Dietmar Lorenz

Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis

Summary Background Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barretts oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barretts oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barretts oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barretts oesophagus and oesophageal adenocarcinoma. Methods We did a meta-analysis of all genome-wide association studies of Barretts oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p<5 × 10−8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches—including functional annotation databases and gene-based and pathway-based methods—to identify pathophysiologically relevant cellular mechanisms. Findings Our sample comprised 6167 patients with Barretts oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barretts oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10−10), MSRA (rs17749155; p=5·2 × 10−10), LINC00208 and BLK (rs10108511; p=2·1 × 10−9), KHDRBS2 (rs62423175; p=3·0 × 10−9), TPPP and CEP72 (rs9918259; p=3·2 × 10−9), TMOD1 (rs7852462; p=1·5 × 10−8), SATB2 (rs139606545; p=2·0 × 10−8), and HTR3C and ABCC5 (rs9823696; p=1·6 × 10−8). The locus identified near HTR3C and ABCC5 (rs9823696) was associated specifically with oesophageal adenocarcinoma (p=1·6 × 10−8) and was independent of Barretts oesophagus development (p=0·45). A ninth novel risk locus was identified within the gene LPA (rs12207195; posterior probability 0·925) after reweighting with significantly enriched annotations. The strongest disease pathways identified (p<10−6) belonged to muscle cell differentiation and to mesenchyme development and differentiation. Interpretation Our meta-analysis of genome-wide association studies doubled the number of known risk loci for Barretts oesophagus and oesophageal adenocarcinoma and revealed new insights into causes of these diseases. Furthermore, the specific association between oesophageal adenocarcinoma and the locus near HTR3C and ABCC5 might constitute a novel genetic marker for prediction of the transition from Barretts oesophagus to oesophageal adenocarcinoma. Fine-mapping and functional studies of new risk loci could lead to identification of key molecules in the development of Barretts oesophagus and oesophageal adenocarcinoma, which might encourage development of advanced prevention and intervention strategies. Funding US National Cancer Institute, US National Institutes of Health, National Health and Medical Research Council of Australia, Swedish Cancer Society, Medical Research Council UK, Cambridge NIHR Biomedical Research Centre, Cambridge Experimental Cancer Medicine Centre, Else Kröner Fresenius Stiftung, Wellcome Trust, Cancer Research UK, AstraZeneca UK, University Hospitals of Leicester, University of Oxford, Australian Research Council.

Expression of |[alpha]|-methylacyl coenzyme A racemase in the dysplasia carcinoma sequence associated with Barrett's esophagus

Two different studies demonstrated α-methylacyl coenzyme A racemase (AMACR) to be a highly specific marker in Barretts neoplastic lesions. Reactive atypia was positive in 3/30 cases in these studies. We present a retrospective study of early Barretts adenocarcinoma treated with surgery (2000–2005, n=29; M:F=5:1, median age 67 years). We analyzed the role of AMACR expression in reactive and neoplastic lesions associated with the disease of 77 different specimens (60 biopsy and 17 surgical specimens) of these patients. In our cohort, 70% of cases demonstrated infiltration of the submucosa, 38% were poorly differentiated, and/or 31% demonstrated lymph vessel infiltration. We used a multi-tissue array, with reactive and neoplastic samples for each patient to analyze the immunoreactivity of AMACR. Barretts epithelium that was negative for dysplasia and columnar epithelial cell changes indefinite for dysplasia (n=30) did not demonstrate AMACR immunoreactivity. AMACR immunoreactivity was demonstrated in 27% (8/30) of cases of Barretts epithelium with columnar epithelial cell changes indefinite for dysplasia. Altogether 91% of cases with low-grade dysplasia were AMACR-positive and 96% of cases with high-grade dysplasia and early Barretts adenocarcinoma were positive for AMACR. In summary, the sensitivity of AMACR expression in low-grade dysplasia and subsequent early Barretts adenocarcinoma was significantly higher in our study compared with previous data. This might be a new diagnostic marker for dysplasia carcinoma sequence in Barretts low-grade neoplastic lesions. Further studies are required to investigate this point with well-defined controls having at least 5-years follow-up.

Prognostic risk factors of early esophageal adenocarcinomas.

