Intraoperative thyroid frozen section: indications, results and consequences.

Background: Frozen section (FS) analysis is strongly influenced by the experience of surgeons and pathologists. We analyzed its performance in a secondary care hospital with surgical and pathologic experience transferred from a university hospital. Methods: Indications, results, and consequences of all thyroid FS performed between January 1, 2021 and December 31, 2022 were critically reviewed. Results: FS was performed in 90 (26.5%) of 340 procedures. Indications consisted in a suspicious fine needle biopsy in 28 (31.1%) cases, (99m) Technetium-Methoxy-Isobutyl-Isonitrile (MIBI) retaining hypofunctional nodules in 25 (27.8%), the intraoperative appearance in 18 (20%), the sonographic appearance in 18 (20%) and a positron emission tomography (PET) positive result in 1 case (1.1%). Malignancy was diagnosed in 21 (23.3%) and confirmed by final histology in all cases (100%). In the remaining 69 (76.7%) FS displaying no positive malignancy criteria, final histology delivered benign in 62 (89.8%) and malignant diagnoses in 7 cases (10.1%). 25% of thyroid carcinomas could not be diagnosed by FS. FS sensitivity was consequently 75% (95% CI: 55.1-89.3%). All missed malignancies were papillary thyroid carcinomas of follicular variant (fvPTC). FS sensitivity was lowest in MIBI positive hypofunctional nodules (33%) and Bethesda III (50%) as opposed to Bethesda V (92.9%) and to those cases with suspicious sonographic or intraoperative appearance (71.4%). Two-staged surgery was necessary in 10 (15.8%) of carcinomas. Conclusions: Sensitivity of FS in a secondary care hospital offering surgical and pathologic experience from a specialized university center is 75% and mainly reduced by the prevalence of fvPTC. Omitting FS in Bethesda III and MIBI positive hypofunctional nodules might improve FS performance.

Tumour area infiltration and cell count in endoscopic biopsies of therapy-naive upper GI tract carcinomas by QuPath analysis: implications for predictive biomarker testing.

Guidelines regulate how many (tumour-bearing) tissue particles should be sampled during gastric cancer biopsy to obtain representative results in predictive biomarker testing. Little is known about how well these guidelines are applied, how the number of tissue particles correlates with the actual tumour-infiltrated area and how many absolute tumour cells are captured. The study included endoscopic biopsies of untreated carcinomas of the upper gastrointestinal (GI)-tract during the 2016-2020 review period. Archival (H&E)-stained histological sections were digitised and the tumour areas were manually annotated. The tumour-bearing tissue area and absolute carcinoma cell count per case were determined by image analysis and compared with a reference primary surgical specimen. Biopsies from 253 patients were analysed. The following mean values were determined: (a) tumour tissue particle number: 6.5 (range: 1-25, standard deviation (SD) = 3.33), (b) number of tumour-bearing tissue particles: 4.7 (range: 1-20, SD = 2.80), (c) tumour-infiltrated area: 7.5 mm2 (range: 0.18-59.46 mm2, SD = 6.67 mm2), (d) absolute tumour cell count: 13,492 (range: 193-92,834, SD = 14,185) and (e) tumour cell count in a primary surgical specimen (tumour size: 6.7 cm): 105,200,176. The guideline-recommended tissue particle count of 10 was not achieved in 208 patients (82.2%) and the required tumour-bearing tissue particle count of 5 was not achieved in 133 patients (52.6%). Tissue particle count, tumour-infiltrated area and tumour cell count were only weakly correlated. Most cases featured an infiltrated area ≥ 4.5 mm2 (156, 61.7%). Cases with more tissue particles showed only a moderate increase in infiltrated area and tumour cells compared to cases with fewer particles. Biopsies are often used to determine predictive biomarkers, particularly Her2/neu and PD-L1. Diagnostic standards to ensure representative material have been suggested in guidelines to reduce false-negative predictions. However, the real-world practice seems to substantially deviate from recommended standards. To the best of our knowledge, this is the first systematic study describing the relationships between endoscopic tissue fragment number, actual infiltrated tumour area and carcinoma cell number. The data question the tissue particle number as a quality assessment parameter. We advocate histopathological reports indicating on which basis statements on therapy-relevant biomarkers were made. Digital pathology has the potential to objectively quantify the tissue for documentation, quality assessment and future clinical studies.

