Minimally invasive surgery for gastro-oesophageal junction adenocarcinoma: Current evidence and future perspectives

Minimally invasive surgery is increasingly indicated in the management of malignant disease.Although oesophagectomy is a difficult operation,with a long learning curve,there is actually a shift towards the laparoscopic/thoracoscopic/robotic approach,due to the advantages of visualization,surgeon comfort(robotic surgery)and the possibility of the whole team to see the operation as well as and the operating surgeon.Although currently there are still many controversial topics,about the surgical treatment of patients with gastro-oesophageal junction(GOJ)adenocarcinoma,such as the type of open or minimally invasive surgical approach,the type of oesophago-gastric resection,the type of lymph node dissection and others,the minimally invasive approach has proven to be a way to reduce postoperative complications of resection,especially by decreasing pulmonary complications.The implementation of new technologies allowed the widening of the range of indications for this type of surgical approach.The short-term and long-term results,as well as the benefits for the patient-reduced surgical trauma,quick and easy recovery-offer this type of surgical treatment the premises for future development.This article reviews the updates and perspectives on the minimally invasive approach for GOJ adenocarcinoma.

Upper aerodigestive tract disorders and gastro-oesophageal reflux disease

A wide variety of symptoms and diseases of the upper aerodigestive tract are associated to gastro-oesophageal reflux disease(GORD). These disorders comprise a large variety of conditions such as asthma, chronic otitis media and sinusitis, chronic cough, and laryngeal disorders including paroxysmal laryngospasm. Laryngopharyngeal reflux disease is an extraoesophageal variant of GORD that can affect the larynx and pharynx. Despite numerous research efforts, the diagnosis of laryngopharyngeal reflux often remains elusive,unproven and controversial, and its treatment is then still empiric. Aim of this paper is to review the current literature on upper aerodigestive tract disorders in relation to pathologic gastro-oesophageal reflux, focusing in particular on the pathophysiology base and results of the surgical treatment of GORD.

Impact of postoperative TNM stages after neoadjuvant therapy on prognosis of adenocarcinoma of the gastro-oesophageal junction tumours

AIM To compare prognostic relevance of postoperative tumour/node/metastasis(TMN) stages between patients with and without neoadjuvant treatment. METHODS Data from patients with adenocarcinoma of the gastrooesophageal junction(AEG) who had undergone surgical resection at a single German university centre were retrospectively analysed. Patients with or without neoadjuvant preoperative treatment were selected by exact matching based on preoperative staging. Standard assessment of preoperative(c)TNM stage was based on endoscopic ultrasound and computed tomography of the thorax and abdomen, according to the American Joint Committee on Cancer/Union for International Cancer Control classification system. Patients with cT1cN0cM0 and cT2cN0cM0 stages were excluded from the study, as these patients are generally not recommended for pretreatment. Longterm survival among the various postoperative TNM stages was compared between the groups of patients with or without neoadjuvant treatment. For statistical assessments, a P-value of ≤ 0.05 was considered significant.RESULTS The study included a total of 174 patients. The group of patients who had received preoperative neoadjuvant treatment included more cases of AEG(Siewert) type 1 carcinoma(P < 0.001), and consequently oesophagectomy was performed more frequently among these patients(P < 0.001). The two groups(with or without preoperative neoadjuvant treatment) had comparable preoperative T stages, but the group of patients with preoperative neoadjuvant treatment presented a higher rate of preoperative N-positive disease(P = 0.020). Overall long-term survival was not different between the two groups of patients according to tumours of different AEG classifications, receipt of oesophagectomy or gastrectomy, nor between patients with similar postoperative TNM stage, resection margin and grading. However, an improvement of long-term survival was found for patients with nodal down-staging after neoadjuvant therapy(P = 0.053).CONCLUSION The prognostic relevance of postoperative TNM stages is similar for AEG in patients with or without neoadjuvant preoperative treatment, but treatment-related nodal down-staging prognosticates longer-term survival.

