Die Fremdkörperingestion – eine seltene Ursache persistierender, unklarer abdomineller Schmerzen

Anamnese und klinischer befund: Ein 50-jähriger Patient stellt sich mit rechtsseitigen Unterbauchschmerzen in der Notaufnahme vor. Er gibt an, dass jene Beschwerden seit ca. 5 Monaten bestünden und bei der Miktion an Intensität zunähmen.Untersuchungen: Nach einer Vielzahl frustraner diagnostischer Maßnahmen (CT Abdomen, MR-Sellink, Ileokoloskopie) gelingt es letztlich mittels Darmsonografie, einen ingestierten Zahnstocher im terminalen Ileum als Ursache für die Beschwerden zu identifizieren. Jener perforiert die Darmwand lokal und affektiert die angrenzende Blasenwand bei jeder Erhöhung des intraabdominellen Druckes schmerzhaft.Therapie und verlauf: Explorative Laparotomie mit Nachweis eines entzündlichen Konglomerattumors mit ileosigmoidaler Fistel im rechten Unterbauch. Die Entzündungsreaktion wird durch einen das terminale Ileum zweifach perforierenden Zahnstocher verursacht. Die operative Versorgung erfolgt mittels Ileumsegmentresektion und Sigmaresektion mit End-zu-End-Anastomosierung. Im postoperativen Verlauf kommt es zu einer subkutanen Wundheilungsstörung, die mittels VAC-Therapie versorgt wird. Am 16. postoperativen Tag kann der Patient in einem guten Allgemeinzustand nach Hause entlassen werden.Folgerung: Eine Fremdkörperingestion stellt eine seltene, aber relevante Differenzialdiagnose unklarer abdomineller Schmerzen, insbesondere im Kindesalter, dar. Neben einer ausführlichen Anamnese sollte als primäre apparative Maßnahme stets zunächst eine qualifizierte und sorgfältig durchgeführte Abdomensonografie erfolgen, mithilfe derer auch strahlentransparente ingestierte Fremdkörper detektiert werden können.</p

Overcoming tumor-mediated immunosuppression

Mechanisms of tumor-mediated immunosuppression have been described for several solid and hematological tumors. Tumors inhibit immune responses by attraction of immunosuppressive lymphocytic populations, secretion of immunosuppressive cytokines or expression of surface molecules, which inhibit immune responses by induction of anergy or apoptosis in tumor-infiltrating lymphocytes. This tumor-mediated immunosuppression represents a major obstacle to many immunotherapeutic or conventional therapeutic approaches. In this review we discuss how tumor-mediated immunosuppression interferes with different immunotherapeutic approaches and then give an overview of strategies to overcome it. Particular emphasis is placed on agents or approaches already transferred into clinical settings. Finally the success of immune checkpoint inhibitors targeting CTLA-4 or the PD-1 pathway highlights the enormous therapeutic potential of an effective overcoming of tumor-mediated immunosuppression

Immune responses against shared antigens are common in esophago-gastric cancer and can be enhanced using CD40-activated B cells

Background Specific immune response is a hallmark of cancer immunotherapy and shared tumor-associated antigens (TAAs) are important targets. Recent advances using combined cellular therapy against multiple TAAs renewed the interest in this class of antigens. Our study aims to determine the role of TAAs in esophago-gastric adenocarcinoma (EGA).Methods RNA expression was assessed by NanoString in tumor samples of 41 treatment-naïve EGA patients. Endogenous T cell and antibody responses against the 10 most relevant TAAs were determined by FluoroSpot and protein-bound bead assays. Digital image analysis was used to evaluate the correlation of TAAs and T-cell abundance. T-cell receptor sequencing, in vitro expansion with autologous CD40-activated B cells (CD40Bs) and in vitro cytotoxicity assays were applied to determine specific expansion, clonality and cytotoxic activity of expanded T cells.Results 68.3% of patients expressed ≥5 TAAs simultaneously with coregulated clusters, which were similar to data from The Cancer Genome Atlas (n=505). Endogenous cellular or humoral responses against ≥1 TAA were detectable in 75.0% and 53.7% of patients, respectively. We found a correlation of T-cell abundance and the expression of TAAs and genes related to antigen presentation. TAA-specific T-cell responses were polyclonal, could be induced or enhanced using autologous CD40Bs and were cytotoxic in vitro. Despite the frequent expression of TAAs co-occurrence with immune responses was rare.Conclusions We identified the most relevant TAAs in EGA for monitoring of clinical trials and as therapeutic targets. Antigen-escape rather than missing immune response should be considered as mechanism underlying immunotherapy resistance of EGA

Microwave ablation enhances tumor-specific immune response in patients with hepatocellular carcinoma

