RNA-based liquid biopsies for better clinical management of Barrett’s esophagus and esophageal adenocarcinoma

In the past decades the incidence of esophageal adenocarcinoma (EAC) has increased dramatically in most Western populations. Due to the lack of symptoms EAC is often detected in a late stage, contributing to a poor 5-year survival rate. The potential of RNA (coding and miRNA) as circulating biomarker in blood has already been shown for many cancer entities but requires further investigation for EAC. In this study we will explore several RNA types in blood, including microRNA, messenger RNA, long non-coding RNA and circular RNA as a potential liquid biomarker to facilitate early diagnosis, prognosis and monitoring of esophageal adenocarcinoma We have been collecting blood and tissue samples from patients with non-dysplastic Barrett’s esophagus (NDBE), high-grade dysplasia (HGD) and EAC. Currently, our biobank includes >5000 samples from 120 patients. A proof-of-concept study was conducted including 17 patients from three groups (EAC, HGD and NDBE). For each patient, biopsies from diseased tissue and healthy tissue as well as blood were collected and analyzed using small RNA and total RNA sequencing. Gene expression analysis was performed to identify differentially expressed genes across the three groups. The highest number of significantly differentially expressed m(i)RNAs were present in the tissues of EAC versus NDBE patients, while these differences were much lower or even absent in the plasma samples. Moreover, we have identified between 1500 and 7500 unique circular RNAs in individual EAC cancer patients’ plasma, indicating promising opportunities for a blood-based liquid biomarker for BE and EAC. Currently, we are collecting additional samples to significantly increase the power of the differential expression study as well as to verify the results of our proof-of-concept study

Definitions and treatment of oligometastatic oesophagogastric cancer according to multidisciplinary tumour boards in Europe

Oesophageal neoplasm; Oligometastasis; RadiosurgeryNeoplàsia esofàgica; Oligometàstasi; RadiocirurgiaNeoplasia esofágica; Oligometástasis; RadiocirugíaBackground Consensus about the definition and treatment of oligometastatic oesophagogastric cancer is lacking. Objective To assess the definition and treatment of oligometastatic oesophagogastric cancer across multidisciplinary tumour boards (MDTs) in Europe. Material and methods European expert centers (n = 49) were requested to discuss 15 real-life cases in their MDT with at least a medical, surgical, and radiation oncologist present. The cases varied in terms of location and number of metastases, histology, timing of detection (i.e. synchronous versus metachronous), primary tumour treatment status, and response to systemic therapy. The primary outcome was the agreement in the definition of oligometastatic disease at diagnosis and after systemic therapy. The secondary outcome was the agreement in treatment strategies. Treatment strategies for oligometastatic disease were categorised into upfront local treatment (i.e. metastasectomy or stereotactic radiotherapy), systemic therapy followed by restaging to consider local treatment or systemic therapy alone. The agreement across MDTs was scored to be either absent/poor (<50%), fair (50%–75%), or consensus (≥75%). Results A total of 47 MDTs across 16 countries fully discussed the cases (96%). Oligometastatic disease was considered in patients with 1–2 metastases in either the liver, lung, retroperitoneal lymph nodes, adrenal gland, soft tissue or bone (consensus). At follow-up, oligometastatic disease was considered after a median of 18 weeks of systemic therapy when no progression or progression in size only of the oligometastatic lesion(s) was seen (consensus). If at restaging after a median of 18 weeks of systemic therapy the number of lesions progressed, this was not considered as oligometastatic disease (fair agreement). There was no consensus on treatment strategies for oligometastatic disease. Conclusion A broad consensus on definitions of oligometastatic oesophagogastric cancer was found among MDTs of oesophagogastric cancer expert centres in Europe. However, high practice variability in treatment strategies exists

Evaluation of parenteral nutrition use in patients undergoing major upper gastro-intestinal surgery

