Spontaneous Regression of Ovarian Carcinoma After Septic Peritonitis; A Unique Case Report

Despite advances in therapy, ovarian cancer remains the most lethal gynecological malignancy and prognosis has not substantially improved over the past 3 decades. Immunotherapy is a promising new treatment option. However, the immunosuppressive cancer microenvironment must be overcome for immunotherapy to be successful. Here, we present a unique case of spontaneous regression of ovarian carcinoma after septic peritonitis. A 79-year-old woman was diagnosed with stage IIIc ovarian cancer. The omental cake biopsy was complicated by sepsis. Although the patient recovered, her physical condition did not allow further treatment for her ovarian cancer. After 6 months, spontaneous regression of the tumor was observed during surgery. Analysis of the immune infiltrate in the tissues showed a shift from a pro-tumorigenic to an anti-tumorigenic immune response after sepsis. Strong activation of the immune system during sepsis overruled the immunosuppressive tumor microenvironment and allowed for a potent anti-tumor immune response. More understanding of immunological responses in cases with cancer and septic peritonitis might be crucial to identify potential new targets for immunotherapy

Use of directed acyclic graphs (DAGs) to identify confounders in applied health research: review and recommendations

Abstract Background Directed acyclic graphs (DAGs) are an increasingly popular approach for identifying confounding variables that require conditioning when estimating causal effects. This review examined the use of DAGs in applied health research to inform recommendations for improving their transparency and utility in future research. Methods Original health research articles published during 1999–2017 mentioning ‘directed acyclic graphs’ (or similar) or citing DAGitty were identified from Scopus, Web of Science, Medline and Embase. Data were extracted on the reporting of: estimands, DAGs and adjustment sets, alongside the characteristics of each article’s largest DAG. Results A total of 234 articles were identified that reported using DAGs. A fifth (n = 48, 21%) reported their target estimand(s) and half (n = 115, 48%) reported the adjustment set(s) implied by their DAG(s). Two-thirds of the articles (n = 144, 62%) made at least one DAG available. DAGs varied in size but averaged 12 nodes [interquartile range (IQR): 9–16, range: 3–28] and 29 arcs (IQR: 19–42, range: 3–99). The median saturation (i.e. percentage of total possible arcs) was 46% (IQR: 31–67, range: 12–100). 37% (n = 53) of the DAGs included unobserved variables, 17% (n = 25) included ‘super-nodes’ (i.e. nodes containing more than one variable) and 34% (n = 49) were visually arranged so that the constituent arcs flowed in the same direction (e.g. top-to-bottom). Conclusion There is substantial variation in the use and reporting of DAGs in applied health research. Although this partly reflects their flexibility, it also highlights some potential areas for improvement. This review hence offers several recommendations to improve the reporting and use of DAGs in future research

Pre-existing chromatin accessibility and gene expression differences among naive CD4+ T cells influence effector potential

CD4+ T cells have a remarkable potential to differentiate into diverse effector lineages following activation. Here, we probe the heterogeneity present among naive CD4+ T cells before encountering their cognate antigen to ask whether their effector potential is modulated by pre-existing transcriptional and chromatin landscape differences. Single-cell RNA sequencing shows that key drivers of variability are genes involved in T cell receptor (TCR) signaling. Using CD5 expression as a readout of the strength of tonic TCR interactions with self-peptide MHC, and sorting on the ends of this self-reactivity spectrum, we find that pre-existing transcriptional differences among naive CD4+ T cells impact follicular helper T (TFH) cell versus non-TFH effector lineage choice. Moreover, our data implicate TCR signal strength during thymic development in establishing differences in naive CD4+ T cell chromatin landscapes that ultimately shape their effector potential

Human type 1 and type 2 conventional dendritic cells express indoleamine 2,3-dioxygenase 1 with functional effects on T cell priming

Dendritic cells (DCs) are key regulators of the immune system that shape T cell responses. Regulation of T cell induction by DCs may occur via the intracellular enzyme indoleamine 2,3-dioxygenase 1 (IDO), which catalyzes conversion of the essential amino acid tryptophan into kynurenine. Here, we examined the role of IDO in human peripheral blood plasmacytoid DCs (pDCs), and type 1 and type 2 conventional DCs (cDC1s and cDC2s). Our data demonstrate that under homeostatic conditions, IDO is selectively expressed by cDC1s. IFN-γ or TLR ligation further increases IDO expression in cDC1s and induces modest expression of the enzyme in cDC2s, but not pDCs. IDO expressed by conventional DCs is functionally active as measured by kynurenine production. Furthermore, IDO activity in TLR-stimulated cDC1s and cDC2s inhibits T cell proliferation in settings were DC-T cell cell-cell contact does not play a role. Selective inhibition of IDO1 with epacadostat, an inhibitor currently tested in clinical trials, rescued T cell proliferation without affecting DC maturation status or their ability to cross-present soluble antigen. Our findings provide new insights into the functional specialization of human blood DC subsets and suggest a possible synergistic enhancement of therapeutic efficacy by combining DC-based cancer vaccines with IDO inhibition

