The effectivity of targeted therapy and immunotherapy in patients with advanced metastatic and non-metastatic cancer of the esophagus and esophago-gastric junction.

Therapies that target specific tumor drivers or immune checkpoints are increasingly explored for esophageal cancer patients. This review addresses developments in therapies with targeted anti-human epidermal growth factor receptor 2 (HER2) agents and immune checkpoint inhibitors in patients with stage IV esophageal cancer. First-line palliative treatment with the anti-HER2 agent trastuzumab in combination with chemotherapy has been approved for use in patients with HER2 positive gastro-esophageal adenocarcinoma. Neoadjuvant chemoradiotherapy plus perioperative trastuzumab however has not demonstrated a survival benefit in advanced esophageal cancer patients eligible for surgery. Potentially better responses are expected with dual agent anti-HER2 therapy instead of monotherapy. In the metastatic setting, the antibody-drug conjugate trastuzumab deruxtecan is effective after progression on trastuzumab. Nivolumab and pembrolizumab, antibodies blocking the programmed cell death 1 (PD-1) receptor on T cells, have recently gained approval for clinical use in esophageal cancer patients for specific indications. Synergistic effects might be achieved with combinations of immune checkpoint inhibitors that target PD-1 on T cells or PD ligand 1 (PD-L1) on tumor cells and anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) receptor on T cells. Multiple clinical trials investigating combinations of targeted and immunotherapies, with or without (neo)adjuvant chemo(radio)therapy, for curative and palliative treatment, are underway, and are expected to deliver a long-awaited improvement in the prognosis of esophageal cancer patients.

Pattern of recurrence in patients with a pathologically complete response after neoadjuvant chemoradiotherapy and surgery for oesophageal cancer.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) and surgery is a widely used treatment for locally advanced resectable oesophageal cancer, with 20-50 per cent of patients having a pathological complete response (pCR). Disease, however, still recurs in 20-30 per cent of these patients. The aim of this study was to assess the pattern of recurrence in patients with a pCR after nCRT and surgery. METHODS: All patients with a pCR after nCRT and surgery included in the phase II and III CROSS (ChemoRadiotherapy for Oesophageal followed by Surgery Study) trials (April 2001 to December 2008) and after the CROSS trials (September 2009 to October 2017) were identified. The site of recurrence was compared with the applied radiation and surgical fields. Outcomes were median time to recurrence, and overall and progression-free survival. RESULTS: A total of 141 patients with a median follow-up of 100 (i.q.r. 64-134) months were included. Some 29 of 141 patients (20,6 per cent) developed recurrence. Of these, four had isolated locoregional recurrence, 15 had distant recurrence only, and ten had both locoregional and distant recurrence. Among the 14 patients with locoregional recurrences, five had recurrence within the radiation field, seven outside the radiation field, and two at the border. Median time to recurrence was 24 (10-62) months. The 5-year overall survival rate was 74 per cent and the recurrence-free survival rate was 70 per cent. CONCLUSION: Despite good overall survival, recurrence still occurred in 21 per cent of patients. Most recurrences were distant, outside the radiation and surgical fields.

Residual disease after neoadjuvant chemoradiotherapy for oesophageal cancer: locations undetected by endoscopic biopsies in the preSANO trial.