The Impact of the COVID Pandemic on Adrenal Surgery at an Academic Endocrine Surgery Unit.

COVID-19 has severely affected the delivery of surgical care worldwide. The aim of the present study was to evaluate its impact on adrenal surgery at our academic endocrine center. All primary adrenal surgeries performed at the University Hospital of Cologne, Germany between 01.01.2019 and 31.07.2022 were included. This time frame was divided into pre-Covid (before 02/20), acute Covid (until 05/21), and post acute period (after 05/2021). Demographics, clinic-pathologic characteristics and treatment of these patients were analyzed. One hundred adrenalectomies were included: 22 before, 30 during, and 48 after the acute phase. The percentage of Conn adenomas and pheochromocytomas decreased during the acute phase (from 45.4 to 26.6% and from 18 to 10%, respectively) in favor of Cushing adenomas and suspicious tumors (from 4.5 to 20% and from 31.8 to 36.6%). About 90.9% of tumors resected for suspicion of malignancy were confirmed malignant by final histopathology, as opposed to 71.4% and 52.6% before and after the acute phase. The operative technique was similar during the three phases (63% retroperitoneoscopic, 34% laparoscopic and 2% open resections), with a significantly shorter operative time for retroperitoneoscopy (p=0.04). ICU monitoring demand increased during the acute phase (from 13.6% to 43.3%), according to the increase in Cushing adenomas and malignant tumors. During the acute phase of COVID-19 pandemic adrenal surgery for Cushing and malignant tumors increased, while a delay in pheochromocytoma surgery to the post acute phase was observed. The suspicion of malignancy formulated by the endocrine tumor board was accurate in 90.9% of cases.

The tight junction protein claudin 6 is a potential target for patient-individualized treatment in esophageal and gastric adenocarcinoma and is associated with poor prognosis.

BACKGROUND: The prognosis of esophageal adenocarcinoma (EAC) and gastric adenocarcinoma (GAC) remains poor, and new therapeutic approaches are urgently needed. Claudin 6 (CLDN6) is an oncofetal antigen that is largely absent in healthy tissues and upregulated in several cancers, making it a promising therapeutical target. In this study, the expression of CLDN6 was assessed in an large Caucasian EAC and GAC cohort. METHODS: RNA-Seq data from 89 EACs and 371 GACs were obtained from The Cancer Genome Atlas project and EAC/GAC cases were stratified by CLDN6 mRNA expression based on a survival-associated cutoff. For groups with CLDN6 expression above or below this cutoff, differential gene expression analyses were performed using DESeq, and dysregulated biological pathways were identified using the Enrichr tool. Additionally, CLDN6 protein expression was assessed in more than 800 EACs and almost 600 GACs using a CLDN6-specific immunohistochemical antibody (clone 58-4B-2) that is currently used in Phase I/II trials to identify patients with CLDN6-positive tumors (NCT05262530; NCT04503278). The expression of CLDN6 was also correlated with histopathological parameters and overall survival (OS). RESULTS: EACs and GACs with high CLDN6 mRNA levels displayed an overexpression of pathways regulating the cell cycle, DNA replication, and receptor / extracellular matrix interactions. CLDN6 protein expression was associated with shorter OS in EAC and GAC, both in treatment-naïve subgroups and cohorts receiving neoadjuvant therapy. In multivariate analysis, CLDN6 protein expression was an independent adverse prognostic factor in EAC associated with a shorter OS (HR: 1.75; p = 0.01) and GAC (HR: 2.74; p = 0.028). CONCLUSIONS: High expression of CLDN6 mRNA is associated with the dysregulation of distinct biological pathways regulating cell growth, proliferation, and cell-matrix interactions. Clinically, the expression of CLDN6 protein is a valuable adverse prognostic marker in EAC and GAC.

Morphological, clinical and molecular characteristics in ARID1a­deficient microsatellite­stable oesophageal adenocarcinoma.

