Treatment of local recurrence of esophageal cancer following Ivor-Lewis esophagectomy-Experiences of a high-volume center.

PURPOSE: Patients with local recurrence of esophageal cancer have a highly decreased overall survival. There is currently no standardized treatment algorithm for this group. This retrospective cohort study aimed to evaluate the survival of patients with local recurrence, despite receiving individualized treatment options. METHODS: 241 of 1791 patients were diagnosed with a local recurrence following Ivor-Lewis esophagectomy at the University Hospital of Cologne. 59 patients, who were diagnosed only with a local recurrence of adeno- or squamous cell carcinoma and received their individualized therapy regimes at our high-volume center, were included. RESULTS: The study included 52 patients with adenocarcinoma and 7 with squamous cell carcinoma. Among these, 6 patients underwent resection, 19 received solely chemotherapy, 29 received chemoradiotherapy, and 5 were provided with best supportive care. Patients who underwent resection showed a better survival outcome compared to patients without resection (median OS: not reached vs. 15.1 months, p = 0.012). Best supportive care and palliative care were found to be independent risk factors for shorter overall survival compared to curative intended treatment options like local resection or chemoradiotherapy. CONCLUSION: In this study, different treatment strategies for patients with local recurrence of esophageal cancer were depicted. Resection as well as chemoradiotherapy could play a role in selected patients. Further prospective studies are needed to improve the selection of eligible patients.

Upregulation of the histone γ-H2AX correlates with worse patient survival and basal-like subtype in pancreatic ductal adenocarcinoma.

PURPOSE: Patients with pancreatic ductal adenocarcinoma (PDAC) have yet to experience significant benefits from targeted therapy. Olaparib is currently the only active substance in BRCA-mutated PDACs that successfully influences the DNA repair of carcinoma cells. H2AX belongs to the histone family and is known as a part of the DNA repair system. The inhibition of γ-H2AX could lead to the inhibition of mitotically active tumor cells. Therefore, we aimed to evaluate the predictive value of the γ-H2AX in patients with PDAC. METHODS: All included patients (n = 311) received a pancreatic resection with curative intention in one of our PANCALYZE study centers. Subsequently, they were enrolled in a standardized follow-up protocol. Immunohistochemical stainings for γ-H2AX were conducted on tissue microarrays. RESULTS: Patients exhibiting high levels of γ-H2AX expression experience more frequent R1 resections, indicating advanced tumor stages in this subgroup. Additionally, patients with high γ-H2AX expression demonstrated significantly poorer survival compared to those with low expression (median OS: 15 vs. 25 months, p < 0.001). In multivariate analyses, high γ-H2AX expression could be identified as an independent risk factor for worse patient survival. Moreover, high γ-H2AX expression could be more frequently observed in the more aggressive basal-like subtype. CONCLUSION: γ-H2AX can be characterized as a predictive biomarker for poorer patient survival. Consequently, upcoming clinical trials focused on the efficacy of targeted therapies influencing the DNA repair system and radiotherapy should evaluate γ-H2AX as a potential biomarker for therapy response. Furthermore, γ-H2AX may serve as a viable target for treatment in the future.

Copy-number-gain of telomerase reverse transcriptase (hTERT) is associated with an unfavorable prognosis in esophageal adenocarcinoma.

Esophageal adenocarcinoma exhibits one of the highest mortality rates among all cancer entities. Multimodal therapy strategies have improved patients' survival significantly. However, patients in early stages are currently limited to receiving only local therapies, even though some patients within this group showcase short survival periods. Until now, there has been no widely established clinically used biomarker to detect these high-risk patients. Telomerase reverse transcriptase (TERT), a gene encoding a crucial subunit of the telomerase enzyme, plays a significant role in establishing cancer cell immortality and is under suspicion for its potential contribution to tumor progression. Therefore, we aimed to evaluate the clinical relevance of the TERT amplification status. We included 643 patients with esophageal adenocarcinoma, who underwent Ivor-Lewis esophagectomy at the University Hospital of Cologne. The TERT amplification status was characterized using fluorescence in situ hybridization. Clinicopathological values and patients' overall survival were compared between patients with and without TERT amplification. Further sub-cohort analyses were conducted for patients with pT1N0-3 tumor stage. Eighty-One patients (12.6%) exhibited TERT amplification. Patients with amplified TERT showed significantly worse overall survival (median OS: 22.6 vs. 36.8 months, p = 0.009). Interestingly, TERT amplification could be characterized as an independent risk factor for worse overall survival in multivariate analysis in patients with pT1N0-3 tumor stage (HR = 2.440, 95% CI 1.095-5.440, p = 0.029). In this study, we describe the TERT amplification status as an independent risk factor for worse survival in patients diagnosed with esophageal adenocarcinoma at pT1N0-3 tumor stage, encompassing cases involving tumor infiltration of the lamina propria, muscularis mucosae, and/or submucosa. Based on our findings, we put forth the proposition that evaluating the TERT amplification status may serve as a valuable tool in identifying a specific subgroup of patients, namely those with TERT amplification and pT1N0-3 tumor-stage esophageal adenocarcinoma. The patients of this subgroup could potentially benefit from enhanced follow-up protocols, more aggressive treatment approaches, or possible targeted TERT inhibition therapies, all aimed at improving their overall clinical outcomes.