Abstract Background After major upper gastro-intestinal surgery, enteral feeding is often hampered. There is still no consensus on which route of nutrition is preferable in patients undergoing this type of surgery. Current ESPEN guidelines recommend parenteral nutrition in undernourished patients, if caloric requirements cannot be met orally/enterally within 7 days and enteral nutrition is contraindicated. Objective The current practice of systematic parenteral nutrition at the thoracic surgery ward of the University Hospitals Leuven was evaluated based on the ESPEN guidelines. Method This prospective observational study included patients undergoing upper gastro-intestinal surgery and receiving postoperative parenteral nutrition. Parenteral nutrition use was considered appropriate when patients were undernourished and unable to obtain adequate caloric requirements by oral or enteral feeding within 7 days. Results Twenty-five out of 35 patients were nutritionally at risk. In 9 of 25 patients, the indication for parenteral nutrition was considered justified. As the intestinal tract below the anastomosis site remains accessible in the total studied population, enteral nutrition might be an option. Unfortunately, an appropriate jejunostomy tube was not available at our institution. Conclusion In accordance to the ESPEN guidelines, enteral nutrition can replace parenteral nutrition in most thoracic surgery patients, but only if an appropriate enteral access is available

Proposal for the delineation of neoadjuvant target volumes in oesophageal cancer

PURPOSE: To define instructions for delineation of target volumes in the neoadjuvant setting in oesophageal cancer. MATERIALS AND METHODS: Radiation oncologists of five European centres participated in the following consensus process: [1] revision of published (MEDLINE) and national/institutional delineation guidelines; [2] first delineation round of five cases (patient 1-5) according to national/institutional guidelines; [3] consensus meeting to discuss the results of step 1 and 2, followed by a target volume delineation proposal; [4] circulation of proposed instructions for target volume delineation and atlas for feedback; [5] second delineation round of five new cases (patient 6-10) to peer review and validate (two additional centres) the agreed delineation guidelines and atlas; [6] final consensus on the delineation guidelines depicted in an atlas. Target volumes of the delineation rounds were compared between centres by Dice similarity coefficient (DSC) and maximum/mean undirected Hausdorff distances (Hmax/Hmean). RESULTS: In the first delineation round, the consistency between centres was moderate (CTVtotal: DSC = 0.59-0.88; Hmean = 0.2-0.4 cm). Delineations in the second round were much more consistent. Lowest variability was obtained between centres participating in the consensus meeting (CTVtotal: DSC: p < 0.050 between rounds for patients 6/7/8/10; Hmean: p < 0.050 for patients 7/8/10), compared to validation centres (CTVtotal: DSC: p < 0.050 between validation and consensus meeting centres for patients 6/7/8; Hmean: p < 0.050 for patients 7/10). A proposal for delineation of target volumes and an atlas were generated. CONCLUSION: We proposed instructions for target volume delineation and an atlas for the neoadjuvant radiation treatment in oesophageal cancer. These will enable a more uniform delineation of patients in clinical practice and clinical trials

Definition, diagnosis and treatment of oligometastatic oesophagogastric cancer: A Delphi consensus study in Europe

BACKGROUND Local treatment improves the outcomes for oligometastatic disease (OMD, i.e. an intermediate state between locoregional and widespread disseminated disease). However, consensus about the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer is lacking. The aim of this study was to develop a multidisciplinary European consensus statement on the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer. METHODS In total, 65 specialists in the multidisciplinary treatment for oesophagogastric cancer from 49 expert centres across 16 European countries were requested to participate in this Delphi study. The consensus finding process consisted of a starting meeting, 2 online Delphi questionnaire rounds and an online consensus meeting. Input for Delphi questionnaires consisted of (1) a systematic review on definitions of oligometastatic oesophagogastric cancer and (2) a discussion of real-life clinical cases by multidisciplinary teams. Experts were asked to score each statement on a 5-point Likert scale. The agreement was scored to be either absent/poor (<50%), fair (50%-75%) or consensus (≥75%). RESULTS A total of 48 experts participated in the starting meeting, both Delphi rounds, and the consensus meeting (overall response rate: 71%). OMD was considered in patients with metastatic oesophagogastric cancer limited to 1 organ with ≤3 metastases or 1 extra-regional lymph node station (consensus). In addition, OMD was considered in patients without progression at restaging after systemic therapy (consensus). For patients with synchronous or metachronous OMD with a disease-free interval ≤2 years, systemic therapy followed by restaging to consider local treatment was considered as treatment (consensus). For metachronous OMD with a disease-free interval >2 years, either upfront local treatment or systemic treatment followed by restaging was considered as treatment (fair agreement). CONCLUSION The OMEC project has resulted in a multidisciplinary European consensus statement for the definition, diagnosis and treatment of oligometastatic oesophagogastric adenocarcinoma and squamous cell cancer. This can be used to standardise inclusion criteria for future clinical trials

