively increased in younger patients (60-74 years: OR 1.26, 95% CI 1.15-1.38; 45-59 years: OR 1.36, 95% CI 1.24-1.48; 18-44 years: OR 1.55, 95% CI 1.41-1.69). The results remained consistent when stratified by year of birth, and period of eradication. Other risk factors for retreatment included female (OR 1.24, 95% CI 1.18-1.30), triple therapy containing metronidazole (OR 2.30, 95% CI 2.12-2.50), and shorter duration of therapy (10 days: OR 0.88, 95% CI 0.79-0.97; 14 days: OR 0.67, 95% CI 0.58-0.77 vs 7 days). CONCLUSIONS: While failure rates of clarithromycin-containing triple therapy progressively increased over the past 15 years, the failure rate was particularly high among younger patients, which could undermine the potential benefits of early H. pylori eradication.

Improving Outcome of Superior Mediastinal Lymph Node Dissection During Esophagectomy: A Novel Approach Combining Continuous and Intermittent Recurrent Laryngeal Nerve Monitoring.

OBJECTIVE: This study aimed at demonstrating the effects and learning curve of utilizing combined intermittent and continuous recurrent laryngeal nerve (RLN) monitoring for lymphadenectomy during esophagectomy. BACKGROUND: RLN lymphadenectomy is oncologically important but is technically demanding. Vocal cord (VC) palsy as a result from RLN injury, carries significant morbidities. METHODS: This is a retrospective study of consecutive esophageal squamous cell carcinoma (ESCC) patients who underwent transthoracic esophagectomy from 2010 to 2020. Combined nerve monitoring (CNM) included: CNM which involved a periodic stimulating left vagal electrode and intermittent nerve monitoring which utilized a stimulating probe to identify the RLNs. The integrity of the RLNs was assessed both intermittently and continuously. This technique was introduced in 2014. Patients were divided into "before CNM" and "CNM" groups. The primary outcome was the difference in number of RLN lymph nodes harvested and VC palsy rate. Learning curves were demonstrated by cumulative sum (CUSUM) analysis. RESULTS: Two hundred and fifty-five patients were included with 157 patients in "CNM" group. The mean number of RLN lymph nodes harvested was significantly higher (4.31 vs 0.45, P < 0.0001) for the "CNM" group. VC palsy rates were significantly lower (17.8% vs 32.7%, P = 0.007). There was an initial increase in VC palsy rate, peaked at around 46 cases. The increase in lymph nodes harvested above the mean plateaued at around 96 cases. CONCLUSIONS: CNM helped improve bilateral RLN lymphadenectomy. Lymph node harvesting was increased with reduction of VC palsy after a learning curve.

Neoadjuvant Chemoradiotherapy Using Cisplatin and 5-Fluorouracil (PF) Versus Carboplatin and Paclitaxel (CROSS Regimen) for Esophageal Squamous Cell Carcinoma (ESCC): A Propensity Score-matched Study.

OBJECTIVE: This study compared the efficacy of PF-based and CROSS-based neoadjuvant chemoradiotherapy for ESCC. BACKGROUND: PF-based regimen has been a standard regimen for ESCC, but it has been replaced by the CROSS regimen in the past few years, despite no prospective head-to-head comparative study has been performed. METHODS: This is a single center retrospective study. Records of all ESCC patients who have received neoadjuvant PF with 40 Gy radiotherapy in 20 daily fractions (PFRT Group) or CROSS with 41.4 Gy radiotherapy in 23 daily fractions (CROSS Group) during the period 2002 to 2019 were retrieved. Propensity score matching (1:1) was performed to minimize baseline differences. The primary and secondary endpoints were overall survival and clinicopathological response. Subgroup analysis ("CROSS Eligibility") was performed based on tumor length, cT-stage, cM-stage, age, and performance status. RESULTS: One hundred (out of 109) patients (CROSS group) and propensity score matched 100 (out of 210) patients (PFRT group) were included. Esophagectomy rates in CROSS and PFRT group were 69% and 76%, respectively (P = 0.268). R0 resection rates were 85.5% and 81.6% (P = 0.525) and the pathological complete remission rates were 24.6% and 35.5% (P = 0.154). By intention-to-treat, the median survival was 16.7 and 32.7 months (P = 0.083). For "CROSS Eligible subgroup," the median survival of the CROSS and PFRT group was 21.6 versus 44.9 months (P = 0.093). CONCLUSIONS: There is no statistically difference in survival or clinicopathological outcome between both groups, but the trend favors PFRT. Prospective head-to-head comparison and novel strategies to improve the outcomes in resectable ESCC are warranted.

