Primäre und sekundäre Resistenzmechanismen der EGFR Blockade

Die Blockade des EGF Rezeptors ist fester Bestandteil in der Therapie von Kopf-Hals Plattenepithelkarzinomen. Trotz zahlreicher klinisch, translationaler und präklinischer Forschungen konnte bis zum heutigen Tag kein prädiktiver Biomarker für die Behandlung von Kopf-Hals Karzinomen validiert werden. Die dargestellten Arbeiten zeigen sehr gut die Chancen und gleichzeitig die Limitationen von translationaler Forschung mit dem Ziel der Definition prädiktiver Biomarker auf. Patientenproben sind in der Regel FFPE fixiert, bergen den Nachteil der z.T. langen Lagerung einhergehend mit Nukleinsäuredegradierung und sind nur für einen Teil interessanter Fragestellungen zu gebrauchen. Weiterhin findet in der Regel eine multimodale Behandlung statt, die den Stellenwert eines einzelnen biologischen Charakteristikums, wie in den Arbeiten beispielhaft an Amphiregulin oder EGFRvIII Expression gezeigt, in der Interpretation erschweren. Präklinische Modelle, die die Erkrankungssituation 1:1 widerspiegeln, gibt es nicht. Ein präklinisches Modell, dass nah am Ausgangstumor bleibt, ist das PDX Modell. Es konnte gezeigt werden, dass eine grosse Zahl von Kopf-Hals Tumor Xenograftmodellen sehr gut geeignet sind, Hypothesen zu generieren

Treatment Stratification in First-Line Recurrent or Metastatic Head and Neck Cancer, on Behalf of the EORTC Young Investigator Head and Neck Cancer Group

Multiple factors differentially influence treatment decisions in the first line treatment of recurrent/metastatic HNSCC. The EORTC Young investigator group launched a survey among treating physicians to explore the main influencing factors for treatment stratification. The questionnaire was posted as a web-survey link from May to August 2020. Next to defining the factors that mostly influence therapeutic decision the survey was complemented by a clinical case discussion of five patient cases. A total of 118 responses from 19 countries were collected. The key factors identified to guide treatment decision were performance status, PD-L1 Expression, time from last systemic treatment above or below 6 months, and disease burden.Prospective evaluation of patient characteristics and additional potential predictive biomarkers for novel treatment options remains an important question to stratify personalized treatment for RM HNSCC

Quality of Life of Patients with Head and Neck Cancer Receiving Cetuximab, Fluorouracil, Cisplatin Comparing to Cetuximab, Fluorouracil, Cisplatin, and Docetaxel within the CEFCID Trial

Introduction: CeFCiD was a multicenter phase II study comparing the efficacy of cetuximab (C), 5-flourouracil, and cisplatin with the same regimen adding docetaxel (D) in recurrent/metastatic head and neck cancer. The primary analysis trial did not demonstrate survival benefit from therapy intensification in first-line recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). The current analysis of the trial assessed the impact of treatment on quality of life (QoL). Methods: The European Organization for Research and Treatment of Cancer Quality of life Questionnaire QLQ-C30 and the tumor-specific module for head and neck cancer (QLQ-H&N35) were used to assess QoL at baseline (visit 1), after 2 (visit 3), 4 (visit 5), and 6 (visit 7) cycles of chemotherapy. Results: Of 180 patients included in this study, 86 patients (47.8%) completed the questionnaires at baseline. Considering selected scores over treatment time, there was no difference in global QoL, dyspnea, swallowing, and speech between the treatment arms in the course. For fatigue, a significant increase from baseline to visit 3 (p = 0.02), visit 5 (p = 0.002), and to visit 7 (p = 0.003) was observed for patients receiving D, cisplatin or carboplatin (P), 5-fluorouracil (F), and C. At the end of chemotherapy, the manifestation of fatigue was similar compared in the 2 treatment arms. Discussion/Conclusion: Therapy intensification not adversely affects selected scores of QoL of patients with recurrent and/or metastatic SCCHN. Nevertheless, fatigue seems to be pronounced in patients treated with D

Distinct immune evasion in APOBEC‐enriched, HPV‐negative HNSCC

Immune checkpoint inhibition leads to response in some patients with head and neck squamous cell carcinoma (HNSCC). Robust biomarkers are lacking to date. We analyzed viral status, gene expression signatures, mutational load and mutational signatures in whole exome and RNA-sequencing data of the HNSCC TCGA dataset (n = 496) and a validation set (DKTK MASTER cohort, n = 10). Public single-cell gene expression data from 17 HPV-negative HNSCC were separately reanalyzed. APOBEC3-associated TCW motif mutations but not total single nucleotide variant burden were significantly associated with inflammation. This association was restricted to HPV-negative HNSCC samples. An APOBEC-enriched, HPV-negative subgroup was identified, that showed higher T-cell inflammation and immune checkpoint expression, as well as expression of APOBEC3 genes. Mutations in immune-evasion pathways were also enriched in these tumors. Analysis of single-cell sequencing data identified expression of APOBEC3B and 3C genes in malignant cells. We identified an APOBEC-enriched subgroup of HPV-negative HNSCC with a distinct immunogenic phenotype, potentially mediating response to immunotherapy

Essential data variables for a minimum dataset for head and neck cancer trials and clinical research:HNCIG consensus recommendations and database

