Risk factors for immune-related adverse effects during CPI therapy in patients with head and neck malignancies – a single center study

IntroductionCheckpoint inhibitors, such as PD1 inhibitors, represent an important pillar in the therapy of advanced malignancies of the head and neck region. The most relevant complications are immune-related adverse effects (irAEs), which represent an immense burden for patients. Currently, no sufficient stratification measures are available to identify patients at increased risk of irAEs. The aim of this retrospective study was to examine whether demographic, histopathological, clinical, or laboratory values at the start of CPI therapy represent a risk factor for the later occurrence of autoimmune complications.Material and methodsData from 35 patients between 2018 and 2021 who received therapy with nivolumab or pembrolizumab for head and neck malignancy were analyzed and assessed for any associations with the subsequent occurrence of irAEs.ResultsIrAE developed in 37% of patients, with pneumonitis being the most common form (14%). Pneumonitis was found in patients with an average significantly lower T-stage of primary tumors. An increase in basophilic leukocytes was found in patients with dermatitis later in the course. When thyroiditis developed later, the patients had a higher CPS score and lower monocyte levels.DiscussionEven though individual laboratory values at the beginning of therapy might show a statistical association with the later occurrence of irAEs, neither demographic, histopathological, nor laboratory chemistry values seem to be able to generate a sound and reliable risk profile for this type of complication. Therefore, patients need to be educated and sensitized to irAEs, and regular screening for irAEs should be carried out

Prediction of Groundwater Flow and Transport Processes in an Urban Area: A Combined Approach of Field Testing and Numerical Modeling

Drinking water supply in urban areas is challenging due to different kinds of water use and potential groundwater contamination. We investigate an area where drinking water production is close to different contaminated sites. The study site is characterized by a high complexity of the tectonic and geological setting with a gravel and a karstic aquifer. The two aquifers are partly connected, partly disconnected by an aquitard. To avoid drinking water contamination, artificial groundwater recharge with surface water into the gravel aquifer is used to create a hydraulic barrier between the contaminated sites and the water abstraction wells. Trace compounds, that were found in former times in the surface water but not nowadays, are still detected in the extracted drinking water. Different studies have been performed such as numerical modeling, intensive groundwater monitoring and investigation of drilling cores to get a differentiated overview of the distribution of the contaminants. Back-diffusion from the matrix due to changing hydraulic boundary was stated to be the reason for the actual distribution of the contaminants. In a first approach due to the lack of experimental data or evidence from field measurements, the permeabilities of the karstic aquifer were assumed as homogeneous. In our study, we seek to identify the flow and transport processes within the system including the fracture network in a combined approach of field work and 3D modeling with FEFLOW. During a field campaign we acquired water samples for the analysis of stable water isotopes as well as organic and inorganic compounds. Furthermore, tritium and helium samples were taken to estimate water ages and to determine the flow through the fracture networks. A combination of existing and recently obtained data was used to build and validate a 3D flow and transport model. The simulation of different scenarios such as the water flow for varying injection and extraction rates as well as particle transport from different sources is carried out. To investigate the effect of subsurface heterogeneity, PEST, an independent parameter estimation and uncertainty analysis software, was used. With the calibrated model we will be able to optimize the operational conditions of artificial recharge and drinking water production especially at the boundaries of the production field. Hence, we can provide guidelines for an improved water resource management

Expression of Kallikrein-related peptidase 6 in primary mucosal malignant melanoma of the head and neck

Mucosal melanomas of the head and neck (MMHN) are aggressive tumors with poor prognosis, different opposed to cutaneous melanoma. In this study, we characterized primary mucosal malignant melanoma for the expression of Kallikrein-related peptidase 6 (KLK6), a member of the KLK family with relevance to the malignant phenotype in various cancer types including cutaneous melanoma. Paraffin-embedded MMHN of 22 patients were stained immunohistochemically for KLK6 and results were correlated with clinical and pathological data. In 77.3% (17/22) of MMHN cases, positive KLK6 staining was found. Staining pattern for tumor cells showed a predominant cytoplasmic staining. However, in six cases we also observed a prominent nuclear staining. MMHN with a high KLK6 expression showed significantly better outcome concerning local recurrence-free survival (p = 0.013) and nuclear KLK6 staining was significantly associated with the survival status (p = 0.027). Overexpression of KLK6 was detected in more than 70% of MMHN and approximately 40% of tumors showed a strong expression pattern. Correlation between clinical outcome of MMHN patients and overexpression of KLK6 has not been addressed so far. Our data demonstrate for the first time increased levels of KLK6 in MMHN and strengthen the hypothesis that there might be a context-specific regulation and function of KLK6 in mucosal melanoma