MicroRNA-338-5p reverses chemoresistance and inhibits invasion of esophageal squamous cell carcinoma cells by targeting Id-1.

5-Fluorouracil (5-FU) is a chemotherapeutic agent commonly used to treat esophageal squamous cell carcinoma (ESCC), but acquisition of chemoresistance frequently occurs and the underlying mechanisms are not fully understood. We found that microRNA (miR)-338-5p was underexpressed in ESCC cells with acquired 5-FU chemoresistance. Forced expression of miR-338-5p in these cells resulted in downregulation of Id-1, and restoration of both in vitro and in vivo sensitivity to 5-FU treatment. The effects were abolished by reexpression of Id-1. In contrast, miR-338-5p knockdown induced 5-FU resistance in chemosensitive esophageal cell lines, and knockdown of both miR-338-5p and Id-1 resensitized the cells to 5-FU. In addition, miR-338-5p had suppressive effects on migration and invasion of ESCC cells. Luciferase reporter assay confirmed a direct interaction between miR-338-5p and the 3'-UTR of Id-1. We also found that miR-338-5p was significantly downregulated in tumor tissue and serum samples of patients with ESCC. Notably, low serum miR-338-5p expression level was associated with poorer survival and poor response to 5-FU/cisplatin-based neoadjuvant chemoradiotherapy. In summary, we found that miR-338-5p can modulate 5-FU chemoresistance and inhibit invasion-related functions in ESCC by negatively regulating Id-1, and that serum miR-338-5p could be a novel noninvasive prognostic and predictive biomarker in ESCC.

Distribution of lymph node metastases in esophageal carcinoma [TIGER study]: study protocol of a multinational observational study.

BACKGROUND: An important parameter for survival in patients with esophageal carcinoma is lymph node status. The distribution of lymph node metastases depends on tumor characteristics such as tumor location, histology, invasion depth, and on neoadjuvant treatment. The exact distribution is unknown. Neoadjuvant treatment and surgical strategy depends on the distribution pattern of nodal metastases but consensus on the extent of lymphadenectomy has not been reached. The aim of this study is to determine the distribution of lymph node metastases in patients with resectable esophageal or gastro-esophageal junction carcinoma in whom a transthoracic esophagectomy with a 2- or 3-field lymphadenectomy is performed. This can be the foundation for a uniform worldwide staging system and establishment of the optimal surgical strategy for esophageal cancer patients. METHODS: The TIGER study is an international observational cohort study with 50 participating centers. Patients with a resectable esophageal or gastro-esophageal junction carcinoma in whom a transthoracic esophagectomy with a 2- or 3-field lymphadenectomy is performed in participating centers will be included. All lymph node stations will be excised and separately individually analyzed by pathological examination. The aim is to include 5000 patients. The primary endpoint is the distribution of lymph node metastases in esophageal and esophago-gastric junction carcinoma specimens following transthoracic esophagectomy with at least 2-field lymphadenectomy in relation to tumor histology, tumor location, invasion depth, number of lymph nodes and lymph node metastases, pre-operative diagnostics, neo-adjuvant therapy and (disease free) survival. DISCUSSION: The TIGER study will provide a roadmap of the location of lymph node metastases in relation to tumor histology, tumor location, invasion depth, number of lymph nodes and lymph node metastases, pre-operative diagnostics, neo-adjuvant therapy and survival. Patient-tailored treatment can be developed based on these results, such as the optimal radiation field and extent of lymphadenectomy based on the primary tumor characteristics. TRIAL REGISTRATION: NCT03222895 , date of registration: July 19th, 2017.

Treatment of Gastric Metaplasia or Dysplasia by Endoscopic Radiofrequency Ablation: A Pilot Study.