BACKGROUND: Active surveillance has been proposed for patients with oesophageal cancer in whom there is a complete clinical response after neoadjuvant chemoradiotherapy (nCRT). However, endoscopic biopsies have limited negative predictive value in detecting residual disease. This study determined the location of residual tumour following surgery to improve surveillance and endoscopic strategies. METHODS: The present study was based on patients who participated in the prospective preSANO trial with adenocarcinoma or squamous cell carcinoma of the oesophagus or oesophagogastric junction treated in four Dutch hospitals between 2013 and 2016. Resection specimens and endoscopic biopsies taken during clinical response evaluations after nCRT were reviewed by two expert gastrointestinal pathologists. The exact location of residual disease in the oesophageal wall was determined in resection specimens. Endoscopic biopsies were assessed for the presence of structures representing the submucosal layer of the oesophageal wall. RESULTS: In total, 119 eligible patients underwent clinical response evaluations after nCRT followed by standard surgery. Residual tumour was present in endoscopic biopsies from 70 patients, confirmed on histological analysis of the resected organ. Residual tumour was present in the resection specimen from 27 of the other 49 patients, despite endoscopic biopsies being negative. Of these 27 patients, residual tumour was located in the mucosa in 18, and in the submucosa beneath tumour-free mucosa in eight. One patient had tumour in muscle beneath tumour-free mucosa and submucosa. CONCLUSION: Most residual disease after nCRT missed by endoscopic biopsies was located in the mucosa. Active surveillance could be improved by more sampling and considering submucosal biopsies.

ANTECEDENTES: Se ha propuesto un seguimiento activo para los pacientes con cáncer de esófago en los que se logra una respuesta clínica completa tras quimiorradioterapia neoadyuvante (neoadjuvant chemoradiotherapy, nCRT). Sin embargo, las biopsias endoscópicas tienen un valor predictivo limitado para detectar la enfermedad residual. En este estudio se evaluó la localización del tumor residual tras la cirugía para poder determinar estrategias de seguimiento y endoscópicas. MÉTODOS: Este estudio se basa en pacientes que participaron en el ensayo prospectivo preSANO (adenocarcinoma o carcinoma escamoso del esófago o unión esofagogástrica en cuatro hospitales de los Países Bajos entre 2013 y 2016). Los especímenes quirúrgicos, así como las biopsias endoscópicas efectuadas durante las evaluaciones de la respuesta clínica después de nCRT fueron revisadas por dos patólogos gastrointestinales expertos. En los especímenes de resección, se determinó la localización exacta de la enfermedad residual en la pared del esófago. Se evaluaron las biopsias endoscópicas para identificar estructuras que constituyeran la capa submucosa de la pared del esófago. RESULTADOS: En total, 119 pacientes elegibles fueron sometidos a evaluaciones de la respuesta clínica tras nCRT seguida de cirugía estándar. Se detectó tumor residual en las biopsias endoscópicas de 70 pacientes, luego confirmadas en la histología de la pieza extirpada. Se identificó tumor residual en la pieza de resección de 27 de los otros 49 pacientes, a pesar de que las biopsias endoscópicas fueron negativas. En estos 27 pacientes, 18 presentaban tumor residual en la mucosa y ocho pacientes en la submucosa mas allá de una mucosa libre de tumor. Un paciente tenía tumor en el músculo más allá de una mucosa y submucosa libres de tumor. CONCLUSIÓN: La mayoría de los casos de enfermedad residual tras nCRT que no se detectaron en las biopsias endoscópicas, se localizaban en la mucosa. El seguimiento activo podría mejorar con la toma de más muestras y considerando las biopsias submucosas.

Interventions that Facilitate Shared Decision-Making in Cancers with Active Surveillance as Treatment Option: a Systematic Review of Literature.

PURPOSE OF REVIEW: Medical decisions concerning active surveillance are complex, especially when evidence on superiority of one of the treatments is lacking. Decision aids have been developed to facilitate shared decision-making on whether to pursue an active surveillance strategy. However, it is unclear how these decision aids are designed and which outcomes are considered relevant. The purpose of this study is to systematically review all decision aids in the field of oncological active surveillance strategies and outcomes used by authors to assess their efficacy. RECENT FINDINGS: A search was performed in Embase, Medline, Web of Science, Cochrane, PsycINFO Ovid and Google Scholar until June 2019. Eligible studies concerned interventions aiming to facilitate shared decision-making for patients confronted with several treatment alternatives, with active surveillance being one of the treatment alternatives. Twenty-three eligible articles were included. Twenty-one articles included patients with prostate cancer, one with thyroid cancer and one with ovarian cancer. Interventions mostly consisted of an interactive web-based decision aid format. After categorization of outcomes, seven main groups were identified: knowledge, involvement in decision-making, decisional conflict, treatment preference, decision regret, anxiety and health-related outcomes. Although active surveillance has been implemented for several malignancies, interventions that facilitate shared decision-making between active surveillance and other equally effective treatment alternatives are scarce. Future research should focus on developing interventions for malignancies like rectal cancer and oesophageal cancer as well. The efficacy of interventions is mostly assessed using short-term outcomes.