Objective:To define prognostic risk factors in patients with early adenocarcinomas of the esophagus (eACEs) who were treated by esophagectomy. Background:Although endoscopic resection (ER) is more accepted for eACEs limited to the mucosa, the reported prevalence of lymph node metastases once the tumor infiltrates the submucosa seems to necessitate surgery in these cases. Methods:We analyzed the results of 168 patients who had an esophageal resection because of an eACE. On the basis of specimen histologies and clinical follow-up (median, 64 months), we investigated the influence of lymph node metastases (N+), tumor infiltration depth, tumor differentiation (G1–3), and lymphatic or venous infiltration (L+ or V+) on overall and tumor-specific survival and recurrence rates. Results:The 5-year survival rate was 79%. Lymph node infiltration was the only prognostic factor for the overall survival [hazard ratio (HR), 2.856; 1.314–6.207; P = 0.008], tumor-specific survival (HR, 8.336; 2.734–25.418; P < 0.001), and tumor recurrence (HR, 8.031; 3.041–21.206; P < 0.001) that was consistently present in all multivariate hazard Cox regression analyses. A total of 47% of the patients who had an N+ status developed tumor recurrences compared with 5.2% of those who had no lymph node involvement (P = <0.001). We found a significant correlation between N+ status and increasing depth of tumor infiltration (P = 0.004), lymphatic vessel infiltration (P = 0.002), tumor differentiation (G1 + G2 vs G3; P = 0.014) and vascular infiltration (P = 0.01). Conclusions:Lymph node status is the only independent risk factor for survival and recurrence rates. Tumor infiltration depth correlates with the rate of the lymph node metastases, but a clear watershed between deep mucosal and submucosal infiltration does not exist. As a consequence, careful staging procedures, including diagnostic ER, are mandatory to determine which patients can be treated by ER and which require an esophagectomy.

Barrett’s Adenocarcinoma of the Esophagus: Better Outcomes Through New Methods of Diagnosis and Treatment

BACKGROUND Esophageal adenocarcinoma has attracted more attention among gastroenterologists recently because of its rapidly rising incidence in Western countries. Many new epidemiological findings have been published, and there have been numerous technical advances in diagnostic procedures and in multimodal treatment based on the staging of the disease. METHODS In this paper, we selectively review the literature on esophageal adenocarcinoma, also considering the evidence-based recommendations contained in the guidelines of the German Society for Digestive and Metabolic Diseases (Deutsche Gesellschaft für Verdauungs- und Stoffwechselkrankheiten, DGVS) as well as the latest data from our own research team. RESULTS AND CONCLUSION here have been major recent advances in the diagnosis and treatment of esophageal adenocarcinoma. New refinements in endoscopic techniques now make endoscopic treatment possible for early esophageal carcinoma. New surgical techniques and new strategies of neoadjuvant chemotherapy have lowered the morbidity and improved the outcome of patients with locally advanced disease. Molecular therapies, too, have shown promising initial results.

[The Rapunzel syndrome: rare manifestation of a trichobezoar of the upper gastrointestinal tract].

Zusammenfassung Das Rapunzel-Syndrom ist eine seltene Manifestation eines Trichobezoars des Magens mit „zopfartiger“ Ausdehnung in den Dünndarm, die im Extremfall bis ins Kolon reichen kann. Wir berichten über die operative Entfernung eines solchen Bezoars mittels Gastrotomie bei einer 4-jährigen Patientin – der 3. publizierte Fall in der deutschen Literatur. Das Syndrom findet sich hauptsächlich bei jüngeren Mädchen mit Trichophagie, deren psychodynamischer Hintergrund häufig Ausdruck einer frühkindlichen Deprivation mit hoher Komorbidität zu schwerwiegenden kinderpsychiatrischen Erkrankungen ist. Die Symptome sind unspezifisch und können verschiedene andere gastrointestinale Erkrankungen imitieren. Klinische Charakteristika sind ein verschieblicher Tumor im Oberbauch, Gewichtsverlust und eine Alopezie. Die Therapie der Wahl ist die operative Entfernung der meist aufgrund der Ausdehnung endoskopisch nicht extrahierbaren Trichobezoare unter Berücksichtigung des gesamten intestinalen Anteils. Die frühe Diagnose und Behandlung des Rapunzel- Syndroms ist von großer Bedeutung um spätere fatale Komplikationen, wie Magenperforation oder Wandnekrosen des Dünndarms zu verhindern. Eine intensive psychiatrische Mitbehandlung ist zur Prophylaxe von Rezidiven erforderlich.Abstract The Rapunzel syndrome is a rare manifestation of a gastric trichobezoar with a „tail“ extending throughout the small intestine and sometimes even to the colon. We report on the surgical removal of such a bezoar in a 4-year-old patient by gastrotomy – the third published case in the German literature. The syndrome is mainly seen in young girls with trichophagia psychodynamically associated with early childhood deprivation and a high comorbidity of serious pediatric psychiatric disorders. The symptoms are nonspecific and may mimic those of other pathologic gastrointestinal conditions. Clinical characteristics are a movable mass in the epigastrium and alopecia. The therapy of choice is surgery of the trichobezoar together with the whole intestinal „tail,“ as in most cases endoscopic removal fails due to the large extension. Early diagnosis and treatment of the Rapunzel syndrome is of eminent importance in order to avoid later fatal complications such as gastric perforation and intestinal necroses. Intensive psychiatric follow-up is mandatory for preventing relapses.