Organotypic Co-Cultures as a Novel 3D Model for Head and Neck Squamous Cell Carcinoma

Background: Head and neck squamous cell carcinomas (HNSCC) are phenotypically and molecularly heterogeneous and frequently develop therapy resistance. Reliable patient-derived 3D tumor models are urgently needed to further study the complex pathogenesis of these tumors and to overcome treatment failure. Methods: We developed a three-dimensional organotypic co-culture (3D-OTC) model for HNSCC that maintains the architecture and cell composition of the individual tumor. A dermal equivalent (DE), composed of healthy human-derived fibroblasts and viscose fibers, served as a scaffold for the patient sample. DEs were co-cultivated with 13 vital HNSCC explants (non-human papillomavirus (HPV) driven, n = 7; HPV-driven, n = 6). Fractionated irradiation was applied to 5 samples (non-HPV-driven, n = 2; HPV-driven n = 3). To evaluate expression of ki-67, cleaved caspase-3, pan-cytokeratin, p16INK4a, CD45, ∝smooth muscle actin and vimentin over time, immunohistochemistry and immunofluorescence staining were performed Patient checkup data were collected for up to 32 months after first diagnosis. Results: All non-HPV-driven 3D-OTCs encompassed proliferative cancer cells during cultivation for up to 21 days. Proliferation indices of primaries and 3D-OTCs were comparable and consistent over time. Overall, tumor explants displayed heterogeneous growth patterns (i.e., invasive, expansive, silent). Cancer-associated fibroblasts and leukocytes could be detected for up to 21 days. HPV DNA was detectable in both primary and 3D-OTCs (day 14) of HPV-driven tumors. However, p16INK4a expression levels were varying. Morphological alterations and radioresistant tumor cells were detected in 3D-OTC after fractionated irradiation in HPV-driven and non-driven samples. Conclusions: Our 3D-OTC model for HNSCC supports cancer cell survival and proliferation in their original microenvironment. The model enables investigation of invasive cancer growth and might, in the future, serve as a platform to perform sensitivity testing upon treatment to predict therapy response

Sampling strategy for karst waters

To optimize sampling strategy in a small water supply in Northwestern Switzerland, event-specific sampling of turbidity and microorganisms was conducted. These data were compared with previously performed tracer tests and water quality data from routine drinking water sampling 1 to 4 times a year. Whereas the data from routine sampling only give information on the general behaviour of karst springs, event-specific sampling gives specific information of the karst system and residence times of microorganisms. In addition, previously conducted tracer test gave partly wrong evidence on the input locations of microorganisms. Furthermore, the present sampling strategy can not account for microbial risk. Therefore, karst systems with short response times on precipitation in the order of hours should be equipped for automatic sampling. After the transgression of defined tolerance values of e.g. turbidity, a sample device should be activated to take several samples and send a signal to the local authorities who should collect the bottles from the sampling device and take them to the laboratory for analysis

Undercover Investigations - Forschung für eine nachhaltige Planung urbaner Infrastruktur im Raum Basel

In den nächsten zwanzig Jahren werden in der Nordwestschweiz grosse Infrastrukturprojekte geplant, die zum Teil unter sehr herausfordernden Untergrundverhältnissen realisiert werden sollen. Für eine Beurteilung der Beeinflussung der Verkehrsinfrastrukturen auf die Untergrundressourcen bedarf es einer unabhängigen, praxisorientierten, geologischen, hydrogeologischen und geotechnischen Begleitung. Im Rahmen von Forschungsprojekten erarbeitet das Team der Angewandten und Umweltgeologie (AUG) hierzu anwendungsorientierte Grundlagen in enger Zusammenarbeit mit den Kantonen und Bundesfachstellen. Dieser Beitrag illustriert exemplarisch für das in Basel geplante Autobahnbauwerk “Rheintunnel” und den S-Bahntunnel “Herzstück”, wie komplexe geologische Randbedingungen berücksichtigt und eine nachhaltige thermische Nutzung urbaner Untergrundressourcen realisiert werden können