BACKGROUND/AIMS: Patients with gastric intestinal metaplasia and dysplasia are at increased risk of gastric cancer development. We tested the feasibility of using endoscopic radiofrequency ablation for the treatment of dysplasia and metaplasia in the stomach. METHODOLOGY: Patients who had histologically confirmed low-grade gastric dysplasia or IM were recruited. Endoscopic RFA was performed at 8 week-intervals for a maximum of 3 sessions. All patients were followed up by endoscopy until 12 months post-RFA. The primary outcome was the complete eradication of dysplasia or IM on follow-up. Secondary outcome was adverse events related to RFA. RESULTS: A total of 12 patients were recruited. Four patients had low-grade dysplasia and the remaining 8 patients had non-dysplastic IM at baseline. At one year after RFA, complete eradication of dysplasia was noted in four patients with low-grade dysplasia (100%). Gastric IM persisted in all patients with baseline metaplasia but the severity of IM improved in 6 (75%) patients. Endoscopic RFA was safe with minimal complications encountered. CONCLUSIONS: RFA successfully eradicated low-grade dysplasia of the stomach. Gastric IM however persisted after RFA but most patients had evidence of histological improvement on follow up.

Hospital Authority audit of the outcome of endoscopic resection of superficial upper gastro-intestinal lesions in Hong Kong.

OBJECTIVES: To review the short-term outcome of endoscopic resection of superficial upper gastro-intestinal lesions in Hong Kong. DESIGN: Historical cohort study. SETTING: All Hospital Authority hospitals in Hong Kong. PATIENTS: This was a multicentre retrospective study of all patients who underwent endoscopic resection of superficial upper gastro-intestinal lesions between January 2010 and June 2013 in all government-funded hospitals in Hong Kong. MAIN OUTCOME MEASURES: Indication of the procedures, peri-procedural and procedural parameters, oncological outcomes, morbidity, and mortality. RESULTS: During the study period, 187 lesions in 168 patients were resected. Endoscopic mucosal resection was performed in 34 (18.2%) lesions and endoscopic submucosal dissection in 153 (81.8%) lesions. The mean size of the lesions was 2.6 (standard deviation, 1.8) cm. The 30-day morbidity rate was 14.4%, and perforations and severe bleeding occurred in 4.3% and 3.2% of the patients, respectively. Among patients who had dysplasia or carcinoma, R0 resection was achieved in 78% and the piecemeal resection rate was 11.8%. Lateral margin involvement was 14% and vertical margin involvement was 8%. Local recurrence occurred in 9% of patients and 15% had residual disease. The 2-year overall survival rate and disease-specific survival rate was 90.6% and 100%, respectively. CONCLUSION: Endoscopic mucosal resection and endoscopic submucosal dissection were introduced in low-to-moderate-volume hospitals with acceptable morbidity rates. The short-term survival was excellent. However, other oncological outcomes were higher than those observed in high-volume centres and more secondary procedures were required.

Divergent trends of hospitalizations for upper and lower gastrointestinal bleeding based on population prescriptions of aspirin, proton pump inhibitors and Helicobacter pylori eradication therapy: Trends of upper and lower gastrointestinal bleeding.

BACKGROUND: With the increasing use of medications that alter the risk of gastrointestinal bleeding (GIB), comprising aspirin, proton pump inhibitors (PPIs), and Helicobacter pylori eradication therapies, the trends of GIB are evolving. OBJECTIVE: The aim of this study is to determine and predict the trends of GIB and to evaluate the effects of population prescriptions of these medications on GIB incidences. METHODS: We retrieved patients hospitalized for GIB in all public hospitals in Hong Kong between 2009 and 2019. Monthly age- and sex-standardized GIB data were fitted and predicted, based on population prescriptions of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), anticoagulants, other antiplatelet drugs, PPIs, and H. pylori therapies, using autoregressive integrated moving average model for time series analysis. RESULTS: The incidence of upper GIB (UGIB) showed a clear declining trend while lower GIB (LGIB) decreased slightly. Older population (>80 years) had the greatest decline in UGIB but was associated with an increase in LGIB. Prescriptions of PPIs and aspirin increased significantly with time. PPIs prescriptions were negatively associated with UGIB incidence (coefficient log(PPIs) -4.58; 95% confidence interval [CI]: -5.69, -3.47). H. pylori eradication in the previous month showed a nonsignificant trend on UGIB (coefficient -0.14; 95% CI: -0.30, 0.02). In contrast, aspirin increased the incidences of UGIB (coefficient 0.06; 95% CI: 0.04, 0.07) and LGIB (coefficient 0.04; 95% CI: 0.03, 0.05). NSAIDs, anticoagulants, and other antiplatelet drugs were not significantly associated with the trend of either UGIB or LGIB. UGIB is predicted to decline continuously but LGIB is projected to rise, particularly with increasing use of aspirin. CONCLUSIONS: UGIB incidences were decreasing and had been surpassed by LGIB. Based on population prescriptions of aspirin and PPIs, divergent trends of upper and lower GIB are expected, especially in elderly.