Diagnostic criteria and symptom grading for delayed gastric conduit emptying after esophagectomy for cancer: international expert consensus based on a modified Delphi process.

Delayed gastric conduit emptying (DGCE) after esophagectomy for cancer is associated with adverse outcomes and troubling symptoms. Widely accepted diagnostic criteria and a symptom grading tool for DGCE are missing. This hampers the interpretation and comparison of studies. A modified Delphi process, using repeated web-based questionnaires, combined with live interim group discussions was conducted by 33 experts within the field, from Europe, North America, and Asia. DGCE was divided into early DGCE if present within 14 days of surgery and late if present later than 14 days after surgery. The final criteria for early DGCE, accepted by 25 of 27 (93%) experts, were as follows: >500 mL diurnal nasogastric tube output measured on the morning of postoperative day 5 or later or >100% increased gastric tube width on frontal chest x-ray projection together with the presence of an air-fluid level. The final criteria for late DGCE accepted by 89% of the experts were as follows: the patient should have 'quite a bit' or 'very much' of at least two of the following symptoms; early satiety/fullness, vomiting, nausea, regurgitation or inability to meet caloric need by oral intake and delayed contrast passage on upper gastrointestinal water-soluble contrast radiogram or on timed barium swallow. A symptom grading tool for late DGCE was constructed grading each symptom as: 'not at all', 'a little', 'quite a bit', or 'very much', generating 0, 1, 2, or 3 points, respectively. For the five symptoms retained in the diagnostic criteria for late DGCE, the minimum score would be 0, and the maximum score would be 15. The final symptom grading tool for late DGCE was accepted by 27 of 31 (87%) experts. For the first time, diagnostic criteria for early and late DGCE and a symptom grading tool for late DGCE are available, based on an international expert consensus process.

Quality of Life During and After Completion of Neoadjuvant Chemoradiotherapy for Esophageal and Junctional Cancer.

BACKGROUND: The course of health-related quality of life (HRQOL) during and after completion of neoadjuvant chemoradiotherapy (nCRT) for esophageal or junctional carcinoma is unknown. METHODS: This study was a multicenter prospective cohort investigation. Patients with esophageal or cancer to be treated with nCRT plus esophagectomy were eligible for inclusion in the study. The HRQOL of the patients was measured with European Organization for Research and Treatment of Cancer QLQ-C30, QLQ-OG25, and QLQ-CIPN20 questionnaires before and during nCRT, then 2, 4, 6, 8, 10, 12, 14, and 16 weeks after nCRT and before surgery. Predefined end points were based on the hypothesized impact of nCRT. The primary end points were physical functioning, odynophagia, and sensory symptoms. The secondary end points were global quality of life, fatigue, weight loss, and motor symptoms. Mixed modeling analysis was used to evaluate changes over time. RESULTS: Of 106 eligible patients, 96 (91%) were included in the study. The rate of questionnaires returned ranged from 94% to 99% until week 12, then dropped to 78% in week 16 after nCRT. A negative impact of nCRT on all HRQOL end points was observed during the last cycle of nCRT (all p < 0.001) and 2 weeks after nCRT (all p < 0.001). Physical functioning, odynophagia, and sensory symptoms were restored to pretreatment levels respectively 8, 4, and 6 weeks after nCRT. The secondary end points were restored to baseline levels 4-6 weeks after nCRT. Odynophagia, fatigue, and weight loss improved after nCRT compared with baseline levels at respectively 6 (p < 0.001), 16 (p = 0.001), and 12 weeks (p < 0.001). CONCLUSION: After completion of nCRT for esophageal cancer, HRQOL decreases significantly, but all HRQOL end points are restored to baseline levels within 8 weeks. Odynophagia, fatigue, and weight loss improved 6-16 weeks after nCRT compared with baseline levels.