Prediction of postoperative complications after oesophagectomy using machine-learning methods.

BACKGROUND: Oesophagectomy is an operation with a high risk of postoperative complications. The aim of this single-centre retrospective study was to apply machine-learning methods to predict complications (Clavien-Dindo grade IIIa or higher) and specific adverse events. METHODS: Patients with resectable adenocarcinoma or squamous cell carcinoma of the oesophagus and gastro-oesophageal junction who underwent Ivor Lewis oesophagectomy between 2016 and 2021 were included. The tested algorithms were logistic regression after recursive feature elimination, random forest, k-nearest neighbour, support vector machine, and neural network. The algorithms were also compared with a current risk score (the Cologne risk score). RESULTS: 457 patients had Clavien-Dindo grade IIIa or higher complications (52.9 per cent) versus 407 patients with Clavien-Dindo grade 0, I, or II complications (47.1 per cent). After 3-fold imputation and 3-fold cross-validation, the overall accuracies were: logistic regression after recursive feature elimination, 0.528; random forest, 0.535; k-nearest neighbour, 0.491; support vector machine, 0.511; neural network, 0.688; and Cologne risk score, 0.510. For medical complications, the results were: logistic regression after recursive feature elimination, 0.688; random forest, 0.664; k-nearest neighbour, 0.673; support vector machine, 0.681; neural network, 0.692; and Cologne risk score, 0.650. For surgical complications, the results were: logistic regression after recursive feature elimination, 0.621; random forest, 0.617; k-nearest neighbour, 0.620; support vector machine, 0.634; neural network, 0.667; and Cologne risk score, 0.624. The calculated area under the curve of the neural network was 0.672 for Clavien-Dindo grade IIIa or higher, 0.695 for medical complications, and 0.653 for surgical complications. CONCLUSION: The neural network scored the highest accuracies compared with all of the other models for the prediction of postoperative complications after oesophagectomy.

The human gullet or stomach can develop tumours. Surgery can help to cure patients with these tumours. But the operation is risky because sometimes adverse events can happen afterwards. So far, there is no reliable prediction model. It may help to predict the risk of adverse events accurately. For example, patients with a high risk could be observed more thoroughly. Patients with a low risk may not need unnecessary procedures. The information of all patients with an operation at a specialized hospital was collected. Machine learning is a complex mathematical method and was used in this study. It is able to analyse big data sets of information. One machine-learning method called neural network was best in predicting adverse events. Right now, the performance may not be strong enough to fully rely on the prediction. However, refinement of the prediction and more data could improve the neural network in the future.

Long-Term Postsurgical Outcomes of Neoadjuvant Chemoradiation (CROSS) Versus Chemotherapy (FLOT) for Multimodal Treatment of Adenocarcinoma of the Esophagus and the Esophagogastric Junction.