Applications of machine learning models in the prediction of gastric cancer risk in patients after Helicobacter pylori eradication.

BACKGROUND: The risk of gastric cancer after Helicobacter pylori (H. pylori) eradication remains unknown. AIM: To evaluate the performances of seven different machine learning models in predicting gastric cancer risk after H. pylori eradication. METHODS: We identified H. pylori-infected patients who had received clarithromycin-based triple therapy between 2003 and 2014 in Hong Kong. Patients were divided into training (n = 64 238) and validation sets (n = 25 330), according to period of eradication therapy. The data were used to construct seven machine learning models to predict risk of gastric cancer development within 5 years after H. pylori eradication. A total of 26 clinical variables were input into these models. The performances were measured by the area under receiver operating characteristic curve (AUC) analysis. RESULTS: During a mean follow-up of 4.7 years, 0.21% of H. pylori-eradicated patients developed gastric cancer. Of the seven machine learning models, extreme gradient boosting (XGBoost) had the best performance in predicting cancer development (AUC 0.97, 95%CI 0.96-0.98), and was superior to conventional logistic regression (AUC 0.90, 95% CI 0.84-0.92). With the XGBoost model, the number of patients considered at high risk of gastric cancer was 6.6%, with miss rate of 1.9%. Patient age, presence of intestinal metaplasia, and gastric ulcer were the heavily weighted factors used by the XGBoost. CONCLUSION: Based on simple baseline patient information, machine learning model can accurately predict the risk of post-eradication gastric cancer. This model could substantially reduce the number of patients who require endoscopic surveillance.

Transcervical Transtracheal Resection of Cervical Esophageal Smooth Muscle Tumor.

Cervical esophageal smooth muscle tumors are traditionally resected via lateral transcervical with or without video-assisted thoracoscopic approaches. Exposure is frequently limited, however, with risks of recurrent laryngeal nerve and posterior tracheal wall injury and jeopardization of cervical tracheal and cervical esophageal blood supply. We herein describe an anterior transcervical transtracheal approach to counter some of the aforementioned problems and avoid morbidities associated with thoracoscopic surgery when resecting smooth muscle tumors arising from the cervical esophagus.

Computed tomography-based deep-learning prediction of neoadjuvant chemoradiotherapy treatment response in esophageal squamous cell carcinoma.

BACKGROUND: Deep learning is promising to predict treatment response. We aimed to evaluate and validate the predictive performance of the CT-based model using deep learning features for predicting pathologic complete response to neoadjuvant chemoradiotherapy (nCRT) in esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: Patients were retrospectively enrolled between April 2007 and December 2018 from two institutions. We extracted deep learning features of six pre-trained convolutional neural networks, respectively, from pretreatment CT images in the training cohort (n = 161). Support vector machine was adopted as the classifier. Validation was performed in an external testing cohort (n = 70). We assessed the performance using the area under the receiver operating characteristics curve (AUC) and selected an optimal model, which was compared with a radiomics model developed from the training cohort. A clinical model consisting of clinical factors only was also built for baseline comparison. We further conducted a radiogenomics analysis using gene expression profiles to reveal underlying biology associated with radiological prediction. RESULTS: The optimal model with features extracted from ResNet50 achieved an AUC and accuracy of 0.805 (95% CI, 0.696-0.913) and 77.1% (65.6%-86.3%) in the testing cohort, compared with 0.725 (0.605-0.846)) and 67.1% (54.9%-77.9%) for the radiomics model. All the radiological models showed better predictive performance than the clinical model. Radiogenomics analysis suggested a potential association mainly with WNT signaling pathway and tumor microenvironment. CONCLUSIONS: The novel and noninvasive deep learning approach could provide efficient and accurate prediction of treatment response to nCRT in ESCC, and benefit clinical decision making of therapeutic strategy.