Neoadjuvant chemoradiotherapy for resectable oesophageal cancer.

At present, treatment of potentially curable oesophageal cancer includes neoadjuvant chemoradiotherapy followed by oesophagectomy. Alternatively, neoadjuvant chemotherapy is used. To date, strong evidence on the superiority of one modality over the other has not been provided. Currently, up to one-third of patients show a pathologically complete response after neoadjuvant chemoradiotherapy. To optimise the efficacy of neoadjuvant treatment for individual patients, prediction of response to neoadjuvant treatment is highly desired. Therefore, several clinical diagnostic modalities have been investigated for early response evaluation, of which positron emission tomography (PET) has been studied most extensively. To identify patients who might benefit from postponing or even omitting surgery, recent advances have been made in evaluating response after completion of neoadjuvant chemoradiotherapy. This review provides an overview of current evidence and recent advances in neoadjuvant chemoradiotherapy for oesophageal cancer and discusses the use of neoadjuvant chemotherapy compared to chemoradiotherapy. Moreover, clinical response evaluation to neoadjuvant chemoradiotherapy is reviewed.

Patients' preferences for treatment after neoadjuvant chemoradiotherapy for oesophageal cancer.

BACKGROUND: After neoadjuvant chemoradiotherapy (nCRT) plus surgery for oesophageal cancer, 29 per cent of patients have a pathologically complete response in the resection specimen. Active surveillance after nCRT (instead of standard oesophagectomy) may improve health-related quality of life (HRQoL), but patients need to undergo frequent diagnostic tests and it is unknown whether survival is worse than that after standard oesophagectomy. Factors that influence patients' preferences, and trade-offs that patients are willing to make in their choice between surgery and active surveillance were investigated here. METHODS: A prospective discrete-choice experiment was conducted. Patients with oesophageal cancer completed questionnaires 4-6 weeks after nCRT, before surgery. Patients' preferences were quantified using scenarios based on five aspects: 5-year overall survival, short-term HRQoL, long-term HRQoL, the risk that oesophagectomy is still necessary, and the frequency of clinical examinations using endoscopy and PET-CT. Panel latent class analysis was used. RESULTS: Some 100 of 104 patients (96·2 per cent) responded. All aspects, except the frequency of clinical examinations, influenced patients' preferences. Five-year overall survival, the chance that oesophagectomy is still necessary and long-term HRQoL were the most important attributes. On average, based on calculation of the indifference point between standard surgery and active surveillance, patients were willing to trade off 16 per cent 5-year overall survival to reduce the risk that oesophagectomy is necessary from 100 per cent (standard surgery) to 35 per cent (active surveillance). CONCLUSION: Patients are willing to trade off substantial 5-year survival to achieve a reduction in the risk that oesophagectomy is necessary.

Evaluation of PET and laparoscopy in STagIng advanced gastric cancer: a multicenter prospective study (PLASTIC-study).

BACKGROUND: Initial staging of gastric cancer consists of computed tomography (CT) and gastroscopy. In locally advanced (cT3-4) gastric cancer, fluorodeoxyglucose positron emission tomography with CT (FDG-PET/CT or PET) and staging laparoscopy (SL) may have a role in staging, but evidence is scarce. The aim of this study is to evaluate the impact and cost-effectiveness of PET and SL in addition to initial staging in patients with locally advanced gastric cancer. METHODS: This prospective observational cohort study will include all patients with a surgically resectable, advanced gastric adenocarcinoma (cT3-4b, N0-3, M0), that are scheduled for treatment with curative intent after initial staging with gastroscopy and CT. The modalities to be investigated in this study is the addition of PET and SL. The primary outcome of this study is the proportion of patients in whom the PET or SL lead to a change in treatment strategy. Secondary outcome parameters are: diagnostic performance, morbidity and mortality, quality of life, and cost-effectiveness of these additional diagnostic modalities. The study recently started in August 2017 with a duration of 36 months. At least 239 patients need to be included in this study to demonstrate that the diagnostic modalities are break-even. Based on the annual number of gastrectomies in the participating centers, it is estimated that approximately 543 patients are included in this study. DISCUSSION: In this study, it is hypothesized that performing PET and SL for locally advanced gastric adenocarcinomas results in a change of treatment strategy in 27% of patients and an annual cost-reduction in the Netherlands of €916.438 in this patient group by reducing futile treatment. The results of this study may be applicable to all countries with comparable treatment algorithms and health care systems. TRIAL REGISTRATION: NCT03208621 . This trial was registered prospectively on June 30, 2017.