Human type 1 and type 2 conventional dendritic cells express indoleamine 2,3‐dioxygenase 1 with functional effects on T cell priming

Dendritic cells (DCs) are key regulators of the immune system that shape T cell responses. Regulation of T cell induction by DCs may occur via the intracellular enzyme indoleamine 2,3‐dioxygenase 1 (IDO), which catalyzes conversion of the essential amino acid tryptophan into kynurenine. Here, we examined the role of IDO in human peripheral blood plasmacytoid DCs (pDCs), and type 1 and type 2 conventional DCs (cDC1s and cDC2s). Our data demonstrate that under homeostatic conditions, IDO is selectively expressed by cDC1s. IFN‐γ or TLR ligation further increases IDO expression in cDC1s and induces modest expression of the enzyme in cDC2s, but not pDCs. IDO expressed by conventional DCs is functionally active as measured by kynurenine production. Furthermore, IDO activity in TLR‐stimulated cDC1s and cDC2s inhibits T cell proliferation in settings were DC‐T cell cell‐cell contact does not play a role. Selective inhibition of IDO1 with epacadostat, an inhibitor currently tested in clinical trials, rescued T cell proliferation without affecting DC maturation status or their ability to cross‐present soluble antigen. Our findings provide new insights into the functional specialization of human blood DC subsets and suggest a possible synergistic enhancement of therapeutic efficacy by combining DC‐based cancer vaccines with IDO inhibition

Adjuvant dendritic cell vaccination induces tumor-specific immune responses in the majority of stage III melanoma patients

Purpose: To determine the effectiveness of adjuvant dendritic cell (DC) vaccination to induce tumor-specific immunological responses in stage III melanoma patients. Experimental design: Retrospective analysis of stage III melanoma patients, vaccinated with autologous monocyte-derived DC loaded with tumor-associated antigens (TAA) gp100 and tyrosinase after radical lymph node dissection. Skin-test infiltrating lymphocytes (SKILs) obtained from delayed-type hypersensitivity skin-test biopsies were analyzed for the presence of TAA-specific CD8(+) T cells by tetrameric MHC-peptide complexes and by functional TAA-specific T cell assays, defined by peptide-recognition (T2 cells) and/or tumor-recognition (BLM and/or MEL624) with specific production of Th1 cytokines and no Th2 cytokines. Results: Ninety-seven patients were analyzed: 21 with stage IIIA, 34 with stage IIIB, and 42 had stage IIIC disease. Tetramer-positive CD8(+) T cells were present in 68 patients (70%), and 24 of them showed a response against all 3 epitopes tested (gp100: 154-162, gp100: 280-288, and tyrosinase: 369-377) at any point during vaccinations. A functional T cell response was found in 62 patients (64%). Rates of peptide-recognition of gp100: 154-162, gp100: 280-288, and tyrosinase: 369-377 were 40%, 29%, and 45%, respectively. Median recurrence-free survival and distant metastasis-free survival of the whole study population were 23.0 mo and 36.8 mo, respectively. Conclusions: DC vaccination induces a functional TAA-specific T cell response in the majority of stage III melanoma patients, indicating it is more effective in stage III than in stage IV melanoma patients. Furthermore, performing multiple cycles of vaccinations enhances the chance of a broader immune respons

Performance of Sokolow-Lyon index in detection of echocardiographically diagnosed left ventricular hypertrophy in a normal Eastern German population - results of the CARLA study

BACKGROUND: Arterial hypertension is a common disease with high prevalence in the general population. Left ventricular hypertrophy (LVH) is an independent risk factor in arterial hypertension. Electrocardiographic indices like the Sokolow-Lyon index (SLI) are recommended as diagnostic screening methods for LVH. We assessed the diagnostic performance of the SLI in a cohort of a large general population. METHODS: We used electrocardiographic and echocardiographic data from the prospective, population-based cohort study CARdio-vascular Disease, Living and Ageing in Halle (CARLA). Linear and logistic regression models were used to assess the association of SLI with LVH. To assess the impact of the body-mass-index (BMI), we performed interaction analyses. RESULTS: AUC of SLI to predict LVH was 55.3 %, sensitivity of the SLI was 5 %, specificity 97 %. We found a significant association of SLI after covariate-adjustment with echocardiographically detected LVH (increase of left-ventricular mass index, LVMI 7.0 g/m(2) per 1 mV increase of SLI, p < 0.0001). However, this association was mainly caused by an association of SLI with the left-ventricular internal diameter (LVIDd, increase of 0.06 cm/m(2) per 1 mV increase of SLI, p < 0.0001). In obese (BMI > 30 kg/m(2)) we found the strongest association with an increase of 9.2 g/m(2) per 1 mV. CONCLUSIONS: Although statistically significant, relations of SLI and echocardiographic parameters of LVH were weak and mainly driven by the increase in LVIDd, implicating a more eccentric type of LVH in the collective. The relations were strongest when obese subjects were taken into account. Our data do not favour the SLI as a diagnostic screening test to identify patients at risk for LVH, especially in non-obese subjects without eccentric LVH