The Head and Neck Cancer International Group (HNCIG) has undertaken an international modified Delphi process to reach consensus on the essential data variables to be included in a minimum database for HNC research. Endorsed by 19 research organisations representing 34 countries, these recommendations provide the framework to facilitate and harmonise data collection and sharing for HNC research. These variables have also been incorporated into a ready to use downloadable HNCIG minimum database, available from the HNCIG website

The role of PPARγ and TFF-3 in enterocolitis animal model

Die nekrotisierende Enterokolitis ist einer der häufigsten gastrointestinalen Notfälle auf neonatologischen Intensivstationen. Unreife ist der wesentliche Risikofaktor für die Entwicklung einer NEC. Für PPARγ-Agonisten (Glitazone) konnte bei chronisch entzündlichen Darmerkrankungen eine entzündungshemmende Wirkung gezeigt werden. Im Rahmen dieser Arbeit wurde untersucht, ob Glitazone die H/R-induzierte Darmbarrierestörung im Enterokolitismodell der neugeborene Ratte vermindert. Insbesondere untersuchten wir die Rolle von TFF-3, einem Peptid, das sich in verschiedenen Modellen als protektiv erwiesen hat. Schwangere Ratten erhielten während der Tragzeit p.o. Glitazone. Die so behandelten Feten wurden reif oder vorzeitig geboren und dienten als Versuchstiere. Wir verwendeten ein Tiermodell, in dem die Schädigung des Darms durch Hyperkapnie/Reoxygenierung (H/R) hervorgerufen wird. Die intestinale Barrierestörung wurde mittels FITC-Dextran Assay, die Entzündungsantwort als iNOS-Expression und die Apoptose als Caspase 3-Aktivierung gemessen. Wir konnten zeigen, dass Glitazone die H/R-induzierte intestinale Barrierestörung, Entzündungsantwort und Apoptose signifikant vermindern. Weiterhin konnte gezeigt werden, dass Glitazone die fetale, und nach intraperitonealer Gabe auch die neonatale Expression des protektiv wirksamen TFF-3 steigern. Möglicherweise vermittelt die gesteigerte TFF-3-Expression den von uns beobachteten protektiven Effekt der Glitazone im H/R-Tiermodell. Die Arbeit trägt zum besseren Verständnis der Pathophysiologie der NEC bei. Erstmals wurde gezeigt, dass Glitazone die Expression von TFF-3 induzieren. Ob sie darüberhinaus zur Prävention der NEC eingesetzt werden können, bleibt offenNecrotizing enterocolitis is one of the most common gastrointestinal emergencies in preterm infants leading to admission at an intensive care unit. PPARy agonists have repeatedly been associated with reduction of inflammation of the intestine. Within this work we analysed whether administration of PPARy agonists leads to attenuation of gut barrier failure in a H/R animal model of the newborn rat. Furthermore we investigated the role of TFF-3 in intestinal mucosa. Pregnant rats were fed with Pioglitazone, a PPARy agonist. Pups delivered at term and preterm served as animals for induction of enterocolitis through hypercapnia/reoxygenation. Gut barrier failure was assessed by FITC Dextran assay, the intensity of inflammation by the expression of iNOS and the level of apoptosis by activity measurement of caspase-3. We could show that animals in the group whose mother received PPARy agonists during pregnancy had significantly less gut barrier failure, less expression of iNOS and less activity of caspase-3. Furthermore it could be shown that PPARy activation leads to increased expression of TFF-3. This work contributes to a better understanding of the pathophysiology of nec. For the first time we showed that glitazones lead to induction of TFF-3 expression. Whether or not PPARy agonists will play a role in prevention of nec remains elusive

Reactive oxygen species in cancer stem cells of head and neck squamous cancer

Qian X, Nie X, Yao W, et al. Reactive oxygen species in cancer stem cells of head and neck squamous cancer. Seminars in Cancer Biology. 2018;53:248-257

Multiparametric Phenotyping of Circulating Tumor Cells for Analysis of Therapeutic Targets, Oncogenic Signaling Pathways and DNA Repair Markers

Detection of circulating tumor cells (CTCs) has been established as an independent prognostic marker in solid cancer. Multiparametric phenotyping of CTCs could expand the area of application for this liquid biomarker. We evaluated the Amnis® brand ImageStream®X MkII (ISX) (Luminex, Austin, TX, USA) imaging flow cytometer for its suitability for protein expression analysis and monitoring of treatment effects in CTCs. This was carried out using blood samples from patients with head and neck squamous cell carcinoma (n = 16) and breast cancer (n = 8). A protocol for negative enrichment and staining of CTCs was established, allowing quantitative analysis of the therapeutic targets PD–L1 and phosphorylated EGFR (phospho–EGFR), and the treatment response marker γH2AX as an indicator of radiation–induced DNA damage. Spiking experiments revealed a sensitivity of 73% and a specificity of 100% at a cut–off value of ≥3 CTCs, and thus confirmed the suitability of the ISX-based protocol to detect phospho–EGFR and γH2AX foci in CTCs. Analysis of PD–L1/–L2 in both spiked and patient blood samples further showed that assessment of heterogeneity in protein expression within the CTC population was possible. Further validation of the diagnostic potential of this ISX protocol for multiparametric CTC analysis in larger clinical cohorts is warranted