Surgical management of esophageal sarcoma: a multicenter European experience.

Esophageal sarcomas are rare and evidence in literature is scarce making their management difficult. The objective is to report surgical and oncological outcomes of esophageal sarcoma in a large multicenter European cohort. This is a retrospective multicenter study including all patients who underwent en-bloc esophagectomy for esophageal sarcoma in seven European tertiary referral centers between 1987 and 2016. The main outcomes and measures are pathological results, early and long-term outcomes. Among 10,936 esophageal resections for cancer, 21 (0.2%) patients with esophageal sarcoma were identified. The majority of tumors was located in the middle (n = 7) and distal (n = 9) third of the esophagus. Neoadjuvant chemoradiotherapy was performed in five patients. All the patients underwent en-bloc transthoracic esophagectomy (19 open, 2 minimally invasive). Postoperative mortality occurred in 1 patient (5%). One patient received adjuvant chemotherapy. Definitive pathological results were carcinosarcoma (n = 7), leiomyosarcoma (n = 5), and other types of sarcoma (n = 9). Microscopic R1 resection was present in one patient (5%) and seven patients (33%) had positive lymph nodes. Median follow-up was 16 (3-79) months in 20 of 21 patients (95%). One-, 3-, and 5-year overall survival rates were 74%, 43%, and 35%, respectively. One-, 3- and 5-years disease-free survival rates were 58%, 40%, and 33%, respectively. Median overall survival was 6 months in N+ patients vs. 37 months for N0 patients (p = 0.06). At the end of the follow-up period, nine patients had died from cancer recurrences (43%), three patients died from other reasons (14%), one patient was still alive with recurrence (5%) and the seven remaining patients were free of disease (33%). Recurrence was local (n = 3), metastatic (n = 3), or both (n = 4). In conclusion, carcinosarcoma and leiomyosarcoma were the most common esophageal sarcoma histological subtypes. Lymph node involvement was seen in one third of cases. A transthoracic en-bloc esophagectomy with radical lymphadenectomy should be the best surgical option to achieve complete resection. Long-term survival remained poor with a high local and distant recurrence rate.

Impact of neoadjuvant chemoradiotherapy on health-related quality of life in long-term survivors of esophageal or junctional cancer: results from the randomized CROSS trial.