BACKGROUND: The question of the ideal neoadjuvant therapy for locally advanced esophagogastric adenocarcinoma has not been answered to date. Multimodal treatment has become a standard treatment for these adenocarcinomas. Currently, perioperative chemotherapy (FLOT) or neoadjuvant chemoradiation (CROSS) is recommended. METHODS: A monocentric retrospective analysis compared long-term survival after CROSS versus FLOT. The study enrolled patients with adenocarcinoma of the esophagus (EAC) or the esophagogastric junction type I or II undergoing oncologic Ivor-Lewis esophagectomy between January 2012 and December 2019. The primary objective was to determine the long-term outcome in terms of overall survival. The secondary objectives were to determine differences regarding the histopathologic categories after neoadjuvant treatment and the histomorphologic regression. RESULTS: The findings showed no survival advantage for one or the other treatment in this highly standardized cohort. All the patients underwent open (CROSS: 9.4% vs. FLOT: 22%), hybrid (CROSS: 82% vs. FLOT: 72%), or minimally invasive (CROSS: 8.9% vs. FLOT: 5.6%) thoracoabdominal esophagectomy. The median post-surgical follow-up period was 57.6 months (95% confidence interval [CI] 23.2-109.7 months), and the median survival was longer for the CROSS patients (54 months) than for the FLOT patients (37.2 months) (p = 0.053). The overall 5-years survival was 47% for the entire cohort (48% for the CROSS and 43% for the FLOT patients). The CROSS patients showed a better pathologic response and fewer advanced tumor stages. CONCLUSION: The improved pathologic response after CROSS cannot be translated into longer overall survival. To date, the choice of which neoadjuvant treatment to use can be made only on the basis of clinical parameters and the patient's performance status.

Specific Subtypes of Carcinoma-Associated Fibroblasts Are Correlated with Worse Survival in Resectable Pancreatic Ductal Adenocarcinoma.

PURPOSE: The pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer entities. Effective therapy options are still lacking. The tumor microenvironment possibly bears further treatment possibilities. This study aimed to describe the expression patterns of four established carcinoma-associated fibroblast (CAFs) markers and their correlation in PDAC tissue samples. METHODS: This project included 321 patients with PDAC who underwent surgery with a curative intent in one of the PANCALYZE study centers. Immunohistochemical stainings for FAP, PDGFR, periostin, and SMA were performed. The expression patterns of each marker were divided into low- and high-expressing CAFs and correlated with patients' survival. RESULTS: Tumors showing SMAhigh-, PeriostinhighSMAhigh-, or PeriostinhighSMAlowPDGFRlowFAPhigh-positive CAFs demonstrated significantly worse survival. Additionally, a high expression of SMA in PDAC tissue samples was shown to be an independent risk factor for worse survival. CONCLUSION: This project identified three subgroups of PDAC with different expression patterns of CAF markers which showed significantly worse survival. This could be the base for the further characterization of the fibroblast subgroups in PDAC and contribute to the development of new targeted therapy options against CAFs.

Cytokeratin 6 identifies basal-like subtypes of pancreatic ductal adenocarcinoma with decreased survival.

PURPOSE: Rising incidence of pancreatic ductal adenocarcinoma (PDAC) bind with insufficient therapy options showcases a great medical challenge. Further biomarkers are required to identify patients, who will benefit from more aggressive therapy. METHODS: 320 patients were included by the PANCALYZE study group. Cytokeratin 6 (CK6) immunohistochemical staining as a putative marker for the basal-like subtype of PDAC was performed. The correlation between CK6 expression patterns and survival data, as well as various markers of the (inflammatory) tumor microenvironment, were analyzed. RESULTS: We divided the study population based on the expression pattern of CK6. Patients with a high CK6 tumor expression had a significantly shorter survival (p = 0.013), confirmed in a multivariate cox regression model. CK6-expression is an independent marker for a decreased overall survival (HR = 1.655, 95% CI 1.158-2.365, p = 0.006). In addition, the CK6-positive tumors showed significantly less plasma cell infiltration and more cancer-associated fibroblasts (CAFs) expressing Periostin and SMA. CONCLUSIONS: CK6 could be considered as an independent biomarker for a shorter overall survival. CK6 is a clinically easily accessible biomarker for the identification of the basal-like subtype of PDAC. Therefore, it could be taken into consideration in deciding for the more aggressive therapy regimes. Prospectively, studies addressing the chemosensitive characteristics of this subtype are required.

Predicting the HER2 status in oesophageal cancer from tissue microarrays using convolutional neural networks.