ISDE presidential biography: Antoon (Toni) Lerut

status: publishe

De continue zoektocht naar kwaliteitsverbetering na oesofagectomie voor kanker.

Summary Radical surgery currently remains the most realistic chance of cure for cancer of the esophagus or gastro esophageal junction (GEJ). Nowadays experienced centers consistently perform such an aggressive surgery with perioperative mortality rates of 3 to 5% and obtain overall 5-years survival rates of at least 35 to 40%, even after neoadjuvant treatment. Although results have improved, the majority of patients will ultimately die from locoregional or systemic recurrent disease. Furthermore, despite considerable improvements in surgical technique and perioperative care over the last 2 decades, the morbidity and impact on quality of life of esophageal resection remains substantial. As a consequence, careful study of esophageal cancer to obtain new insights and to develop new pathways to improve the quality and the related outcome remain the principal goal of all involved health–care professionals. In this thesis, we have shown that a rigorous analysis of our database of more than 2500 patients, we could assess a number of selected and specific qualitative aspects related to pathological staging, surgical therapy and quality of life indices in esophageal cancer patients. By doing so, we have brought some interesting new insights in addressing the qualitative aspects of the treatment of esophageal cancer at several levels. They were already implemented or will serve to improve and guide ongoing esophageal cancer treatment. Quality of pathological evaluation The 7th edition (2010) of the TNM staging system refining the previous versions, has introduced (as in other cancers) the notion of number of involved lymph nodes but did not take into account characteristics of the lymph node itself despite our group being the first to really highlight the importance of nodal capsular breakthrough on survival. In view of the eighth revision, the impact of the capsular status, being intracapsular or extracapsular involvement, was further examined as prognostic factor. In Chapter 3 (Eur J Cardiothorac Surg. 2014;28:1001-10) extracapsular lymph node invasion was confirmed as an independent negative prognostic factor in pN1 adenocarcinoma patients (i.e. 1 or 2 involved lymph nodes) treated by primary surgery and furthermore it was suggested that incorporating these results in the TNM classification systems could increase its prognostic performance. This paved the way for a large multicentric study described in Chapter 4, involving 6 high volume tertiary referral centers in Europe who underwent primary surgery. Our findings on the impact of extracapsular involvement in pN1 patients were confirmed on this large dataset and furthermore the results suggested that absence of extracapsular involvement in pN1 patients gave a 5-year survival comparable to stage IIB (i.e. pT3N0).These results are a plea to incorporate presence/absence of extracapsular lymph node involvement in the upcoming 8th edition of the UICC/AJJC TNM staging manual. In the current literature there is still no consensus on the definition of a microscopically incomplete resection (the so called R1 resection) as different definition are used and results from the literature are conflicting. Therefore in Chapter 5 (Submitted to Dis Esoph.) an analysis was performed on a homogeneous group of pT3 patients treated with primary surgery. Multivariate analysis showed that besides the number of involved lymph nodes, only a true R1-resection was statistically different from a complete (R0) resection. Chapter 6 (Ann Surg 2014;260: 1023-1029) explored the biological behavior and the prognosis of a specific subtype of esophageal adenocarcinoma: the Signet Ring Cell carcinoma (SRC). In the literature on stomach cancer, this subtype shows a worse prognosis but on the contrary, Literature data on esophageal SRC carcinoma are scarce. In this series on adenocarcinoma patients treated by primary surgery, SRC was shown to have a more aggressive behavior compared to classic adenocarcinoma with more involved lymph nodes, and hence a significant worse 5-year survival. However in lymph node positive patients, SRC 50% group (0% 5-year survival). The survival difference is mainly explained by the higher number of recurrences in the SRC >50% group. Our data also showed that it is impossible to discriminate between ADC and SCR >50% solely based on the preoperative biopsies. Quality of surgery Overall and pulmonary complication rates after open esophagectomy (OO) have remained sufficiently high to encourage the search for alternative operative