Background: Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard of care for patients with esophageal or junctional cancer, but the long-term impact of nCRT on health-related quality of life (HRQOL) is unknown. The purpose of this study is to compare very long-term HRQOL in long-term survivors of esophageal cancer who received nCRT plus surgery or surgery alone. Patients and methods: Patients were randomly assigned to receive nCRT (carboplatin/paclitaxel with 41.4-Gy radiotherapy) plus surgery or surgery alone. HRQOL was measured using EORTC-QLQ-C30, EORTC-QLQ-OES24 and K-BILD questionnaires after a minimum follow-up of 6 years. To allow for examination over time, EORTC-QLQ-C30 and QLQ-OES24 questionnaire scores were compared with pretreatment and 12 months postoperative questionnaire scores. Physical functioning (QLQ-C30), eating problems (QLQ-OES24) and respiratory problems (K-BILD) were predefined primary end points. Predefined secondary end points were global quality of life and fatigue (both QLQ-C30). Results: After a median follow-up of 105 months, 123/368 included patients (33%) were still alive (70 nCRT plus surgery, 53 surgery alone). No statistically significant or clinically relevant differential effects in HRQOL end points were found between both groups. Compared with 1-year postoperative levels, eating problems, physical functioning, global quality of life and fatigue remained at the same level in both groups. Compared with pretreatment levels, eating problems had improved (Cohen's d -0.37, P = 0.011) during long-term follow-up, whereas physical functioning and fatigue were not restored to pretreatment levels in both groups (Cohen's d -0.56 and 0.51, respectively, both P < 0.001). Conclusions: Although physical functioning and fatigue remain reduced after long-term follow-up, no adverse impact of nCRT is apparent on long-term HRQOL compared with patients who were treated with surgery alone. In addition to the earlier reported improvement in survival and the absence of impact on short-term HRQOL, these results support the view that nCRT according to CROSS can be considered as a standard of care. Trial registration number: Netherlands Trial Register NTR487.

Germline variant in MSX1 identified in a Dutch family with clustering of Barrett's esophagus and esophageal adenocarcinoma.

The vast majority of esophageal adenocarcinoma cases are sporadic and caused by somatic mutations. However, over the last decades several families have been identified with clustering of Barrett's esophagus and esophageal adenocarcinoma. This observation suggests that one or more hereditary factors may play a role in the initiation of Barrett's esophagus and esophageal adenocarcinoma in these families. A Dutch family with clustering of Barrett's esophagus and esophageal adenocarcinoma was identified. Normal DNA obtained from the proband diagnosed with Barrett's esophagus was analyzed with SNP array and exome sequencing. A custom-made panel consisting of potential germline variants was verified in the normal DNA of the affected family members. In addition, the respective tumors were analyzed for somatic loss of the wild type allele or the presence of an inactivating somatic mutation in the wild type allele. Exome sequencing revealed 244 candidate variants in the normal DNA of the proband, of which 212 variants were verified successfully. After the normal DNA of the affected family members was analyzed for the presence of the 212 potential germline variants and subsequently the respective tumors, only one potential germline variant in MSX1 (chr4: 4861985 T > G, c.359T > G, p.V120G, NM_002448) showed loss of the wild type allele in the tumor DNAs of the affected family members. A germline variant in MSX1 was identified in a Dutch family with clustering of Barrett's esophagus and esophageal adenocarcinoma. This finding indicates that the germline defect in MSX1 may be associated with Barrett's esophagus and cancer in this particular family.

[Organ-sparing treatment in oesophagus cancer: feasible and safe?] / Orgaansparende behandeling bij slokdarmcarcinoom.

In many countries, neoadjuvant chemoradiotherapy (nCRT) plus surgery is standard treatment for resectable oesophageal cancer. After nCRT, up to 30% of all patients have no residual disease in the resection specimen. Consequently, an active surveillance approach, in which patients undergo frequent clinical investigations after nCRT instead of standard oesophagectomy, is increasingly applied in selected patients. Here, we describe outcomes for three patients who underwent active surveillance. A 63-year old woman was considered unfit for surgery after nCRT. Four years after completion of nCRT, she still had no signs of disease recurrence. The second patient, a 57-year old woman, refused surgery when no residual disease was detectable after nCRT. One year following treatment, she developed a vertebral metastasis, in the absence of locoregional disease. The third patient concerned a 66-year old man with a clinically complete response after nCRT, who also refused surgery. During active surveillance, he developed a locoregional regrowth and underwent a radical oesophagectomy.

Active surveillance in clinically complete responders after neoadjuvant chemoradiotherapy for esophageal or junctional cancer.

Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is standard of care for locally advanced esophageal cancer in many countries. After nCRT up to one third of all patients have a pathologically complete response in the resection specimen, posing an ethical imperative to reconsider the necessity of standard surgery in all operable patients after nCRT. An active surveillance strategy following nCRT, in which patients are subjected to frequent clinical investigations after the completion of neoadjuvant therapy, has been evaluated in other types of cancer with promising results. In esophageal cancer, both patients who are cured by neoadjuvant therapy alone as well as patients with subclinical disseminated disease at the time of completion of neoadjuvant therapy may benefit from such an organ sparing approach. Active surveillance is currently applied in selected patients with esophageal cancer who refuse surgery or are medically unfit for major surgery after completion of nCRT, but this strategy is not (yet) adopted as an alternative to standard surgery or definitive chemoradiation. The available literature is scarce, but suggests that long-term oncological outcomes after active surveillance are noninferior compared to standard surgical resection, providing justification for comparison of both treatments in a phase III trial. This review gives an overview of the current knowledge regarding active surveillance after completion of nCRT in esophageal cancer and outlines future research perspectives.

Loss of SRY-box2 (SOX2) expression and its impact on survival of patients with oesophageal adenocarcinoma.

BACKGROUND: Oesophageal adenocarcinoma (OAC) is a highly aggressive malignancy with poor survival, which is highly variable amongst patients with comparable conventional prognosticators. Therefore molecular biomarkers are urgently needed to improve the prediction of survival in these patients. SRY (sex determining region Y)-box 2, also known as SOX2, is a transcription factor involved in embryonal development of the gastrointestinal tract as well as in carcinogenesis. The purpose of this study was to see whether SOX2 expression is associated with survival in patients with OAC. METHODS: SOX2 was studied by immunohistochemistry in patients who had undergone potentially curative oesophagectomy for adenocarcinoma. Protein expression of SOX2 was evaluated using tissue microarrays from resection specimens, and results were analysed in relation to the clinical data by Cox regression analysis. SOX2 was evaluated in two independent OAC cohorts (Rotterdam cohort and a multicentre UK cohort). RESULTS: Loss of SOX2 expression was independently predictive of adverse overall survival in the multivariable analysis, adjusted for known factors influencing survival, in both cohorts (Rotterdam cohort: hazard ratio (HR) 1·42, 95 per cent c.i. 1·07 to 1·89, P = 0·016; UK cohort: HR 1·54, 1·08 to 2·19, P = 0·017). When combined with clinicopathological staging, loss of SOX2 showed an increased effect in patients with pT1-2 tumours (P = 0·010) and node-negative OAC (P = 0·038), with an incrementally adverse effect on overall survival for stage I OAC with SOX2 loss (HR 3·18, 1·18 to 8·56; P = 0·022). CONCLUSION: SOX2 is an independent prognostic factor for long-term survival in OAC, especially in patients with stage I OAC.

[A woman with abdominal pain and absence of defaecation]. / Een vrouw met acute buikpijn en uitblijvende ontlasting.

A 62-years-old female presented to the Emergency Department with abdominal pain and absence of defaecation for two days. CT revealed an ileus with a change in the diameter of the small intestine and a segment without contrast in the intestinal wall. Laparotomy confirmed that a segment of the ileum was ischaemic.

Multimodality treatment for esophageal adenocarcinoma: multi-center propensity-score matched study.

