Prognostic significance of tumor-associated macrophages in endometrial adenocarcinoma.

OBJECTIVE: Endometrial adenocarcinoma is one of the most common gynecologic malignancies worldwide and in stages confined to the uterus considered to have an excellent prognosis. However, in advanced or recurrent cases when surgery fails to achieve disease control other treatment options are less effective. Thus, new therapeutic avenues are needed. METHODS: To provide the rationale for the use of novel agents that target immune checkpoints 163 type I endometrial cancer samples were immunohistochemically screened for the presence of CD163(+) tumor-associated macrophages and Foxp3(+) regulatory T cells. Further, a D2-40-based evaluation of lymph vessel density and lymphovascular space invasion was carried out. Correlation analysis with clinicopathological parameters was performed; Kaplan-Meier curves were generated; multivariate analysis was undertaken as appropriate. RESULTS: A substantial amount of tumor-associated macrophages and regulatory T cells was detected in all specimens characterizing endometrial cancer as an immunogenic tumor. However, only the increased infiltration of tumor-associated macrophages was proportionally associated with advanced FIGO stages, high tumor grade, increased lymph vessel density, lymphovascular space invasion and lymph node metastasis. Thus, the presence of tumor-associated macrophages indicates aggressive tumor behavior and appeared to be an independent prognostic factor for recurrence-free survival. CONCLUSIONS: Our results make future therapeutic approaches that target tumor-associated macrophages reasonable to improve the outcome of women with advanced or recurrent endometrial adenocarcinoma.

Infective Endocarditis Requiring Mitral Valve Replacement During Second Trimester of Pregnancy.

Infective endocarditis requiring mitral valve replacement during pregnancy is a rare event. We present a case of infective endocarditis of the mitral valve during second trimester and report maternal and perinatal outcomes. Prompt identification and interdisciplinary treatment is crucial; maternal and fetal follow-up including serial fetal neurosonography is recommended.

Immune Profiling of Vulvar Squamous Cell Cancer Discovers a Macrophage-rich Subtype Associated with Poor Prognosis.

The incidence rates of vulvar squamous cell cancer (VSCC) have increased over the past decades, requiring personalized oncologic approaches. Currently, lymph node involvement is a key factor in determining prognosis and treatment options. However, there is a need for additional immune-related biomarkers to provide more precise treatment and prognostic information. Here, we used IHC and expression data to characterize immune cells and their spatial distribution in VSCC. Hierarchical clustering analysis identified distinct immune subtypes, of which the macrophage-rich subtype was associated with adverse outcome. This is consistent with our findings of increased lymphogenesis, lymphatic invasion, and lymph node involvement associated with high macrophage infiltration. Further in vitro studies showed that VSCC-associated macrophages expressed VEGF-A and subsequently induced VEGF-A in the VSCC cell line A-431, providing experimental support for a pro-lymphangiogenic role of macrophages in VSCC. Taken together, immune profiling in VSCC revealed tumor processes, identified a subset of patients with adverse outcome, and provided a valuable biomarker for risk stratification and therapeutic decision making for anti-VEGF treatment, ultimately contributing to the advancement of precision medicine in VSCC. SIGNIFICANCE: Immunoprofiling in VSCC reveals subtypes with distinct clinical and biological behavior. Of these, the macrophage-rich VSCC subtype is characterized by poor clinical outcome and increased VEGF-A expression, providing a biomarker for risk stratification and therapeutic sensitivity.

Peripartum Cardiomyopathy: Diagnostic and Prognostic Value of Cardiac Magnetic Resonance in the Acute Stage.

This study aimed to evaluate the diagnostic and prognostic value of cardiac magnetic resonance in acute peripartum cardiomyopathy (PPCM). A total of 17 patients with PPCM in the acute stage and 15 healthy controls were retrospectively analyzed regarding myocardial function, edema, late gadolinium enhancement (LGE), and T1 and T2 mappings (T1, T2). Echocardiographic follow-ups were performed. Functional recovery was defined as a left ventricular ejection fraction (LVEF) of ≥50%. Patients with PPCM displayed biventricular dysfunction with reduced myocardial strain parameters and left ventricular and atrial dilatation, as well as diffuse myocardial edema (T2 signal intensity ratio: 2.10 ± 0.34 vs. 1.58 ± 0.21, p < 0.001; T1: 1070 ± 51 ms vs. 980 ± 28 ms, p = 0.001; T2: 63 ± 5 ms vs. 53 ± 2 ms, p < 0.001). Visual myocardial edema was present in 10 patients (59%). LGE was positive in 2 patients (12%). A total of 13 patients (76%) showed full LVEF recovery. The absence of visual myocardial edema and impairment of strain parameters were associated with delayed LVEF recovery. Multivariable Cox regression analysis revealed global longitudinal strain as an independent prognostic factor for LVEF recovery. In conclusion, biventricular systolic dysfunction with diffuse myocardial edema seems to be present in acute PPCM. Myocardial edema and strain may have prognostic value for LVEF recovery.