Publications describe the relevance of the AT-rich interactive domain-containing protein 1A (ARID1a) mutation in gastric adenocarcinoma, which occurs predominantly in the microsatellite instable (MSI)- and Epstein-Barr virus (EBV)-associated subtypes. It is unclear whether potential therapeutic, prognostic or morphologic descriptions are not epiphenomena of MSI (or EBV). Since personalised therapeutics are largely lacking for oesophageal adenocarcinoma (EAC), clinical trials investigating the efficacy of these therapeutics specifically in this subgroup are useful. To the best of our knowledge, this was the first study analysing the relevant tumour subset of microsatellite-stable (MSS) EAC with loss of function of ARID1a. A total of 875 patients with EAC and data from The Cancer Genome Atlas (TCGA) were analysed. Statistical analyses associating previously known molecular characteristics of the present tumour cohort, overall survival, morphological growth patterns and tumour heterogeneity issues were considered. Subsequently, 10% of EAC were ARID1a-deficient, the majority of which were MSS (7.5%). There was no characteristic growth pattern. Approximately 60% of tumours were PD-L1 positive to varying degrees. TP53 mutations occurred together with ARID1a defective EAC in the present cohort and in the TCGA collective. The extent of 7.5% MSS-EAC with ARID1a loss was unaffected by neoadjuvant therapy. ARID1a loss was often detected to be homogeneous (92%). ARID1a loss is not an epiphenomenon of MSI in EAC. The high homogeneity of ARID1a loss tumour clones could be considered an argument for the effectiveness of potential therapeutics. Since the majority of genomic ARID1a alterations result in protein loss, immunohistochemistry is a useful screening technique, especially in the absence of morphological characteristics.

Differentiated Thyroid Cancer in Adolescents: Single Center Experience and Considerations for Surgical Management and Radioiodine Treatment

Objective: Differentiated thyroid cancer (DTC) in adolescents rare but with a favorable outcome, despite higher rates of cervical lymph node and pulmonary metastasis compared to adults. The aim of this study was to critically evaluate treatment of adolescents with DTC at a single center. Methods: Patients receiving postoperative radioiodine treatment (RAIT) for DTC between 2005 and 2020 at our institution were screened to identify adolescents according to the World Health Organization definition (10-19 years of age). Demographics, clinico-pathological characteristics, treatment and outcome were analyzed. Results: Among 1,897 DTC patients, 23 (1.3%) were adolescents with a median (range) age of 16 (10-18) years. The female to male ratio was 3.6:1. Sixty percent had classic papillary thyroid cancer, with follicular variant in 40%, which was higher than previously reported (15-25%) for this age group. pT-status was pT1 in 9 (39.2%), pT2 in 8 (34.8%), pT3 in 3 (13%) and pT4 in 3 (13%) patients. In 19 (82.6%) patients, central lymphadenectomy was performed and metastasis was seen in 57%. All patients received RAIT with initial activities of 1.2 (n=1, 4.3%), 2 (n=12, 52.2%) or 3.7 GBq (n=10, 43.5%). Eighteen (78.2%) patients were free of biochemical and radiologic disease at a median follow-up of 60.7 months. Second-line surgery for lymph node relapse was necessary in 3 (13%) cases. There was one disease-associated death. Conclusion: Despite high rates of metastasis, most patients were cured, and second-line surgery was rarely required. Further prospective studies are needed to determine whether less aggressive surgical management or omitting adjuvant RAIT are feasible in patients with limited stages at diagnosis.

Dissecting the inflammatory tumor microenvironment of esophageal adenocarcinoma: mast cells and natural killer cells are favorable prognostic factors and associated with less extensive disease.

PURPOSE: Esophageal adenocarcinoma (EAC) remains a challenging and lethal cancer entity. A promising target for new therapeutic approaches, as demonstrated by the success of immune checkpoint inhibitors, are tumor-associated immune cells and the tumor microenvironment (TME). However, the understanding of the TME in esophageal cancer remains limited and requires further investigation. METHODS: Over 900 EAC samples were included, including patients treated with primary surgery and neoadjuvant (radio-)chemotherapy. The immune cell infiltrates of mast cells (MC), natural killer cells (NK cells), plasma cells (PC), and eosinophilic cells (EC) were assessed semi-quantitatively and correlated with histopathological parameters and overall survival (OS). RESULTS: A high presence of all four immune cell types significantly correlated with a less extensive tumor stage and a lower frequency of lymph node metastasis, and, in case of NK cells, with less distant metastasis. The presence of MC and NK cells was favorably associated with a prolonged OS in the total cohort (MC: p < 0.001; NK cells: p = 0.004) and patients without neoadjuvant treatment (MC: p < 0.001; NK cells: p = 0.01). NK cells were a favorable prognostic factor in the total cohort (p = 0.007) and in the treatment-naïve subgroup (p = 0.04). Additionally, MC were a favorable prognostic factor in patients with lymph node metastasis (p = 0.009). CONCLUSION: Our results indicate a complex and important role of mast cells, NK cells, and the other assessed immune cells in the tumor microenvironment of EAC. Therefore, they are one further step to a better understanding of the immune cell environment and the potential therapeutic implications in this cancer entity.