techniques. The main purposes of these techniques are to achieve similar cure rates with less morbidity/mortality, which may lead to a better postoperative quality of life whilst guaranteeing the same oncologic outcome. In chapter 7 (Eur J Cardiothorac Surg. 2011;40:1455-63), we have shown that minimally invasive esophagectomy compared to open transthoracic esophagectomy in early cancers of the esophagus and gastro-esophageal junction had decreased significantly pulmonary complications and subsequent admissions to ICU. Minimally invasive esophagectomy had improved the quality of life after 3 months but differences between both groups faded away at one year. From this experience we have been able to gradually expand the use of this technique in more advanced cancer without jeopardizing the oncologic aspects of the surgery. The Achilles heel of gastric pull up after any esophagectomy is anastomotic leak and the subsequent risk of stricture interfering with the patient’s ability to swallow. In Chapter 8 ( submitted to J Surg Oncol.) a promising new semi-mechanical anastomotic technique was compared to the classical surgical hand-sewn anastomosis. The need for dilatation and especially the need for repeated dilatations were significantly lower after semi-mechanical anastomosis with comparable anastomotic leakage rate. Furthermore an analysis of the QOL dysphagia (sub) scores showed a clinically relevant improved dysphagia score for semi-solids and saliva in the early postoperative phase in the SMA group. Our results confirmed that the semi-mechanical anastomosis can be used safely after gastric tubulation thus not compromising resection of the lesser curvature, an important oncologic principle for distal-half and gastro-esophageal tumors. This type of anastomosis has become our anastomosis of choice whenever possible. The main aims of neoadjuvant treatment are to enhance the number of R0-resections and thus lowering the number of recurrences in particular locoregional recurrence after surgery. From the literature it is well known that the best survival rates after neoadjuvant treatment followed by surgery are seen after pathological complete respons (pCR). However little is known about the recurrence pattern after neoadjuvant chemo-radiotherapy followed by surgery, especially in case of pathological complete response. This was examined in Chapter 8 (Br J Surg 2013;100:267-73). With a complete response achieved in one third of the patients, a statistically significant improved 3-year survival and decreased recurrence rate was shown for complete responders. Nevertheless, with distant metastasis in one third and loco-regional failure in one out of 7 patients, pathological complete response is not synonymous with ‘cure’ or perfect locoregional control. Even in case of pathological complete response, aggressive surgical approach is thus still warranted. Health related quality of life Health-related quality of life has become increasingly important in treating cancer patients. This is especially true for esophageal cancer surgery which is known to have an important negative impact on patient’s HRQL. Several studies on this subject have already been published but due to small population samples, differences in surgical approaches and/or in the questionnaires used to evaluate HRQL, results have been inconsistent and difficult to analyse. Furthermore, little is known about the impact of preoperative HRQL on postoperative morbidity and likewise, the impact of postoperative complications on postoperative HRQL. Chapter 9 (Eur J Cardiothorac Surg ;44:525-33) is devoted to the relations between HRQOL and the postoperative course. In our study, independent prognosticators for a longer LOS (>10 days) were: medical and surgical complications, readmission to intensive care unit and poor physical functioning. Furthermore, our data suggested that early discharge correlates with improved postoperative HRQL outcomes. The different chapters/parts of this thesis project have highlighted the importance of the continuous quest of quality improvement as the key to improved results and survival in esophageal cancer treatment. So today cure is no longer an accident and surgery is now offering the patient a realistic perspective for a long-term survival combined with a good quality of life.nrpages: 276status: publishe

Extracapsular lymph node involvement after neoadjuvant chemoradiation in esophageal carcinoma: how to interpret?

status: publishe

In regards to Allen et al. (Int J radiat oncol biol phys 2006;65: 640-645)

A

Preoperative weight loss and underweight: When it is becoming clinically significant in esophageal cancer

status: publishe