BACKGROUND: Fast and accurate diagnostics are key for personalised medicine. Particularly in cancer, precise diagnosis is a prerequisite for targeted therapies, which can prolong lives. In this work, we focus on the automatic identification of gastroesophageal adenocarcinoma (GEA) patients that qualify for a personalised therapy targeting epidermal growth factor receptor 2 (HER2). We present a deep-learning method for scoring microscopy images of GEA for the presence of HER2 overexpression. METHODS: Our method is based on convolutional neural networks (CNNs) trained on a rich dataset of 1602 patient samples and tested on an independent set of 307 patient samples. We additionally verified the CNN's generalisation capabilities with an independent dataset with 653 samples from a separate clinical centre. We incorporated an attention mechanism in the network architecture to identify the tissue regions, which are important for the prediction outcome. Our solution allows for direct automated detection of HER2 in immunohistochemistry-stained tissue slides without the need for manual assessment and additional costly in situ hybridisation (ISH) tests. RESULTS: We show accuracy of 0.94, precision of 0.97, and recall of 0.95. Importantly, our approach offers accurate predictions in cases that pathologists cannot resolve and that require additional ISH testing. We confirmed our findings in an independent dataset collected in a different clinical centre. The attention-based CNN exploits morphological information in microscopy images and is superior to a predictive model based on the staining intensity only. CONCLUSIONS: We demonstrate that our approach not only automates an important diagnostic process for GEA patients but also paves the way for the discovery of new morphological features that were previously unknown for GEA pathology.

X-linked inhibitor of apoptosis protein is a prognostic marker for a favorable outcome in three identified subsets in resectable adenocarcinoma of the pancreas.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is currently one of the leading causes of cancer death worldwide. Therefore, building further subgroups as well as enabling individual patient therapy and diagnostics are needed. X-linked inhibitor of apoptosis protein (XIAP) is known to modulate apoptotic and inflammatory pathways. Its expression was found to correlate with patients' survival in other tumor entities. This study aims to examine the role of XIAP in patients with PDAC in relation to the inflammatory microenvironment. METHODS: The PANCALYZE multicenter study group included 257 patients with PDAC. Paraffin-embedded tumor samples were stained immunohistochemically for CD3, CD20, CD38, CD56, CD66b, CD117, and CD163 and XIAP. These stainings were further analyzed digitally with QuPath and survival analyses were done. RESULTS: XIAP-positive patients with T-cell, respectively, neutrophil enriched tumors survived significantly longer compared to XIAP-negative patients (CD3: 37.6 vs. 24.6 months, p = 0.028; CD66b: 34.1 vs. 14.9 months, p = 0.027). Additionally, XIAP-positive patients showed better survival in the lymph node-negative population (48.4 vs. 24.2 months, p = 0.019). Regarding the total population, our findings did not show a correlation between XIAP expression and survival. In multivariate cox regression analyzes XIAP proves to be an independent factor for better survival in the identified subgroups (CD3: p = 0.043; CD66b: p = 0.012, N0: p = 0.040). CONCLUSION: We found XIAP-positive subgroups with significantly better survival in patients with PDAC in T-cell-rich, neutrophil-rich, or lymph node-negative cohorts. This could lead to further individualized cancer treatment with less aggressive therapy protocols for XIAP-positive tumors or more intensive follow-up for XIAP-negative tumors.

Machine learning for optimized individual survival prediction in resectable upper gastrointestinal cancer.

PURPOSE: Surgical oncologists are frequently confronted with the question of expected long-term prognosis. The aim of this study was to apply machine learning algorithms to optimize survival prediction after oncological resection of gastroesophageal cancers. METHODS: Eligible patients underwent oncological resection of gastric or distal esophageal cancer between 2001 and 2020 at Heidelberg University Hospital, Department of General Surgery. Machine learning methods such as multi-task logistic regression and survival forests were compared with usual algorithms to establish an individual estimation. RESULTS: The study included 117 variables with a total of 1360 patients. The overall missingness was 1.3%. Out of eight machine learning algorithms, the random survival forest (RSF) performed best with a concordance index of 0.736 and an integrated Brier score of 0.166. The RSF demonstrated a mean area under the curve (AUC) of 0.814 over a time period of 10 years after diagnosis. The most important long-term outcome predictor was lymph node ratio with a mean AUC of 0.730. A numeric risk score was calculated by the RSF for each patient and three risk groups were defined accordingly. Median survival time was 18.8 months in the high-risk group, 44.6 months in the medium-risk group and above 10 years in the low-risk group. CONCLUSION: The results of this study suggest that RSF is most appropriate to accurately answer the question of long-term prognosis. Furthermore, we could establish a compact risk score model with 20 input parameters and thus provide a clinical tool to improve prediction of oncological outcome after upper gastrointestinal surgery.