Using an Endoluminal Functional Lumen Imaging Probe (EndoFLIP™) to Compare Pyloric Function in Patients with Gastroparesis to Patients After Esophagectomy.

BACKGROUND: Gastroparesis (GP) occurs in patients after upper gastrointestinal surgery, in patients with diabetes or systemic sclerosis and in idiopathic GP patients. As pyloric dysfunction is considered one of the underlying mechanisms, measuring this mechanism with EndoFLIP™ can lead to a better understanding of the disease. METHODS: Between November 2021 and March 2022, we performed a retrospective single-centre study of all patients who had non-surgical GP, post-surgical GP and no sign of GP after esophagectomy and who underwent our post-surgery follow-up program with surveillance endoscopies and further exams. EndoFLIP™ was used to perform measurements of the pylorus, and distensibility was measured at 40 ml, 45 ml and 50 ml balloon filling. RESULTS: We included 66 patients, and successful application of the EndoFLIP™ was achieved in all interventions (n = 66, 100%). We identified 18 patients suffering from non-surgical GP, 23 patients suffering from GP after surgery and 25 patients without GP after esophagectomy. At 40, 45 and 50 ml balloon filling, the mean distensibility in gastroparetic patients was 8.2, 6.2 and 4.5 mm2/mmHg; 5.4, 5.1 and 4.7 mm2/mmHg in post-surgical patients suffering of GP; and 8.5, 7.6 and 6.3 mm2/mmHg in asymptomatic post-surgical patients. Differences between symptomatic and asymptomatic patients were significant. CONCLUSION: Measurement with EndoFLIP™ showed that asymptomatic post-surgery patients seem to have a higher pyloric distensibility. Pyloric distensibility and symptoms of GP seem to correspond.

Outcome of endoscopic vacuum therapy for duodenal perforation.

BACKGROUND: Duodenal defects are complex clinical situations, and their management is challenging and associated with high mortality. Besides surgery, endoscopic treatment options exist, but the size and location of the perforation can limit their application. We present a retrospective study, demonstrating a successful application of endoscopic vacuum therapy (EVT) for duodenal leaks. METHODS: We performed a retrospective study of all patients who underwent EVT for duodenal perforations between 2016 and 2021 at two tertiary centers. We analyzed demographic and clinical patient characteristics, surgical outcomes, leak characteristics, sponge-related complications, and success rate. RESULTS: Indications for treatment with EVT in the duodenum consisted of leak after duodenal suture of a perforated ulcer (n = 4), iatrogenic perforation after endoscopic resection (n = 2), iatrogenic perforation during surgery (n = 2), and anastomotic leak after upper gastrointestinal surgery (n = 2). EVT was used as a first-line treatment in seven patients and as a second-line treatment in three patients. EVT was successfully applied in all interventions (n = 10, 100%). Overall, EVT lead to definitive closure of the defects in eight out of ten patients (80%). No severe EVT-related adverse events occurred. CONCLUSION: EVT is safe and technically feasible, so it emerges as a promising endoscopic treatment option for duodenal leaks. However, multidisciplinary collaboration and management are important to reduce the occurrence of postoperative complications, and to improve recovery rates.

FGFR2-amplified tumor clones are markedly heterogeneously distributed in carcinomas of the upper gastrointestinal tract.