Supportive evidence for FOXP1, BARX1, and FOXF1 as genetic risk loci for the development of esophageal adenocarcinoma.

The Barretts and Esophageal Adenocarcinoma Consortium (BEACON) recently performed a genome‐wide association study (GWAS) on esophageal adenocarcinoma (EAC) and Barretts esophagus. They identified genome‐wide significant association for variants at three genes, namely CRTC1, FOXP1, and BARX1. Furthermore, they replicated an association at the FOXF1 gene that has been previously found in a GWAS on Barretts esophagus. We aimed at further replicating the association at these and other loci that showed suggestive association with P < 10−4 in the BEACON sample. In total, we tested 88 SNPs in an independent sample consisting of 1065 EAC cases and 1019 controls of German descent. We could replicate the association at FOXP1, BARX1, and FOXF1 with nominal significance and thereby confirm that genetic variants at these genes confer EAC risk. In addition, we found association of variants near the genes XRCC2 and GATA6 that were strongly (P < 10−5) although not genome‐wide significantly associated with the BEACON GWAS. Therefore, both variants and corresponding genes represent promising candidates for future EAC association studies on independent samples.

pT2 Adenocarcinoma of the Esophagus: Early or Advanced Cancer?

BACKGROUND There is an increasing trend to include patients with esophageal carcinoma invading the muscularis propria (pT2) in neoadjuvant therapy regimens. But it is unclear which patients have prognostic benefit from this strategy. The aim of this study was to assess the prognosis and prognostic factors in patients with pT2 esophageal adenocarcinoma to further optimize treatment strategies. METHODS Included were patients with pT2 esophageal adenocarcinoma treated operatively at three centers specializing in upper gastrointestinal surgery. There were 159 patients (139 male) without induction therapy; median age was 64.5 years. Survival was analyzed by univariate and multivariate analysis. RESULTS In 37% of patients (n = 59), no lymph node involvement (pN0) was detected. Overall 5-year survival rate for all patients was 37%; for pN0 patients it was 62%, and for patients with lymph node metastases (pN+) it was 24%. Median number of examined lymph nodes was 26. Extracapsular lymph node involvement (ELNI) was evident in 55 of 100 pN+ patients with a 5-year survival rate of 14%. Patients without ELNI had a 5-year survival rate of 36% (p = 0.041). Results were comparable in all participating hospitals. Thirty-day and 90-day mortality rates of the entire collective were 2.6% and 3.8%, respectively. Multivariate analysis of prognosis revealed the lymph node ratio (p < 0.001) and the pN-ELNI category (p = 0.005) as significant parameters (pN0 hazard ratio 1 [reference]; pN+ without ELNI hazard ratio 2.2, 95% confidence interval: 1.2 to 3.8); pN+ with ELNI hazard ratio 2.5, 95% confidence interval: 1.5 to 4.5). CONCLUSIONS The prognosis of patients with esophageal adenocarcinoma invading the muscularis propria without lymph node metastasis is very good. However, in this study, about 30% had extracapsular lymph node involvement, which reflects particularly aggressive biological tumor behavior.

The Barrett‐associated variants at GDF7 and TBX5 also increase esophageal adenocarcinoma risk

Barretts esophagus (BE) and esophageal adenocarcinoma (EAC) represent two stages within the esophagitis‐metaplasia‐dysplasia‐adenocarcinoma sequence. Previously genetic risk factors have been identified that confer risk to BE and EAC development. However, to which extent the genetic variants confer risk to different stages of the BE/EAC sequence remains mainly unknown. In this study we analyzed three most recently identified BE variants at the genes GDF7 (rs3072), TBX5 (rs2701108), and ALDH1A2 (rs3784262) separately in BE and EAC samples in order to determine their risk effects during BE/EAC sequence. Our data show that rs3072 at GDF7 and rs2701108 at TBX5 are also associated with EAC and conclude that both loci confer disease risk also at later stages of the BE/EAC sequence. In contrast, rs3784262 at ALDH1A2 was highly significantly associated with BE, but showed no association with EAC. Our data do not provide evidence that the ALDH1A2 locus confers equal risk in early and late stages of BE/EAC sequence.