HER2 inhibition in gastro-oesophageal cancer:A review drawing on lessons learned from breast cancer

Human epidermal growth factor receptor 2(HER2)-inhibition is an important therapeutic strategy in HER2-amplified gastro-oesophageal cancer(GOC).A significant proportion of GOC patients display HER2 amplification,yet HER2 inhibition in these patients has not displayed the success seen in HER2 amplified breast cancer.Much of the current evidence surrounding HER2 has been obtained from studies in breast cancer,and we are only recently beginning to improve our understanding of HER2-amplified GOC.Whilst there are numerous licensed HER2 inhibitors in breast cancer,trastuzumab remains the only licensed HER2 inhibitor for HER2-amplified GOC.Clinical trials investigating lapatinib,trastuzumab emtansine,pertuzumab and MM-111 in GOC have demonstrated disappointing results and have not yet changed the treatment paradigm.Trastuzumab deruxtecan may hold promise and is currently being investigated in phase Ⅱ trials.HER2 amplified GOC differs from breast cancer due to inherent differences in the HER2 amino-truncation and mutation rate,loss of HER2 expression,alterations in HER2 signalling pathways and differences in insulin-like growth factor-1 receptor and MET expression.Epigenetic alterations involving different micro RNA profiles in GOC as compared to breast cancer and intrinsic differences in the immune environment are likely to play a role.The key to effective treatment of HER2 amplified GOC lies in understanding these mechanisms and tailoring HER2 inhibition for GOC patients in order to improve clinical outcomes.

Gastro-oesophageal reflux disease and eosinophilic oesophagitis: What is the relationship?

Eosinophilic oesophagitis(EoE) and gastro-oesophageal reflux disease(GORD) are the most common causes of chronic oesophagitis and dysphagia associated with oesophageal mucosal eosinophilia. Distinguishing between the two is imperative but challenging due to overlapping clinical and histological features. A diagnosis of EoE requires clinical, histological and endoscopic correlation whereas a diagnosis of GORD is mainly clinical without the need for other investigations. Both entities may exhibit oesophageal eosinophilia at a similar level making a histological distinction between them difficult. Although the term proton-pump inhibitor responsive oesophageal eosinophilia has recently been retracted from the guidelines, a relationship between Eo E and GORD still exists. This relationship is complex as they may coexist, either interacting bidirectionally or are unrelated. This review aims to outline the differences and potential relationship between the two conditions, with specific focus on histology, immunology, pathogenesis and treatment.

Efficacy of Drugs Used in Gastro-Oesophageal Reflux:Network Meta-Analysis

Introduction: It is important to rank the clinical efficacy of different anti-reflux agents to promote their rational use. Objective: To combine the results of randomized clinical trials that have compared the incidence of symptoms related to gastro-oesophageal reflux (GER) with/without endoscopic evidence of oesophagitis in a network meta-analysis and thus rank the main anti-reflux therapies according to the magnitude of their clinical efficacy. Method: Inclusion criteria: 1) randomized controlled trials that compare anti-reflux agents (alginates (ALG), proton-pump inhibitors (PPI), H2 histamine receptor antagonists (H2RA), antacids (AA), gastrokinetics (GK)) in open designs as compared to placebo or in comparative designs (head-to-head);2) outcome of interest measured in some scale representing the significant improvement of reflux symptoms;3) GER diagnosis with/without oesophagitis endoscopic evidence. We collected available clinical trials for each one of the direct comparisons. The Odds Ratio (OR) was used additionally to calculating lnOR and its Standard Error (SE[lnOR]) to measure effects in a network meta-analysis. Results: Network meta-analysis has placebo as a reference intervention. Initial treatments with PPI or ALG are the two interventions that significantly differ from the others: H2RA, AA and GK. At the same time, the latter are significantly different from the placebo. In contrast to placebo, ORs for ALG, PPI, H2RA, AA and GK were 4.72 (95% CI: 3.39, 6.57), 4.00 (95% CI: 3.30, 4.85), 1.73 (95% CI: 1.54, 1.95), 1.41 (95% CI: 1.12, 1.76), and 1.86 (95% CI: 1.32, 2.63), respectively. Conclusion: ALG or PPI seem to be the two most effective alternatives in short-time management of GER with or without oesophagitis.

Overlap of functional heartburn and gastroesophageal reflux disease with irritable bowel syndrome

Several studies indicate a significant degree of overlap between irritable bowel syndrome(IBS)and gastroesophageal reflux disease(GERD).Likewise,both functional heartburn(FH)and IBS are functional digestive disorders that may occur in the same patients.However,data establishing a solid link between FH and IBS are lacking,mainly because the clinical definition of FH has undergone substantial changes over the years.The available literature on the overlap between GERD or FH and IBS highlights considerable heterogeneity in terms of the criteria and diagnostic procedures used to assess heartburn and IBS.In particular,several epidemiological studies included patients with concomitant IBS and GERD without any attempt to distinguish FH(as defined by the RomeⅢcriteria)from GERD via pathophysiological investigations.Independent of these critical issues,there is preliminary evidence supporting a significantdegree of FH-IBS overlap.This underscores the need for studies based on updated diagnostic criteria and accurate pathophysiological classifications,particularly to distinguish FH from GERD.This distinction would represent an essential starting point to achieving a better understanding of pathophysiology in the subclasses of patients with GERD and FH and properly assessing the different degrees of overlap between IBS and the subcategories of heartburn.The present review article intends to appraise and critically discuss current evidence supporting a possible concomitance of GERD or FH with IBS in the same patients and to highlight the pathophysiological relationships between these disorders.