BACKGROUND: FGFR2 is a therapy-relevant target in tumors of the upper gastrointestinal tract (GIT), and clinical trials are currently underway to test the efficacy of FGFR2 inhibitors. Tumor heterogeneity is one of the relevant causes of treatment failure. Almost nothing is known about the heterogeneous distribution of FGFR2-amplified clones in adenocarcinomas of the upper GIT. PATIENTS AND METHODS: To assess FGFR2 gene copy number alteration and intratumoral heterogeneity of upper GIT adenocarcinomas, we analyzed 893 patient-derived formalin-fixed paraffin-embedded tumor specimens, including primary operated and neoadjuvant-treated tumors (462 gastric carcinomas and 429 esophageal adenocarcinomas) as well as complementary lymph node and distant metastasis by fluorescence in situ hybridization. RESULTS: Twenty-six gastric tumors (5.6%) and 21 esophageal adenocarcinomas (4.9%) showed FGFR2 amplification. Overall, 93% of gastric carcinomas and 83% of esophageal carcinomas showed heterogeneous amplification. FGFR2 amplification was found in different histological growth patterns, including intestinal and diffuse type according to the Lauren classification. In the primary gastric carcinoma group, FGFR2 amplification was associated with poor prognosis (p = 0.005). CONCLUSION: Homogeneous FGFR2 amplification in tumors of the upper GIT is the exception. This has highly relevant implications in the nature of FGFR2 diagnostics (sufficient tumor cell number, determination of amplification at metastasis versus primary tumor, etc.) and on the response probability of appropriate inhibitors. It is relevant that the often poorly treatable and aggressive subtype of diffuse carcinomas (poorly cohesive carcinomas) also shows FGFR2 amplification and that an individualized therapy option with FGFR2 inhibitors could be an option in this group.

Assessment of pyloric sphincter physiology after Ivor-Lewis esophagectomy using an endoluminal functional lumen imaging probe.

OBJECTIVE OF THE STUDY: The most common functional complication after Ivor-Lewis esophagectomy is the delayed emptying of the gastric conduit (DGCE) for which several diagnostic tools are available, e.g. chest X-ray, upper esophagogastroduodenoscopy (EGD) and water-soluble contrast radiogram. However, none of these diagnostic tools evaluate the pylorus itself. Our study demonstrates the successful measurement of pyloric distensibility in patients with DGCE after esophagectomy and in those without it. METHODS AND PROCEDURES: Between May 2021 and October 2021, we performed a retrospective single-centre study of all patients who had an oncological Ivor-Lewis esophagectomy and underwent our post-surgery follow-up programme with surveillance endoscopies and computed tomography scans. EndoFlip™ was used to perform measurements of the pylorus under endoscopic control, and distensibility was measured at 40 ml, 45 ml and 50 ml balloon filling. RESULTS: We included 70 patients, and EndoFlip™ measurement was feasible in all patients. Successful application of EndoFlip™ was achieved in all interventions (n = 70, 100%). 51 patients showed a normal postoperative course, whereas 19 patients suffered from DGCE. Distensibility proved to be smaller in patients with symptoms of DGCE compared to asymptomatic patients. For 40 ml, 45 ml and 50 ml, the mean distensibility was 6.4 vs 10.1, 5.7 vs 7.9 and 4.5 vs 6.3 mm2/mmHg. The differences were significant for all three balloon fillings. No severe EndoFlip™ treatment-related adverse events occurred. CONCLUSION: Measurement with EndoFlip™ is a safe and technically feasible endoscopic option for measuring the distensibility of the pylorus. Our study shows that the distensibility in asymptomatic patients after esophagectomy is significantly higher than that in patients suffering from DGCE. However, more studies need to be conducted to demonstrate the general use of EndoFlip™ measurement of the pylorus after esophagectomy.

Targeted Therapy for Adrenocortical Carcinoma: A Genomic-Based Search for Available and Emerging Options.

In rare diseases such as adrenocortical carcinoma (ACC), in silico analysis can help select promising therapy options. We screened all drugs approved by the FDA and those in current clinical studies to identify drugs that target genomic alterations, also known to be present in patients with ACC. We identified FDA-approved drugs in the My Cancer Genome and National Cancer Institute databases and identified genetic alterations that could predict drug response. In total, 155 FDA-approved drugs and 905 drugs in clinical trials were identified and linked to 375 genes of 89 TCGA patients. The most frequent potentially targetable genetic alterations included TP53 (20%), BRD9 (13%), TERT (13%), CTNNB1 (13%), CDK4 (7%), FLT4 (7%), and MDM2 (7%). We identified TP53-modulating drugs to be possibly effective in 20-26% of patients, followed by the Wnt signaling pathway inhibitors (15%), Telomelysin and INO5401 (13%), FHD-609 (13%), etc. According to our data, 67% of ACC patients exhibited genomic alterations that might be targeted by FDA-approved drugs or drugs being tested in current clinical trials. Although there are not many current therapy options directly targeting reported ACC alterations, this study identifies emerging options that could be tested in clinical trials.