Transjugular intrahepatic portosystemic shunt, local thrombaspiration, and lysis for management of fulminant portomesenteric thrombosis and atraumatic splenic rupture due to vector-vaccine-induced thrombotic thrombocytopenia: a case report.

INTRODUCTION: Recombinant adenoviral vector vaccines against severe acute respiratory syndrome coronavirus 2 have been observed to be associated with vaccine-induced immune thrombotic thrombocytopenia. Though vaccine-induced immune thrombotic thrombocytopenia is a rare complication after vaccination with recombinant adenoviral vector vaccines, it can lead to severe complications. In vaccine-induced immune thrombotic thrombocytopenia, the vector vaccine induces heparin-independent production of platelet factor 4 autoantibodies, resulting in platelet activation and aggregation. Therefore, patients suffering from vaccine-induced immune thrombotic thrombocytopenia particularly present with signs of arterial or venous thrombosis, often at atypical sites, but also signs of bleeding due to disseminated intravascular coagulation and severe thrombocytopenia. We describe herein a rare case of fulminant portomesenteric thrombosis and atraumatic splenic rupture due to vaccine-induced immune thrombotic thrombocytopenia. This case report presents the diagnosis and treatment of a healthy 29-year-old male Caucasian patient suffering from an extended portomesenteric thrombosis associated with atraumatic splenic rupture due to vaccine-induced immune thrombotic thrombocytopenia after the first dose of an adenoviral vector vaccine against severe acute respiratory syndrome coronavirus 2 [ChAdOx1 nCoV-19 (AZD1222)]. Therapeutic management of vaccine-induced immune thrombotic thrombocytopenia initially focused on systemic anticoagulation avoiding heparin and the application of steroids and intravenous immune globulins as per the recommendations of international societies of hematology and hemostaseology. Owing to the atraumatic splenic rupture and extended portomesenteric thrombosis, successful management of this case required splenectomy with additional placement of a transjugular intrahepatic portosystemic shunt to perform local thrombaspiration, plus repeated local lysis to reconstitute hepatopetal blood flow. CONCLUSION: The complexity and wide spectrum of the clinical picture in patients suffering from vaccine-induced immune thrombotic thrombocytopenia demand an early interdisciplinary diagnostic and therapeutic approach. Severe cases of portomesenteric thrombosis in vaccine-induced immune thrombotic thrombocytopenia, refractory to conservative management, may require additional placement of a transjugular intrahepatic portosystemic shunt, thrombaspiration, thrombolysis, and surgical intervention for effective management.

Influence of patient sex on outcomes after pancreatic surgery: multicentre study.

BACKGROUND: Recent findings support the hypothesis of sex-related differences in inflammatory and immunological responses to trauma. The aim of this study was to address sex-specific aspects in patients who underwent pancreatic surgery. METHODS: This retrospective study used data from the German StuDoQ registry. Patients who underwent pancreatic surgery between 2010 and 2020 were stratified according to procedure (pancreatic head resection, distal pancreatectomy (DP), total pancreatectomy (TP)). Each cohort underwent propensity score matching (PSM) with the co-variables BMI, ASA, age, coronary heart disease (CHD), diabetes, hypertension with medication, and histology to level the distribution of co-morbidities between men and women. The main outcomes were morbidity and mortality. RESULTS: The total cohort consisted of 10 224 patients (45.3 per cent women). Men had higher ASA grades, and more often had CHD, diabetes, and hypertension with medication. Women had fewer overall complications (57.3 versus 60.1 per cent; P = 0.005) and a lower mortality rate (3.4 versus 4.9 per cent; P < 0.001). Rates of pancreatic surgery-specific complications, such as clinically relevant postoperative pancreatic fistula (POPF) (grade B/C: 14 versus 17 per cent; P < 0.001), delayed gastric emptying (grade B/C: 7.8 versus 9.2 per cent; P = 0.014), and postpancreatectomy haemorrhage (grade B/C: 7.1 versus 9.0 per cent; P < 0.001), were also lower in women. After PSM, 8358 patients were analysed. In the pancreatic head resection cohort (5318 patients), women had fewer complications (58.6 versus 61.4 per cent; P = 0.044), a lower in-hospital mortality rate (3.6 versus 6.1 per cent; P < 0.001), and less often had clinically relevant POPF (11.6 versus 16.2 per cent; P < 0.001). After DP, the clinically relevant POPF rate was lower in women (22.5 versus 27.3 per cent; P = 0.012). In the TP cohort, men more often developed intra-abdominal abscess requiring drainage (5.0 versus 2.3 per cent; P = 0.050). CONCLUSION: Women had favourable outcomes after pancreatic surgery.