Thermal ablative therapies are standard treatments for localized hepatocellular carcinoma (HCC). In addition to local tumor destruction, ablation leads to abscopal effects in distant lesions most likely mediated by an anti-tumor immune response. Although microwave ablation (MWA) is increasingly substituting other ablative techniques, its systemic immunostimulatory effects are poorly studied. We analyzed tumor-specific immune responses in peripheral blood of HCC patients after thermal ablation with regard to T cell responses and disease outcome. While comprehensive flow cytometric analyses in sequential samples of a prospective patient cohort (n = 23) demonstrated only moderate effects of MWA on circulating immune cell subsets, fluorospot analyses of specific T cell responses against seven tumor-associated antigens (TTAs) revealed de-novo or enhanced tumor-specific immune responses in 30% of patients. This anti-tumor immune response was related to tumor control as Interferon-y and Interleukin-5 T cell responses against TAAs were more frequent in patients with a long-time remission (&amp;gt; 1 year) after MWA (7/16) compared to patients suffering from an early relapse (0/13 patients) and presence of tumor-specific T cell response (IFN-y and/or IL-5) was associated to longer progression-free survival (27.5 vs. 10.0 months). Digital image analysis of immunohistochemically stained archival HCC samples (n = 18) of patients receiving combined MWA and resection revealed a superior disease-free survival of patients with high T cell abundance at the time of thermal ablation (37.4 vs. 13.1 months). Our data demonstrates remarkable immune-related effects of MWA in HCC patients and provides additional evidence for a combination of local ablation and immunotherapy in this challenging disease

Immune checkpoints programmed death 1 ligand 1 and cytotoxic T lymphocyte associated molecule 4 in gastric adenocarcinoma

Remarkable efficacy of immune checkpoint inhibition has been reported for several types of solid tumors and early studies in gastric adenocarcinoma are promising. A detailed knowledge about the natural biology of immune checkpoints in gastric adenocarcinoma is essential for clinical and translational evaluation of these drugs. This study is a comprehensive analysis of cytotoxic T lymphocyte associated molecule 4 (CTLA-4) and programmed death 1 ligand 1 (PD-L1) expression in gastric adenocarcinoma. PD-L1 and CTLA-4 were stained on tumor sections of 127 Caucasian patients with gastric adenocarcinoma by immunohistochemistry (IHC) and somatic mutation profiling was performed using targeted next-generation sequencing. Expression of PD-L1 and CTLA-4 on lymphocytes in tumor sections, tumor-draining lymph nodes (TDLN) and peripheral blood were studied by flow-cytometry and immune-fluorescence microscopy in an additional cohort. PD-L1 and CTLA-4 were expressed in 44.9% (57/127) and 86.6% (110/127) of the analyzed gastric adenocarcinoma samples, respectively. Positive tumor cell staining for PD-L1 or CTLA-4 was associated with inferior overall survival. Somatic mutational analysis did not reveal a correlation to expression of PD-L1 or CTLA-4 on tumor cells. Expression of PD-1 (52.2%), PD-L1 (42.2%) and CTLA-4 (1.6%) on tumor infiltrating T cells was significantly elevated compared to peripheral blood. Of note, PD-1 and PD-L1 were expressed far higher by tumor-infiltrating lymphocytes than CTLA-4. In conclusion, specific immune checkpoint-inhibitors should be evaluated in this disease and the combination with molecular targeted therapies might be of benefit. An extensive immune monitoring should accompany these studies to better understand their mode of action in the tumor microenvironment

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

Background: Consensus about the definition and treatment of oligometastatic oesophagogastric cancer is lacking. Objective: To assess the definition and treatment of oligometastatic oesophagogastric cancer across multidisciplinary tumour boards (MDTs) in Europe. Material and methods: European expert centers (n Z 49) were requested to discuss 15 real-life cases in their MDT with at least a medical, surgical, and radiation oncologist present. The cases varied in terms of location and number of metastases, histology, timing of detection (i.e. synchronous versus metachronous), primary tumour treatment status, and response to systemic therapy. The primary outcome was the agreement in the definition of oligometastatic disease at diagnosis and after systemic therapy. The secondary outcome was the agreement in treatment strategies. Treatment strategies for oligometastatic disease were categorised into up -front local treatment (i.e. metastasectomy or stereotactic radiotherapy), systemic therapy followed by restaging to consider local treatment or systemic therapy alone. The agreement across MDTs was scored to be either absent/poor (= 75%). Results: A total of 47 MDTs across 16 countries fully discussed the cases (96%). Oligometastatic disease was considered in patients with 1-2 metastases in either the liver, lung, retroperitoneal lymph nodes, adrenal gland, soft tissue or bone (consensus). At follow-up, oligometastatic disease was considered after a median of 18 weeks of systemic therapy when no progression or progression in size only of the oligometastatic lesion(s) was seen (consensus). If at restaging after a median of 18 weeks of systemic therapy the number of lesions progressed, this was not considered as oligometastatic disease (fair agreement). There was no consensus on treatment strategies for oligometastatic disease. Conclusion: A broad consensus on definitions of oligometastatic oesophagogastric cancer was found among MDTs of oesophagogastric cancer expert centres in Europe. However, high practice variability in treatment strategies exists. (C) 2022 The Authors. Published by Elsevier Ltd