Circulating immune-related proteins associated with immune checkpoint inhibitor efficacy in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: Most patients with pancreatic ductal adenocarcinoma (PDAC) do not benefit from immune checkpoint inhibitor treatment. However, the phase II study CheckPAC (NCT02866383) showed a clinical benefit (CB) rate of 37% and a response rate of 14% in patients with metastatic PDAC receiving stereotactic radiation therapy and nivolumab with or without ipilimumab. Translational studies were initiated to characterize the patients who would benefit from this treatment. Here, we evaluated the association between treatment outcome and 92 circulating immuno-oncology-related proteins in patients from the CheckPAC trial. MATERIALS AND METHODS: The study included 78 patients with chemoresistant metastatic PDAC treated with nivolumab ± ipilimumab combined with radiotherapy. Proteins were measured in serum samples collected at baseline and on treatment with the use of the Olink Target 96 Immuno-Oncology panel. A cohort of 234 patients with metastatic PDAC treated with first-line chemotherapy were also included. RESULTS: High levels of Fas ligand (FASLG) and galectin 1 (Gal-1) and low levels of C-C motif chemokine 4 were associated with CB. High FASLG and Gal-1 were associated with longer progression-free survival in univariable analysis. In the multivariable Cox regression analysis, the association was significant for Gal-1 (P < 0.001) but not significant for FASLG (P = 0.06). A focused unsupervised hierarchal clustering analysis, including T-cell activation and immune checkpoint-related proteins, identified clusters of patients with higher CB rate and higher tumor expression of leukocyte or T-cell markers (CD3, CD45, granzyme B). Thirty-six proteins increased significantly during immunotherapy. Several proteins (including FASLG, checkpoint proteins, and immune activation markers) increased independently of response during immunotherapy but did not increase in the cohort of patients treated with chemotherapy. CONCLUSIONS: Circulating levels of immune-related proteins like FASLG and Gal-1 might be used to predict the efficacy of checkpoint inhibitors in patients with metastatic PDAC.

Personalized circulating tumor DNA in patients with hepatocellular carcinoma: a pilot study.

BACKGROUND: Mutational analysis of circulating tumor DNA (ctDNA) can potentially be used for early detection of recurrence after resection for hepatocellular carcinoma (HCC). Mutations from tumor may be identified in plasma as an early sign of recurrence. We conducted a pilot study investigating if somatic mutations could be detected in plasma in patients undergoing liver resection for HCC and in patients with advanced non-resectable HCC. METHODS AND RESULTS: We prospectively included patients undergoing curative liver resection for HCC. Tumor tissue was investigated with whole exome sequencing and preoperative blood samples were evaluated for ctDNA using targeted next-generation sequencing (NGS) with TruSight Oncology 500 including 523 cancer-associated genes. Subsequently, the method was evaluated in patients with advanced HCC. We included eight patients curatively resected for HCC, where tumor tissue mutations were identified in seven patients. However, only in one patient tumor specific mutations were found in the preoperative blood sample. In all three patients with advanced HCC, tumor mutations were detected in the blood. CONCLUSIONS: In patients with resectable HCC, ctDNA could not be reliably detected using the applied targeted NGS method. In contrast, ctDNA was detected in all patients with advanced HCC. Small tumors, tumor heterogeneity and limited sequencing coverage may explain the lack of detectable ctDNA.

Experimental guinea pig model of dermatophytosis: a simple and useful tool for the evaluation of new diagnostics and antifungals.

The aim of this study was to establish a simple guinea pig model for the purpose of evaluating diagnostic principles and treatment modalities for dermatophytic infections. The following variables were evaluated; pre-treatment of the skin by shaving versus tape stripping, Microsporum canis or Trichophyton mentagrophytes test strains as etiologic agents, differences in inoculum concentrations, and inoculation with and without occlusion. The course of infection was evaluated clinically by redness and lesion scores and mycologically by microscopy, culture, and histopathology. The applicability of the model was evaluated with a recently developed diagnostic pan-dermatophyte PCR and antifungal treatment was tested with an oral solution of itraconazole, 10 mg/kg, once daily during days 3-14 of the test period. Pre-treatment of the skin with a manual razor was for practical reasons preferable to tape stripping. Inoculation under occlusion showed no advantage in the establishment of experimental infections. Infection severity showed some association with the inoculum concentration and subtype of T. mentagrophytes but not in studies involving M. canis. The establishment of dermatophytosis was confirmed by histopathology. Surprisingly, microscopy was found to be less sensitive than culture and the latter was as sensitive as pan-dermatophyte PCR. Itraconazole significantly reduced lesion and redness score, with M. canis infections responding better to itraconazole treatment than those caused by T. mentagrophytes. In conclusion, we established a dermatophytosis animal model, which was proven useful for evaluating diagnostic methods and antifungal susceptibility testing.