Adrenal Surgery in the Era of Multidisciplinary Endocrine Tumor Boards.

Work up of adrenal masses includes assessment of endocrine activity and malignancy risk. There is no indication for surgical removal of nonfunctional adrenal adenomas, according to the guidelines. In the present study, we aimed at evaluating the impact of a university endocrine tumor board on the quality of the indications for adrenal surgery at our institution. One hundred consecutive patients receiving primary adrenal surgery at the University Hospital of Cologne, Germany were included. Their demographics, clinic-pathologic characteristics, treatment and outcome were analyzed. In 55 (55%) cases, indication for surgery consisted in functional benign tumors, including Conn, Cushing adenomas and pheochromocytomas. Forty (40%) tumors were referred to surgery for malignancy suspicion and 5 (5%) myelolipomas were removed due to their size. Eighty-nine percent of surgeries were performed as minimally invasive procedures. Overall morbidity included two (2%) self-limiting pancreatic fistulas after left laparoscopic adrenalectomy for pheochromocytoma. All functional tumors were confirmed benign by final histology. Only 33 (82.5%) of 40 suspicious cases turned out to be malignant. Consequently, nonfunctional benign adenomas were "unnecessarily" removed in only 7 (7%) patients, with 6 (85.7%) of them having a history of extra-adrenal cancer and all of them fulfilling criteria for surgery, according to the international guidelines. In conclusion, the endocrine tumor board provided an excellent adherence to the guidelines with most surgeries being performed either for functional or malignant tumors. In nonfunctional tumors with history of extra adrenal cancer, CT guided biopsy might be considered for obviating surgery.

Fructose-1,6-bisphosphatase 1 (FBP1) is an independent biomarker associated with a favorable prognosis in esophageal adenocarcinoma.

INTRODUCTION: Despite modern multimodal therapeutic regimens, the prognosis of esophageal adenocarcinoma (EAC) is still poor and there is a lack of biological markers estimating the patients' prognosis. Fructose-1,6-biphosphatase (FBP1) is a key enzyme in gluconeogenesis and is associated with tumor initiation in several cancers. Therefore, this study aims to characterize its implication for EAC patients. METHODS AND MATERIALS: A total of 571 EAC patients who underwent multimodal treatment between 1999 and 2017 were analyzed for FBP1 expression using immunohistochemistry. RESULTS: 82.5% of the EACs show FBP1 expression in the tumor albeit with different intensities categorizing specimens accordingly into score 0 (no expression), score 1 (weak expression), score 2 (moderate expression) and score 3 (strong expression) (score 1 = 25.0%, score 2 = 35.9%, score 3 = 21.5%). Intratumoral FBP1 expression was significantly associated with a better prognosis (p = 0.024). This observation was particularly relevant among patients who received primary surgery without neoadjuvant treatment (p = 0.004). In multivariate analysis, elevated FBP1 expression was an independent biomarker associated with a favorable prognosis. DISCUSSION: Despite being associated with a favorable prognosis, the majority of patients with high FBP1 expression also require individualized therapy options to ensure long-term survival. Recently, it has been shown that the presence of the FBP1 protein increases the sensitivity of pancreatic cancer cells to the bromodomain and extraterminal domain (BET) inhibitor JQ1. CONCLUSION: We described for the first time the prognostic and possibly therapeutic relevance of FBP1 in EAC. The efficiency of the BET inhibitor in EAC should be verified in clinical studies and special attention should be paid to the effects of neoadjuvant therapy on FBP1 expression.

Anaplastic thyroid cancer: genome-based search for new targeted therapy options.