Esophagogastric Preservation in the Surgical Management of Proximal Esophageal Cancer.

BACKGROUND: Definitive chemoradiotherapy is offered for most patients with isolated cervical esophageal tumor. Surgery is reserved for locally advanced diseases and salvage for failed chemoradiotherapy. Traditionally, surgery comprises total pharyngolaryngeal esophagectomy and gastric pull-up, which is associated with high morbidity and mortality rates. We hereby propose pharyngo-laryngo-cervico-esophagectomy by a transcervical approach, allowing preservation of the esophagus and stomach below, reducing operative morbidity and mortality. METHODS: A retrospective review of 31 patients who underwent curative pharyngo-laryngo-cervico-esophagectomy for isolated cervical esophageal tumor at the Department of Surgery, The University of Hong Kong, Queen Mary Hospital, between January 1, 2005, and June 30, 2018, was performed. RESULTS: There were 26 male and 5 female patients. Median age was 64.8 years. Seventeen patients underwent definitive surgery. Fourteen patients underwent salvage surgery for failed chemoradiotherapy. Most patients presented with stage III and IV diseases (90.3%). Median length of pharyngoesophageal defect was 14.0 cm (range, 8.0-21.0 cm). Free jejunal flap was used for pharyngoesophageal reconstruction in 77.4%. Eight complications developed in 7 patients (22.6%). There was no in-hospital mortality. Clear radial and longitudinal resection margins were achieved in 96.8%. Median follow-up was 21.5 months. Locoregional recurrence rate was 32.3%. Nine patients died of disease progression (29.0%). Seven died of other causes (22.6%). Median survival was 21.5 months. Overall 2-year survival rate was 36.7%. CONCLUSIONS: Transcervical pharyngo-laryngo-cervico-esophagectomy should be considered in patients with isolated cervical esophageal tumors. Pharyngo-laryngo-cervico-esophagectomy allows adequate tumor resection while preserving the esophagus and stomach below. Operative morbidity and mortality outcomes were improved without compromising oncologic control.

Peroral Endoscopic Myotomy with EndoFLIP and Double-Endoscope: Novel Techniques for Achalasia in Pediatric Population.

BACKGROUND: Experience of peroral endoscopic myotomy (POEM) for treatment of achalasia in pediatric population is limited with varying techniques in different centers. The accurate extent of submucosal tunneling into the gastric cardia and the adequacy of myotomy are the important determining factors to success of POEM. A majority of studies in pediatric population have described using submucosal dye injection for assessing the adequacy of myotomy, however, this is a rather crude and inaccurate method. We herein describe the first case of pediatric achalasia managed with POEM incorporated with novel combined techniques using EndoFLIP® (Endoluminal Functional Lumen Imaging Probe) and double endoscope. METHODS: Esophagogastric junction (EGJ) was identified with a gastroscope. Before POEM, EndoFLIP showed EGJ distensibility index of 1.7 mm2/mmHg. Submucosal tunnel was created from the mucosal entry site at midesophagus down and ∼3 cm beyond the EGJ. Anterior myotomy cutting the circular muscle layer while preserving the longitudinal muscle was performed for 8 cm. Double-endoscope technique was used to confirm the adequacy of myotomy by inserting a smaller endoscope through nostril into stomach and observing the transillumination of the first endoscope at the end of submucosal tunnel. After POEM, repeat EndoFLIP measurements revealed increased distensibility index to 6.0 mm2/mmHg. Endoscopic examination at the end of the procedure showed widely patent EGJ. RESULTS: Eckardt symptoms score improved from 9 to 0. At 7 month after POEM, esophagoscopy showed widely open EGJ with no esophagitis, and high-resolution esophageal manometry revealed normalized lower esophageal sphincter pressure and resting tone. CONCLUSIONS: We introduced the intraoperative use of EndoFLIP system that allows real-time assessment of EGJ distensibility and immediate treatment effect evaluation. Incorporation of double-endoscope POEM was also first described in our pediatric patient for ensuring complete gastric myotomy. From our experiences, POEM for achalasia in pediatric population appears to have encouraging results similar to adult patients.