Background: The primary aim of this study was to compare survival from neoadjuvant chemoradiotherapy plus surgery (NCRS) versus neoadjuvant chemotherapy plus surgery (NCS) for the treatment of esophageal or junctional adenocarcinoma. The secondary aims were to compare pathological effects, short-term mortality and morbidity, and to evaluate the effect of lymph node harvest upon survival in both treatment groups. Methods: Data were collected from 10 European centers from 2001 to 2012. Six hundred and eight patients with stage II or III oesophageal or oesophago-gastric junctional adenocarcinoma were included; 301 in the NCRS group and 307 in the NCS group. Propensity score matching and Cox regression analyses were used to compensate for differences in baseline characteristics. Results: NCRS resulted in significant pathological benefits with more ypT0 (26.7% versus 5%; P < 0.001), more ypN0 (63.3% versus 32.1%; P < 0.001), and reduced R1/2 resection margins (7.7% versus 21.8%; P < 0.001). Analysis of short-term outcomes showed no statistically significant differences in 30-day or 90-day mortality, but increased incidence of anastomotic leak (23.1% versus 6.8%; P < 0.001) in NCRS patients. There were no statistically significant differences between the groups in 3-year overall survival (57.9% versus 53.4%; Hazard Ratio (HR)= 0.89, 95%C.I. 0.67-1.17, P = 0.391) nor disease-free survival (52.9% versus 48.9%; HR = 0.90, 95%C.I. 0.69-1.18, P = 0.443). The pattern of recurrence was also similar (P = 0.660). There was a higher lymph node harvest in the NCS group (27 versus 14; P < 0.001), which was significantly associated with a lower recurrence rate and improved disease free survival within the NCS group. Conclusion: The survival differences between NCRS and NCS maybe modest, if present at all, for the treatment of locally advanced esophageal or junctional adenocarcinoma. Future large-scale randomized trials must control and monitor indicators of the quality of surgery, as the extent of lymphadenectomy appears to influence prognosis in patients treated with NCS, from this large multi-center European study.

Vitamin B12 deficiency after esophagectomy with gastric tube reconstruction for esophageal cancer.

The aim of this study is to determine the prevalence and incidence of vitamin B12 deficiency after esophagectomy for cancer. It is unknown if patients after esophagectomy with gastric tube reconstruction are at an increased risk for vitamin B12 deficiency. A cross-sectional cohort (group A) and a prospective cohort (group B) of patients who underwent esophagectomy for cancer in two tertiary referral centers in the Netherlands were included. Serum levels of holo-transcobalamin (Holo-TC) and methyl malonic acid (MMA) were determined. Vitamin B12 deficiency was defined as Holo-TC < 21 pmol/L and/or MMA > 0.45 µmol/L. Vitamin B12 status was assessed in group A at a single time point between one and three years postoperatively and before and every three months after resection in group B. Ninety-nine patients were analyzed in group A. The median time between surgery and analysis of vitamin B12 deficiency was 19.3 months. In 11 of 99 (11%) patients, vitamin B12 deficiency was detected. In group B, 5 of 88 (5.6%) patients had vitamin B12 deficiency preoperatively, and another 9 (10.2%) patients developed vitamin B12 deficiency after the operation at a median time of 6 months postoperatively. The estimated one-year incidence of vitamin B12 deficiency was 18.2%. None of the patients with vitamin B12 deficiency had a megaloblastic anemia. Vitamin B12 deficiency can be anticipated in 18% of patients after esophagectomy with gastric tube reconstruction for cancer. During follow-up, Holo-TC and MMA levels should be measured to detect vitamin B12 deficiency and commence treatment timely.

Prediction of survival in patients with oesophageal or junctional cancer receiving neoadjuvant chemoradiotherapy and surgery.

BACKGROUND: The value of conventional prognostic factors is unclear in the era of multimodal treatment for oesophageal cancer. This study aimed to quantify the impact of neoadjuvant chemoradiotherapy (nCRT) and surgery on well established prognostic factors, and to develop and validate a prognostic model. METHODS: Patients treated with nCRT plus surgery were included. Multivariable Cox modelling was used to identify prognostic factors for overall survival. A prediction model for individual survival was developed using stepwise backward selection. The model was internally validated leading to a nomogram for use in clinical practice. RESULTS: Some 626 patients who underwent nCRT plus surgery were included. In the multivariable model, only pretreatment cN category and ypN category were independent prognostic factors. The final prognostic model included cN, ypT and ypN categories, and had moderate discrimination (c-index at internal validation 0·63). CONCLUSION: In patients with oesophageal or oesophagogastric cancer treated with nCRT plus surgery, overall survival can best be estimated using a prediction model based on cN, ypT and ypN categories. Predicted survival according to this model showed only moderate correlation with observed survival, emphasizing the need for new prognostic factors to improve survival prediction.