Alpha-Fetoprotein- and CD40Ligand-Expressing Dendritic Cells for Immunotherapy of Hepatocellular Carcinoma.

Dendritic cells (DC) as professional antigen presenting cells are able to prime T-cells against the tumor-associated antigen α-fetoprotein (AFP) for immunotherapy of hepatocellular carcinoma (HCC). However, a strong immunosuppressive tumor environment limits their efficacy in patients. The co-stimulation with CD40Ligand (CD40L) is critical in the maturation of DC and T-cell priming. In this study, the impact of intratumoral (i.t.) CD40L-expressing DC to improve vaccination with murine (m)AFP-transduced DC (Ad-mAFP-DC) was analyzed in subcutaneous (s.c.) and orthotopic murine HCC. Murine DC were adenovirally transduced with Ad-mAFP or Ad-CD40L. Hepa129-mAFP-cells were injected into the right flank or the liver of C3H-mice to induce subcutaneous (s.c.) and orthotopic HCC. For treatments, 106 Ad-mAFP-transduced DC were inoculated s.c. followed by 106 CD40L-expressing DC injected intratumorally (i.t.). S.c. inoculation with Ad-mAFP-transduced DC, as vaccine, induced a delay of tumor-growth of AFP-positive HCC compared to controls. When s.c.-inoculation of Ad-mAFP-DC was combined with i.t.-application of Ad-CD40L-DC synergistic antitumoral effects were observed and complete remissions and long-term survival in 62% of tumor-bearing animals were achieved. Analysis of the tumor environment at different time points revealed that s.c.-vaccination with Ad-mAFP-DC seems to stimulate tumor-specific effector cells, allowing an earlier recruitment of effector T-cells and a Th1 shift within the tumors. After i.t. co-stimulation with Ad-CD40L-DC, production of Th1-cytokines was strongly increased and accompanied by a robust tumor infiltration of mature DC, activated CD4+-, CD8+-T-cells as well as reduction of regulatory T-cells. Moreover, Ad-CD40L-DC induced tumor cell apoptosis. Intratumoral co-stimulation with CD40L-expressing DC significantly improves vaccination with Ad-mAFP-DC in pre-established HCC in vivo. Combined therapy caused an early and strong Th1-shift in the tumor environment as well as higher tumor apoptosis, leading to synergistic tumor regression of HCC. Thus, CD40L co-stimulation represents a promising tool for improving DC-based immunotherapy of HCC.

Tumoral PD-L1 expression defines a subgroup of poor-prognosis vulvar carcinomas with non-viral etiology.

Vulvar cancer is rare but incidence rates are increasing due to an aging population and higher frequencies of young women being affected. In locally advanced, metastatic or recurrent disease prognosis is poor and new treatment modalities are needed. Immune checkpoint blockade of the PD-1/PD-L1 pathway is one of the most important advancements in cancer therapy in the last years. The clinical relevance of PD-L1 expression in vulvar cancer, however, has not been studied so far. We determined PD-L1 expression, numbers of CD3+ T cells, CD20+ B cells, CD68+ monocytes/macrophages, Foxp3+ regulatory T cells and CD163+ tumor-associated macrophages by immunohistochemistry in 103 patients. Correlation analysis with clinicopathological parameters was undertaken; the cause-specific outcome was modeled with competing risk analysis; multivariate Cox regression was used to determine independent predictors of survival. Membranous PD-L1 was expressed in a minority of tumors, defined by HPV-negativity. Its presence geographically correlated with immunocyte-rich regions of cancer islets and was an independent prognostic factor for poor outcome. Our data support the notion that vulvar cancer is an immunomodulatory tumor that harnesses the PD-1/PD-L1 pathway to induce tolerance. Accordingly, immunotherapeutic approaches might have the potential to improve outcome in patients with vulvar cancer and could complement conventional cancer treatment.

Accumulation of ALDH1-positive cells after neoadjuvant chemotherapy predicts treatment resistance and prognosticates poor outcome in ovarian cancer.

Although ovarian cancer is a highly chemosensitive disease, it is only infrequently cured. One of the major reasons lies in the presence of drug-resistant cancer stem-like cells, sufficient to fuel recurrence. We phenotyped cancer stem-like cells by flow cytometry and immunohistochemistry in 55 matched samples before and after taxane/platinum-based neoadjuvant chemotherapy. All used markers of stemness (ALDH1, CD24, CD117, CD133) isolated low frequencies of malignant cells. ALDH1 was the most valuable marker for tracking stemness in vivo. The enrichment of ALDH1 expression after treatment was associated with a poor response to chemotherapy, with platinum resistance and independently prognosticated unfavorable outcome. Our results suggest that increased ALDH1 expression after treatment identifies patients with aggressive tumor phenotypes.