Surgical Therapy of Early Carcinoma of the Esophagus

Background: The modern therapy of early esophageal carcinomas (pT1) requires an excellent cooperation between experienced gastroenterologists, pathologists, and esophageal surgeons. While endoscopic resection (ER) is accepted as the standard curative treatment for mucosal esophageal carcinomas, submucosal tumors are regarded as a strict indication for surgery. There is an ongoing discussion about the operative approach and the extent of lymph node dissection in these cases. Methods: A literature review was performed to evaluate the operative treatment of early esophageal cancer. In view of oncological risk factors, treatment strategies, and operative procedures, current studies are summarized and compared to the results of our own center. Results and Conclusion: In early esophageal cancer, lymph node involvement is the only independent risk factor for survival and recurrence rates. There is evidence that infiltrated lymph nodes (N+) are significantly correlated with tumor infiltration depth, lymphovascular (L1) and microvascular invasion (V1), and poor tumor differentiation (G3). Several studies suggest that early squamous cell carcinomas (eSCCs) and early adenocarcinomas (eACs) have a different tumor biology and therefore need a different treatment strategy. While eSCCs in stage m1 and m2 can be cured by ER, tumors infiltrating the submucosal layer (sm1-3) show a high rate of lymph node metastasis (LNM); thus, surgical resection (SR) is clearly indicated. In tumors with invasion into the deep mucosa (m3) the risk of LNM is up to 11%; however, reliable data are rare and the type of therapy should be discussed with the patients individually. In eACs, ER is the standard curative treatment for all mucosal tumors (m1-m4) and sm1 tumors with low-risk constellation (G1, L0, VO, R0). All high-risk sm1 tumors and those with deeper submucosal infiltration (sm2, sm3) show a high rate of LNM and require SR. The standard operative proce- dure for early esophageal carcinomas is an Ivor-Lewis esophagectomy with radical, at least two-field lymphadenectomy.

Grenzen der Chirurgie bei Karzinomen des oberen Intestinaltraktes

Cancer of the upper gastrointestinal tract is one of the leading causes for cancer related deaths worldwide. While the incidence of esophageal carcinoma is increasing, the incidence of gastric cancer has been continuously decreasing over the past decades. Most patients are often diagnosed with advanced stage disease and the prognosis is still dismal. For many patients surgery is the central part of the therapy; however, improvements in the diagnostic work-up, staging techniques and therapy concepts have led to a more individualized therapeutic approach. Endoscopic treatment of early cancer is well established with high cure rates. In advanced gastric cancer the implementation of multimodal therapies, standardized surgical techniques and optimized perioperative management has led to an improvement in prognosis and outcome. The limitations of surgery in esophagogastric cancer are defined by current scientific results, recent technical developments and patient-specific characteristics. These limitations are continuously changing and require an ongoing review.ZusammenfassungKarzinome des oberen Intestinaltraktes gehören weltweit zu den häufigsten tumorbedingten Todesursachen. Während die Inzidenz der Ösophaguskarzinome kontinuierlich ansteigt, sinkt die Zahl der Neuerkrankungen beim Magenkarzinom in den letzten Jahrzehnten stetig. Die Diagnose wird häufig in einem fortgeschrittenen Tumorstadium gestellt, die Gesamtprognose ist schlecht.Die chirurgische Resektion ist nach wie vor für viele Patienten zentraler Bestandteil der onkologischen Therapie. Allerdings haben Fortschritte in Diagnostik und Therapie ösophagogastraler Karzinome zu einer immer größeren Individualisierung der Therapie geführt. Bei den frühen Karzinomen haben die endoskopischen Resektionen inzwischen einen festen Stellenwert mit hoher Heilungsrate. Bei fortgeschrittenen Tumoren konnte in den letzten Jahren eine deutliche Verbesserung der Prognose durch Implementierung multimodaler Therapiekonzepte, durch die Standardisierung der Operationstechniken sowie des perioperativen Managements erreicht werden. Die Grenzen der Chirurgie werden somit durch aktuelle wissenschaftliche Ergebnisse, chirurgisch-technische Entwicklungen sowie patientenspezifische Faktoren bestimmt. Sie verschieben sich fortwährend und bedürfen deswegen einer ständigen Überprüfung.AbstractCancer of the upper gastrointestinal tract is one of the leading causes for cancer related deaths worldwide. While the incidence of esophageal carcinoma is increasing, the incidence of gastric cancer has been continuously decreasing over the past decades. Most patients are often diagnosed with advanced stage disease and the prognosis is still dismal. For many patients surgery is the central part of the therapy; however, improvements in the diagnostic work-up, staging techniques and therapy concepts have led to a more individualized therapeutic approach. Endoscopic treatment of early cancer is well established with high cure rates. In advanced gastric cancer the implementation of multimodal therapies, standardized surgical techniques and optimized perioperative management has led to an improvement in prognosis and outcome. The limitations of surgery in esophagogastric cancer are defined by current scientific results, recent technical developments and patient-specific characteristics. These limitations are continuously changing and require an ongoing review.