Objective: Anaplastic thyroid cancer (ATC) is one of the most lethal human cancers with meager treatment options. We aimed to identify the targeted drugs already approved by the Food and Drug Administration (FDA) for solid cancer in general, which could be effective in ATC. Design: Database mining. Methods: FDA-approved drugs for targeted therapy were identified by screening the databases of MyCancerGenome and the National Cancer Institute. Drugs were linked to the target genes by querying Drugbank. Subsequently, MyCancerGenome, CIViC, TARGET and OncoKB were mined for genetic alterations which are predicted to lead to drug sensitivity or resistance. We searched the Cancer Genome Atlas database (TCGA) for patients with ATC and probed their sequencing data for genetic alterations which predict a drug response. Results: In the study,155 FDA-approved drugs with 136 potentially targetable genes were identified. Seventeen (52%) of 33 patients found in TCGA had at least one genetic alteration in targetable genes. The point mutation BRAF V600E was seen in 45% of patients. PIK3CA occurred in 18% of cases. Amplifications of ALK and SRC were detected in 3% of cases, respectively. Fifteen percent of the patients displayed a co-mutation of BRAF and PIK3CA. Besides BRAF-inhibitors, the PIK3CA-inhibitor copanlisib showed a genetically predicted response. The 146 (94%) remaining drugs showed no or low (under 4% cases) genetically predicted drug response. Conclusions: While ATC carrying BRAF mutations can benefit from BRAF inhibitors and this effect might be enhanced by a combined strategy including PIK3CA inhibitors in some of the patients, alterations in BRAFWT ATC are not directly targeted by currently FDA-approved options.

There is no correlation between a delayed gastric conduit emptying and the occurrence of an anastomotic leakage after Ivor-Lewis esophagectomy.

INTRODUCTION: Esophagectomy is the gold standard in the surgical therapy of esophageal cancer. It is either performed thoracoabdominal with a intrathoracic anastomosis or in proximal cancers with a three-incision esophagectomy and cervical reconstruction. Delayed gastric conduit emptying (DGCE) is the most common functional postoperative disorder after Ivor-Lewis esophagectomy (IL). Pneumonia is significantly more often in patients with DGCE. It remains unclear if DGCE anastomotic leakage (AL) is associated. Aim of our study is to analyze, if AL is more likely to happen in patients with a DGCE. PATIENTS AND METHODS: 816 patients were included. All patients have had an IL due to esophageal/esophagogastric-junction cancer between 2013 and 2018 in our center. Intrathoracic esophagogastric end-to-side anastomosis was performed with a circular stapling device. The collective has been divided in two groups depending on the occurrence of DGCE. The diagnosis DGCE was determined by clinical and radiologic criteria in accordance with current international expert consensus. RESULTS: 27.7% of all patients suffered from DGCE postoperatively. Female patients had a significantly higher chance to suffer from DGCE than male patients (34.4% vs. 26.2% vs., p = 0.040). Pneumonia was more common in patients with DGCE (13.7% vs. 8.5%, p = 0.025), furthermore hospitalization was longer in DGCE patients (median 17 days vs. 14d, p < 0.001). There was no difference in the rate of type II anastomotic leakage, (5.8% in both groups DGCE). All patients with ECCG type II AL (n = 47; 5.8%) were treated successfully by endoluminal/endoscopic therapy. The subgroup analysis showed that ASA ≥ III (7.6% vs. 4.4%, p = 0.05) and the histology squamous cell carcinoma (9.8% vs. 4.7%, p = 0.01) were independent risk factors for the occurrence of an AL. CONCLUSION: Our study confirms that DGCE after IL is a common finding in a standardized collective of patients in a high-volume center. This functional disorder is associated with a higher rate of pneumonia and a prolonged hospital stay. Still, there is no association between DGCE and the occurrence of an AL after esophagectomy. The hypothesis, that an DGCE results in a higher pressure on the anastomosis and therefore to an AL in consequence, can be refuted. DGCE is not a pathogenetic factor for an AL.

A new hybrid stent using endoscopic vacuum therapy in treating esophageal leaks: a prospective single-center experience of its safety and feasibility with mid-term follow-up.

Self-expandable metal stents (SEMS) and endoscopic vacuum therapy (EVT) are endoscopic options for treating leaks of the esophagus. VACStent® is a variant of SEMS that aims to combine the advantages of SEMS and EVT in one device. Due to this unique construction, VACStent® can build a barrier to the leak and facilitate wound healing with EVT, all while maintaining intestinal passage. We present the first prospective feasibility study of VACStent® for treating leaks of the upper gastrointestinal tract. Between September 2019 and November 2020, we performed a prospective, investigator-initiated, single-center study and included all patients who underwent endoscopic stenting with VACStent® for various kinds of esophageal leaks, such as spontaneous, iatrogenic or anastomotic leaks. We included 20 patients, who underwent a total of 24 endoscopic VACStent® implantations. Technical success of the application of the VACStent® was achieved in all interventions (n = 24, 100%). Overall, clinical success in closing the leaks with VACStent® treatment was achieved in 60% of patients (12/20). No severe VACStent® treatment-related adverse events occurred. Oral feeding with supplement high-energy drinks failed in all patients due to clogging of the suction tube. VACStent® is a safe and feasible endoscopic treatment option for leaks of the upper gastrointestinal tract. However, our data could not show the expected advantage of orally feeding the patients during the treatment with the VACStent® in its current form. Efficacy of VACStent® compared to EVT or SEMS needs to be investigated in a further study. ClinicalTrials.gov Identifier: NCT03962179.