IL-17B/RB Activation in Pancreatic Stellate Cells Promotes Pancreatic Cancer Metabolism and Growth.

In pancreatic ductal adenocarcinoma (PDAC), the tumor stroma constitutes most of the cell mass and contributes to therapy resistance and progression. Here we show a hitherto unknown metabolic cooperation between pancreatic stellate cells (PSCs) and tumor cells through Interleukin 17B/Interleukin 17B receptor (IL-17B/IL-17RB) signaling. Tumor-derived IL-17B carrying extracellular vesicles (EVs) activated stromal PSCs and induced the expression of IL-17RB. PSCs increased oxidative phosphorylation while reducing mitochondrial turnover. PSCs activated tumor cells in a feedback loop. Tumor cells subsequently increased oxidative phosphorylation and decreased glycolysis partially via IL-6. In vivo, IL-17RB overexpression in PSCs accelerated tumor growth in a co-injection xenograft mouse model. Our results demonstrate a tumor-to-stroma feedback loop increasing tumor metabolism to accelerate tumor growth under optimal nutritional conditions.

Study protocol of an open-label, single arm phase II trial investigating the efficacy, safety and quality of life of neoadjuvant chemotherapy with liposomal irinotecan combined with Oxaliplatin and 5-fluorouracil/Folinic acid followed by curative surgical resection in patients with hepatic Oligometastatic adenocarcinoma of the pancreas (HOLIPANC).

BACKGROUND: According to current guidelines, treatment of patients with hepatic oligometastasis in pancreatic cancer is not reflected and systemic chemotherapy is recommended in those patients. Retrospective data suggest beneficial outcomes in patients with hepatic oligometastasis, though prospective data from clinical trials addressing this particular patient group is not available. METHODS: In this single arm, phase-2 trial, survival data from patients receiving neoadjuvant chemotherapy followed by R0/R1 resection will be compared to historic data from patients with oligometastatic adenocarcinoma of the pancreas. The clinical trial will focus on a well-defined patient collective with metastatic load limited to the liver as target organ with a maximum of five metastases. The combination of liposomal irinotecan (nal-IRI), oxaliplatin (OX) and 5-fluouracil (5-FU)/folinic acid (FA) (nal-IRI + OX+ 5-FU/FA, NAPOX) was chosen as neoadjuvant chemotherapy; the choice was based on an ongoing clinical study in which NAPOX appeared manageable, with promising anti-tumor activity in first-line treatment of patients with metastatic pancreatic adenocarcinoma. In total 150 patients will be enrolled for this trial with an aim of 55 patients receiving a complete macroscopic synchronous tumor and metastatic resection. DISCUSSION: This is the first clinical study to prospectively evaluate the value of multimodality therapy concepts in oligometastatic pancreatic cancer. TRIAL REGISTRATION NUMBERS: EudraCT 2019-002734-37 ; NCT04617457 .

Occurrence of High Microsatellite-Instability/Mismatch Repair Deficiency in Nearly 2,000 Human Adenocarcinomas of the Gastrointestinal Tract, Pancreas, and Bile Ducts: A Study From a Large German Comprehensive Cancer Center.

INTRODUCTION: Knowledge of the high microsatellite-instability (MSI-H)/mismatch repair deficiency (MMRd) status is of increasing interest for personalized neoadjuvant or adjuvant therapy planning. Only a few studies are available on MSI-H distribution in the Northern European Caucasian patient population. In this study, we focused on a large cohort of tumors of the upper gastrointestinal tract. MATERIALS AND METHODS: Surgical material from a total of 1,965 patients was analyzed for MSI-H/MMRd status (including 1,267 carcinomas of the esophagus or stomach). All tumors were analyzed with an internationally recommended immunohistochemical panel consisting of four antibodies (MLH1, MSH2, PMS2, and MSH6). The results were molecularly objectified. RESULTS: Adenocarcinomas with MSI-H/MMRd were detected with the following distribution: esophagus (1.4%), stomach (8.3%), small intestine (18.2%), large intestine (8.5%), intrahepatic bile ducts (1.9%), and pancreas (0%). In case of gastric tumors with MSI-H/MMRd, neoadjuvant therapy did not influence the prognosis of patients (p = 0.94). Within all tumor entities with MSI-H/MMRd, patients with a UICC stage 4 were also represented. In this advanced stage, 11.7% of patients with MSS tumors were diagnosed compared to 0.5% of patients with MSI-H tumors relative to the entire tumor collective. DISCUSSION: In this study, the proportion of MSI-H/MMRd tumors in the stomach is smaller than would have been expected in knowledge of the data published by TCGA or AGRC. Negative prognostic effects regarding MSI-H status and neoadjuvant therapy as described by the MAGIC study group were not seen in our cohort. The extent to which the MSI-H/MMRd status should be known for neoadjuvant therapy planning must be clarified in prospective studies in the future. At present, there is no convincing data to dispense the neoadjuvant therapy for gastric carcinoma. Due to the very convincing, positive data regarding the response rates of MSI-H tumors to treatment with PD1/PD-L1 inhibitors, every metastatic carcinoma of the gastrointestinal tract should be tested for its MSI-H status.