Cancer cell-secreted IGF2 instigates fibroblasts and bone marrow-derived vascular progenitor cells to promote cancer progression.

Local interactions between cancer cells and stroma can produce systemic effects on distant organs to govern cancer progression. Here we show that IGF2 secreted by inhibitor of differentiation (Id1)-overexpressing oesophageal cancer cells instigates VEGFR1-positive bone marrow cells in the tumour macroenvironment to form pre-metastatic niches at distant sites by increasing VEGF secretion from cancer-associated fibroblasts. Cancer cells are then attracted to the metastatic site via the CXCL5/CXCR2 axis. Bone marrow cells transplanted from nude mice bearing Id1-overexpressing oesophageal tumours enhance tumour growth and metastasis in recipient mice, whereas systemic administration of VEGFR1 antibody abrogates these effects. Mechanistically, IGF2 regulates VEGF in fibroblasts via miR-29c in a p53-dependent manner. Analysis of patient serum samples showed that concurrent elevation of IGF2 and VEGF levels may serve as a prognostic biomarker for oesophageal cancer. These findings suggest that the Id1/IGF2/VEGF/VEGFR1 cascade plays a critical role in tumour-driven pathophysiological processes underlying cancer progression.

Dual-Tracer PET/CT Using 18F-FDG and 11C-Acetate in Gastric Adenocarcinoma With Liver Metastasis.

Dual-tracer F-FDG and C-acetate PET/CT has been shown to demonstrate good sensitivity and specificity for the diagnosis of hepatocellular carcinoma. We present a case of gastric adenocarcinoma with liver metastasis with positive uptake of F-FDG and C-acetate highlighting an unusual appearance in dual-tracer PET/CT.

PET/CT in the evaluation of treatment response to neoadjuvant chemoradiotherapy and prognostication in patients with locally advanced esophageal squamous cell carcinoma.

OBJECTIVE: To investigate the role of fluorine-18-fluorodeoxyglucose PET/computed tomography for the prognostication and evaluation of neoadjuvant chemoradiotherapy response in locally advanced esophageal squamous cell carcinoma. METHODS: All consecutive biopsy-proven esophageal squamous cell carcinoma patients with PET/computed tomography at baseline (PET0) and 1 month after the completion of neoadjuvant chemoradiotherapy (PET1) between January 2008 and December 2013, followed by esophagectomy, were included. Maximum and mean standard uptake values (SUVmax and SUVmean), metabolic tumor volume, and total lesion glycolysis of all lesions at PET0 and PET1 were analyzed. Logistic and Cox regressions were used to identify factors predictive of pathological complete remission (pCR), overall survival, and recurrence-free survival. Cut-offs were identified using leave-one-out cross-validation adjusted receiver operator curve-based methods. A Kaplan-Meier model was adopted to compare survivals between groups using log-rank tests. RESULTS: Of a total of 52 patients (45 men, age 21-78 years), pCR was achieved in 21 (40.4%). SUVmax of primary tumor at PET1 was independently predictive of pCR [P=0.013, odds ratio=0.736, 95% confidence interval (CI): 0.578-0.937]; using a leave-one-out cross-validation-adjusted cut-off of 2.7, pCR could be predicted with a sensitivity of 71.0%, a specificity of 66.7%, a positive predictive value of 75.9%, and a negative predictive value of 60.9%. In the subset of 40 patients with standardized treatment included in survival analysis, total lesion glycolysis (P=0.002, hazard ratio: 1.029, 95% CI: 1.01-1.048) and SUVmax (P=0.003, hazard ratio: 1.167, 95% CI: 1.055-1.290) of nodal metastasis at PET0 were independently predictive of overall survival and recurrence-free survival, respectively. CONCLUSION: Baseline total lesion glycolysis and SUVmax of nodal metastases are significant independent predictors of survival, whereas post-treatment SUVmax of the primary tumor is predictive of pCR. However, the predictive value of the latter is modest, which may limit its clinical utility.