Short-term outcome of Ivor Lewis esophagectomy following neoadjuvant chemoradiation versus perioperative chemotherapy in patients with locally advanced adenocarcinoma of the esophagus and gastroesophageal junction: a propensity score-matched analysis.

BACKGROUND: Patients with locally advanced esophageal or gastroesophageal adenocarcinoma benefit from multimodal therapy concepts including neoadjuvant chemoradiation (nCRT), respectively, perioperative chemotherapy (pCT). However, it remains unclear which treatment is superior concerning postoperative morbidity. METHODS: In this study, we compared the postsurgical survival (30-day/90-day/1-year mortality) (primary endpoint), treatment response, and surgical complications (secondary endpoints) of patients who either received nCRT (CROSS protocol) or pCT (FLOT protocol) due to esophageal/gastroesophageal adenocarcinoma. Between January 2013 and December 2017, 873 patients underwent Ivor Lewis esophagectomy in our high-volume center. 339 patients received nCRT and 97 underwent pCT. After 1:1 propensity score matching (matching criteria: sex, age, BMI, ASA score, and Charlson score), 97 patients per subgroup were included for analysis. RESULTS: After matching, tumor response (ypT/ypN) did not differ significantly between nCRT and pCT (p = 0.118, respectively, p = 0.174). Residual nodal metastasis occurred more often after pCT (p = 0.001). Postsurgical mortality was comparable within both groups. No patient died within 30 or 90 days after surgery while the 1-year survival rate was 72.2% for nCRT and 68.0% for pCT (p = 0.47). Only grade 3a complications according to Clavien-Dindo were increased after pCT (p = 0.04). There was a trend towards a higher rate of pylorospasm within the pCT group (nCRT: 23.7% versus pCT: 37.1%) (p = 0.061). Multivariate analysis identified pCT, younger age, and Charlson score as independent variables for pylorospasm. CONCLUSION: Both nCRT and pCT are safe and efficient within the multimodal treatment of esophageal/gastroesophageal adenocarcinoma. We did not observe differences in postoperative morbidity. However, functional aspects such as gastric emptying might be more frequent after pCT.

Palliation of malignant dysphagia with a segmented self-expanding metal stent: A STROBE-compliant article.

ABSTRACT: Self-expanding metal stents (SEMSs) in different geometric shapes are an established palliative treatment for malignant tumors of the esophagus. Mechanical properties and stent design have an impact on patient comfort, migration rate, and removability. SEMS with a segmented design (segSEMS) have recently become available on the market, promising new biomechanical properties for stent placement in benign and malignant esophageal diseases. In this study, we evaluated recurrent dysphagia, quality of life as well as technical success and complications for segmented SEMS-implantation in a retrospective study in palliative patients with dysphagia caused by malignant tumors of the esophagus.Between May 2017 and December 2018, patients presented to the interdisciplinary department of endoscopy of the University Hospital Cologne underwent segmented SEMS placement for malignant dysphagia. Patient follow-up was evaluated, and complications were monitored. Quality of life and functional improvement were monitored using the EORTC QLQ-C30 and QLQ-OE18.A total of 20 consecutive patients (16 men, 4 women; mean age: 65.5, range: 46-82) participated in the study and were treated with 20 segSEMS in total. The success rate of stent placement was 100%. Stent migration occurred in 3 patients (15.0%). Insertion of segSEMS immediately lead to a 48.0% reduction of dysphagia in the first 2 months (P < .001). Pain while eating (odynophagia) could also be significantly reduced by 39.6% over the first 2 months (P < .001).Implantation of segSEMS is a feasible and effective treatment for dysphagia in palliative patients with malignant tumors of the esophagus, offering immediate relief of symptoms and gain of physical functions.