Expression of Immune Checkpoint Regulators IDO, VISTA, LAG3, and TIM3 in Resected Pancreatic Ductal Adenocarcinoma.

Pancreatic cancer features elaborate mechanisms of immune evasion. The potential of new immune molecules was explored to restore the antitumor immune response. If these immune molecules are associated with poor survival, specific drugs could take effect. Here, we analyze the expression of VISTA, LAG3, IDO, and TIM3 on tumor-infiltrating lymphocytes (TILs) and its impact on patient survival. We analyzed 153 pancreatic cancer patients from the prospectively managed database of the multicentered PANCALYZE study. Immunohistochemistry on a tissue microarray assessed VISTA, LAG3, IDO, and TIM3 expression of TILs from the patients undergoing primary resection. Complementarily, we analyzed publicly available transcriptomic data (n = 903). Successful completion of chemotherapy, and lymph node status were independent predictors of survival in the multivariate analysis of the clinicopathologic parameters. Fifteen tumors were exclusively VISTA-positive, thirteen tumors expressed VISTA together with TIM3, and ten tumors expressed VISTA together with IDO. Patients featuring tumors with high numbers of IDO-positive TILs had better patient survival (p = 0.037). VISTA, LAG3, and TIM3 expression did not correlate with survival. The analysis of publicly available data did not show survival differences. Tumors rarely co-express more than two immune molecules at the same time, and VISTA is most frequently co-expressed. Although IDO generally inhibits T-cell proliferation, a high expression of IDO was associated with improved survival. We expect immune checkpoint inhibitors against VISTA, LAG3, and TIM3 to be inefficient in a clinical application.

Interferon-Induced Protein With Multiple Tetratricopeptide Repeats 3 Is Associated With Response to Chemotherapy and Recurrence but Not With Survival.

OBJECTIVES: The interferon-induced protein with multiple tetratricopeptide repeats 3 (IFIT3) seems to be associated with the prognosis in pancreatic cancer. Here we clarify whether the heterogeneity of IFIT3 expression affects previous IFIT3 analysis. METHODS: This retrospective study analyzes pancreatic cancer tissue samples retrieved by surgery from 2 independent patient cohorts. Patients underwent either primary surgery (n = 72) or received neoadjuvant chemotherapy (n = 12). Immunohistochemistry assessed IFIT3 expression and its heterogeneity. Complementarily, we analyzed publicly available transcriptomic data (n = 903). RESULTS: Of the primarily resected tumors, 16.4% were heterogeneous. Patients with IFIT3-negative tumors did not survive longer compared with patients with IFIT3-positive tumors. An analysis of publicly available data confirmed this result. Patients developing lung metastases had the best prognosis (4.8 years) with significantly lower IFIT3 expression compared with liver metastasis (P = 0.0117). Patients receiving neoadjuvant therapy who are IFIT3 negative had a longer disease-free survival (1.2 vs 0.3 years, P = 0.0081). CONCLUSIONS: Low IFIT3 expression is not associated with longer survival. Divergent results from tissue microarray analyses could be explained with tumor heterogeneity. As a single biomarker, IFIT3 is not suitable for predicting disease prognosis. Recurrence of lung metastases and response to neoadjuvant chemotherapy are associated with low IFIT3 expression.

Spatiotemporal Organization of Chemotaxis Pathways in Magnetospirillum gryphiswaldense.

