Extensive preclinical validation of combined RMC-4550 and LY3214996 supports clinical investigation for KRAS mutant pancreatic cancer.

Over 90% of pancreatic cancers present mutations in KRAS, one of the most common oncogenic drivers overall. Currently, most KRAS mutant isoforms cannot be targeted directly. Moreover, targeting single RAS downstream effectors induces adaptive resistance mechanisms. We report here on the combined inhibition of SHP2, upstream of KRAS, using the allosteric inhibitor RMC-4550 and of ERK, downstream of KRAS, using LY3214996. This combination shows synergistic anti-cancer activity in vitro, superior disruption of the MAPK pathway, and increased apoptosis induction compared with single-agent treatments. In vivo, we demonstrate good tolerability and efficacy of the combination, with significant tumor regression in multiple pancreatic ductal adenocarcinoma (PDAC) mouse models. Finally, we show evidence that 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) can be used to assess early drug responses in animal models. Based on these results, we will investigate this drug combination in the SHP2 and ERK inhibition in pancreatic cancer (SHERPA; ClinicalTrials.gov: NCT04916236) clinical trial, enrolling patients with KRAS-mutant PDAC.

[COVID-19-New challenges in dysphagia and respiratory therapy]. / COVID-19 ­ neue Herausforderungen in der Dysphagie- und Atemtherapie.

Coronavirus disease 2019 (COVID-19) can lead to severe disease courses with multiple organ involvement, respiratory and neurological functional impairments. Swallowing disorders (dysphagia) in this patient group can result from primary damage to the central and peripheral neuronal swallowing network but also from the frequently prolonged intensive care treatment and mechanical ventilation. Clinical observations indicate persistence of dysphagia in post-acute COVID-19 syndrome (long COVID), so that these patients probably also need long-term interventions for rehabilitation of safe and sufficient oral feeding. Therefore, structured disease-specific monitoring of dysphagia symptoms should be integrated into the treatment of COVID-19 patients and respiratory therapy should be an essential part of dysphagia management to re-establish cough effectiveness and breathing-swallowing coordination. Challenges arise from necessary adjustments to established treatment standards to prevent infections. Furthermore, the selection and intensity of therapeutic measures have to be adapted to the capacities and the specific pathophysiology of COVID-19 and long COVID patients to prevent further functional deterioration.

[Invasive Eyelid Infections by ß-Hemolytic Streptococci of Serogroup A]. / Invasive Lidinfektionen durch ß-hämolysierende Streptokokken der Serogruppe A.

BACKGROUND: Invasive soft tissue infections by Streptococcus pyogenes are rapidly progressive and potentially life-threatening infectious diseases. These can also affect the eyelid. Aggressive virulence factors and the synthesis of exotoxins can lead to complications, such as periorbital necrotizing fasciitis (PONF) and streptococcal toxic shock syndrome (STSS). The clinical picture is characterized by four patients with invasive eyelid infections. MATERIALS AND METHODS: Photographic documentation, radiological imaging, laboratory and smear diagnostics and intravenous antibiotic therapy were performed on all patients according to the recommendations of the German Robert Koch Institute and the local infectiology board. RESULTS: In all patients, Streptococcus pyogenes was culturally detected in a direct swab. The antibiogram showed sensitivity to the common intravenous antibiotics. The time interval between symptom onset and presentation at the clinic was between two days and one week. All patients had high systemic inflammatory parameters on admission: Pat. 1: CRP 259 mg/l, leukocytes 20.1 giga/l; Pat. 2: CRP 375 mg/l, leukocytes 15.6 giga/l; Pat. 3: CRP 378 mg/l, leukocytes 38.7 giga/l; Pat. 4: CRP 483 mg/l, leukocytes 1.7 giga/l; normal values: CRP < 5 mg/l, leucocytes 4.4 - 11.3 giga/l. In Pat. 2 and 3, a periorbital necrotizing fasciitis was diagnosed due to rapidly progressing necrosis in the area of cutis and subcutis and systemic toxicity. Pat. 3 and 4 met the diagnostic criteria of STSS. Pat. 2, 3 and 4 had to be relocated to an intermediate or intensive care unit with sepsis, despite immediate intravenous antibiotic therapy. Patient 3 underwent surgical debridement during the stay in the intensive care unit. Thanks to interdisciplinary management (ophthalmology, infectiology, ear, nose and throat medicine, internal medicine and intensive care medicine), all patients were finally discharged from our inpatient treatment in a significantly improved general condition. CONCLUSION: Invasive streptococcal infections represent a challenge in the daily routine of an ophthalmologist. Interdisciplinary management and immediate onset of high-dose intravenous antibiotic therapy are crucial for successful treatment.