Characterisation and risk assessment of venous thromboembolism in gastrointestinal cancers

AIM To characterise venous thromboembolism(VTE) in gastrointestinal cancer and assess the clinical utility of risk stratification scoring. METHODS We performed a retrospective analysis using electronic patient records of 910 gastro-oesophageal(GO) cancer and 1299 colorectal cancer(CRC) patients referred to a tertiary cancer centre to identify the incidence of VTE, its relationship to chemotherapy and impact on survival.VTE risk scores were calculated using the Khorana index. Patients were classified as low risk(0 points), intermediate risk(1 to 2 points) or high risk(3 points). Data was analysed to determine the sensitivity of the Khorana score to predict VTE. RESULTS The incidence of VTE was 8.9% for CRC patients and 9.7% for GO cancer patients. Pulmonary emboli(PE) were more common in advanced than in localised CRC(50% vs 21% of events respectively) and lower limb deep vein thrombosis(DVT) were more common in localised than in advanced CRC(62% vs 39% of events respectively). The median time to VTE from cancer diagnosis was 8.3 mo for CRC patients compared to 6.7 mo in GO cancer. In localised CRC median time to VTE was 7.1 mo compared with 10.1 mo in advanced CRC. In contrast in GO cancer, the median time to VTE was 12.5 mo in localised disease and 6.8 mo in advanced disease. No survival difference was seen between patients with and without VTE in this cohort. The majority of patients with CRC in whom VTE was diagnosed had low or intermediate Khorana risk score(94% for localised and 97% in advanced CRC). In GO cancer, all patients scored either intermediate or high risk due to the primary site demonstrating a limitation of the risk assessment score in discriminating high and low risk patients with GO cancers. Additional risk factors were identified in this cohort including surgery, chemotherapy or hospital admission. Overall, 81% of patients with CRC and 77% of patients with GO cancer had one or more of these factors within 4 wk prior to diagnosis VTE. These should be factored into clinical risk assessment scores. CONCLUSION The Khorana score has low sensitivity for thrombotic events in CRC and cannot discriminate low risk patients in high risk cancer sites such as GO cancer.

Does (supra)gastric belching trigger recurrent hiccups?

Twenty-four hours multichannel intraesophageal impedance and pH monitoring in a patient who suffered from recurrent hiccups for more than a year revealed frequent supragastric belching and pathological oesophageal acid exposure. Furthermore, a temporal relationship between the start of a hiccup episode and gastric belching was observed. The data support the hypothesis that there is an association between supragastric belching, persistent recurrent hiccups and gastro-oesophageal reflux disease, and that gastric belching may evoke hiccup attacks.

Cost-Utility Analysis of Nivolumab plus Chemotherapy in the First-Line Treatment of Upper Gastrointestinal Adenocarcinoma

Objective: To evaluate the cost-utility of nivolumab plus chemotherapy compared with chemotherapy alone as the first-line treatment for advanced gastric, gastro-oesophageal junction, and esophageal adenocarcinoma in China. Methods: Based on CheckMate649, a partitioned survival model was carried out with a circulation cycle of 6 weeks to simulate the patient’s lifetime. Sensitivity analysis were adopted to verify the robustness of the results. Results: The results of the base-case analysis showed that both the total cost and utility of the nivolumab group were higher, and the ICUR value was CNY 267498.67/QALY, more than 3 times the GDP per capita of China in 2020. The results of deterministic sensitivity analysis indicated that the three most influential factors were the utility value of PFS state, the cost of nivolumab and the discount rate. The results of probabilistic sensitivity analysis were consistent with those of base-case analysis, proving that the results were robust. The scenario analysis illustrated that economical price of nivolumab was CNY 3652.71. Conclusions: Under the willing-to-pay threshold of three times the GDP per capita of China in 2020, compared with chemotherapy alone, nivolumab plus chemotherapy is not a cost-effective option in China.