Magnetospirillum gryphiswaldense employs iron-rich nanoparticles for magnetic navigation within environmental redox gradients. This behavior termed magneto-aerotaxis was previously shown to rely on the sensory pathway CheOp1, but the precise localization of CheOp1-related chemoreceptor arrays during the cell cycle and its possible interconnection with three other chemotaxis pathways have remained unstudied. Here, we analyzed the localization of chemoreceptor-associated adaptor protein CheW1 and histidine kinase CheA1 by superresolution microscopy in a spatiotemporal manner. CheW1 localized in dynamic clusters that undergo occasional segregation and fusion events at lateral sites of both cell poles. Newly formed smaller clusters originating at midcell before completion of cytokinesis were found to grow in size during the cell cycle. Bipolar CheA1 localization and formation of aerotactic swim halos were affected depending on the fluorescent protein tag, indicating that CheA1 localization is important for aerotaxis. Furthermore, polar CheW1 localization was independent of cheOp2 to cheOp4 but lost in the absence of cheOp1 or cheA1 Results were corroborated by the detection of a direct protein interaction between CheA1 and CheW1 and by the observation that cheOp2- and cheOp3-encoded CheW paralogs localized in spatially distinct smaller clusters at the cell boundary. Although the findings of a minor aerotaxis-related CheOp4 phenotype and weak protein interactions between CheOp1 and CheOp4 by two-hybrid analysis implied that CheW1 and CheW4 might be part of the same chemoreceptor array, CheW4 was localized in spatially distinct polar-lateral arrays independent of CheOp1, suggesting that CheOp1 and CheOp4 are also not connected at the molecular level.IMPORTANCE Magnetotactic bacteria (MTB) use the geomagnetic field for navigation in aquatic redox gradients. However, the highly complex signal transduction networks in these environmental microbes are poorly understood. Here, we analyzed the localization of selected chemotaxis proteins to spatially and temporally resolve chemotaxis array localization in Magnetospirillum gryphiswaldense Our findings suggest that bipolar localization of chemotaxis arrays related to the key signaling pathway CheOp1 is important for aerotaxis and that CheOp1 signaling units assemble independent of the three other chemotaxis pathways present in M. gryphiswaldense Overall, our results provide deeper insights into the complex organization of signaling pathways in MTB and add to the general understanding of environmental bacteria possessing multiple chemotaxis pathways.

Structured Reporting of Solid and Cystic Pancreatic Lesions in CT and MRI: Consensus-Based Structured Report Templates of the German Society of Radiology (DRG). / Strukturierte Befundung von soliden und zystischen Pankreasläsionen im CT und MRT: Konsensus-basierte Befundvorlagen der Deutschen Röntgengesellschaft (DRG).

BACKGROUND: Radiological reports of pancreatic lesions are currently widely formulated as free texts. However, for optimal characterization, staging and operation planning, a wide range of information is required but is sometimes not captured comprehensively. Structured reporting offers the potential for improvement in terms of completeness, reproducibility and clarity of interdisciplinary communication. METHOD: Interdisciplinary consensus finding of structured report templates for solid and cystic pancreatic tumors in computed tomography (CT) and magnetic resonance imaging (MRI) with representatives of the German Society of Radiology (DRG), German Society for General and Visceral Surgery (DGAV), working group Oncological Imaging (ABO) of the German Cancer Society (DKG) and other radiologists, oncologists and surgeons. RESULTS: Among experts in the field of pancreatic imaging, oncology and pancreatic surgery, as well as in a public online survey, structured report templates were developed by consensus. These templates are available on the DRG homepage under www.befundung.drg.de and will be regularly revised to the current state of scientific knowledge by the participating specialist societies and responsible working groups. CONCLUSION: This article presents structured report templates for solid and cystic pancreatic tumors to improve clinical staging (cTNM, ycTNM) in everyday radiology. KEY POINTS: · Structured report templates offer the potential of optimized radiological reporting with regard to completeness, reproducibility and differential diagnosis.. · This article presents consensus-based, structured reports for solid and cystic pancreatic lesions in CT and MRI.. · These structured reports are available open source on the homepage of the German Society of Radiology (DRG) under www.befundung.drg.de.. CITATION FORMAT: · Persigehl T, Baumhauer M, Baeßler B et al. Structured Reporting of Solid and Cystic Pancreatic Lesions in CT and MRI: Consensus-Based Structured Report Templates of the German Society of Radiology (DRG). Fortschr Röntgenstr 2020; 192: 641 - 655.