Role of Tumor-Associated Neutrophils in the Molecular Carcinogenesis of the Lung.

Tumorigenesis is largely influenced by accompanying inflammation. Myeloid cells account for a significant proportion of pro-inflammatory cells within the tumor microenvironment. All steps of tumor formation and progression, such as the suppression of adaptive immune response, angio- and lymphangiogenesis, and the remodeling of the tumor stroma, are to some degree influenced by tumor-associated immune cells. Tumor-associated neutrophils (TANs), together with tumor-associated macrophages and myeloid-derived suppressor cells, count among tumor-associated myeloid cells. Still, the exact molecular mechanisms underlying the tumorigenic effects of TANs have not been investigated in detail. With this review of the literature, we aim to give an overview of the current data on TANs, with a special focus on lung cancer.

Liquid biopsy in non-small cell lung cancer-current status and future outlook-a narrative review.

Lung cancer ranks first as the cause of cancer-associated deaths gobally. The American Cancer Society estimates for 228,820 new cases and 135,720 deaths from lung cancer in the United States for the year 2020. Targeted treatment options have rapidly emerged for non-small cell lung cancer (NSCLC) within the past decade. Screening for molecular aberrations is mainly done by tissue biopsy. However, in some cases a biopsy is not possible, or patients do not consent to it. Hence, liquid biopsy remains the only option. Relevant data about the topic of liquid biopsy, with a special focus on NSCLC, was obtained via a PubMed search. We included mainly literature published from 2010 onwards, omitting older studies whenever possible. With this review of the literature, we give an overview of different liquid biopsy approaches, as well as their respective advantages and disadvantages. We have reviewed the assessment of epidermal growth factor receptor (EGFR) mutation status in particular, and go into detail with current use of liquid biopsy in everyday clinical practice. Today, liquid biopsy is still infrequently used, depending on the treatment center, but popularity is steadily increasing. Various different approaches are already available, but costs and level of sensitivity significantly differ between techniques. By using liquid biopsy more widely in selected patients, complication rates can be reduced, and constant disease monitoring is made considerably easier.

Current Knowledge about Mechanisms of Drug Resistance against ALK Inhibitors in Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer subtypes. Two to seven percent of NSCLC patients harbor gene rearrangements of the anaplastic lymphoma kinase (ALK) gene or, alternatively, harbor chromosomal fusions of ALK with echinoderm microtubule-associated protein-like 4 (EML4). The availability of tyrosine kinase inhibitors targeting ALK (ALK-TKIs) has significantly improved the progression-free and overall survival of NSCLC patients carrying the respective genetic aberrations. Yet, increasing evidence shows that primary or secondary resistance to ALK-inhibitors during the course of treatment represents a relevant clinical problem. This necessitates a switch to second- or third-generation ALK-TKIs and a close observation of NSCLC patients on ALK-TKIs during the course of treatment by repetitive molecular testing. With this review of the literature, we aim at providing an overview of current knowledge about resistance mechanisms to ALK-TKIs in NSCLC.

Prediction of Postoperative Clinical Outcomes in Resected Stage I Non-Small Cell Lung Cancer Focusing on the Preoperative Glasgow Prognostic Score.

Background: The Glasgow Prognostic Score (GPS), which consists of albumin and C-reactive protein (CRP), may predict overall survival (OS) in cancer patients. The aim of this retrospective analysis was to evaluate the clinical impact of the preoperative GPS on patients with resected early stage non-small cell lung cancer (NSCLC). Methods: 300 patients with curatively resected stage I NSCLC were followed-up for OS, recurrence-free survival (RFS), cancer-specific survival (CSS), and death from other causes. Results: 229 patients (76%) had a preoperative GPS of 0, and 71 (24%) a GPS ≥ 1. The three-year probabilities of RFS, OS, CSS, and death from other causes were 81%, 84%, 88%, and 96% in patients with GPS = 0, and 79%, 74%, 91%, and 82% in patients with a GPS ≥ 1, respectively. GPS ≥ 1 was significantly associated with a higher risk of death from other causes (p = 0.022), serving as an independent predictor of death from other causes (p = 0.034). Pathologically elevated CRP levels (CRP > 5 mg/L) were found in 91 patients (30%). The mean CRP level was 7.88 ± 15.80 mg/L (0.5-135.6 mg/L). Pre-treatment CRP level was significantly associated with coronary heart disease (p < 0.0001), histology (p = 0.013), tumor size (p = 0.018), tumor stage (p = 0.002), and vascular invasion (p = 0.017). Conclusion: The preoperative GPS predicts adverse survival outcomes in patients with resected stage I NSCLC.

Targeted treatment of ovarian cancer--the multiple - kinase - inhibitor sorafenib as a potential option.

Ovarian cancer (OC) is ranked as the eighth most common gynecological malignancy and is the leading cause of gynecological cancer-related deaths in women worldwide. The response to platinum- and taxane-based chemotherapy is very often poor, and targeted-therapeutics are currently being tested in patients with OC. Sorafenib is a non-selective multiple kinase inhibitor with proven antiproliferative effects in thyroid, renal and hepatocellular carcinoma. Sorafenib acts on vascular endothelial growth factor (VEGF) and on platelet-derived growth factor (PDGF) related pathways. It also influences the rat sarcoma proto-oncogene/rat fibrosarcoma protein kinase/mitogen activated protein kinase (RAS/RAF/MAPK) pathway and blocks tumor growth factor beta-1 (TGF-ß-1)-mediated epithelial-mesenchymal transition (EMT). Sorafenib also acts at the epigenetic level altering the histone acetylation pattern. There have been phase I, II and III studies investigation sorafenib in OC. We review several trials in which sorafenib has been administered as single-agent or combined with other chemotherapeutics. Unfortunately, the effect of sorafenib was usually modest and complete response was rarely observed. Adverse effects occurred frequently, including rash, diarrhea, edema and weight gain. Sorafenib evidently blocks EMT in vitro. However, in the conducted trials, sorafenib was administered to patients with highly advanced tumors. We posit that blocking EMT may be more effective in early-stage disease. We also presume that sorafenib would work particularly well in the treatment of clear cell OC, since this type of OC has different molecular characteristics from usual OC and is less sensitive to standard chemotherapy. Furthermore, the combination of sorafenib with other multiple-kinase inhibiting agents, e.g. ABT-869, a targeted-agent mainly acting in the VEGF and PDGF pathways, should be investigated in further detail. It is probable that synergistic effects can be achieved.

Malignant ascites in ovarian cancer and the role of targeted therapeutics.

Ovarian cancer (OC) is the eighth most lethal gynecological malignancy and the main cause of gynecological cancer death in industrialized countries. Malignant ascites is often found in OC, with about 10% of patients suffering from recurrent OC. Tumor cells in OC-associated malignant ascites promote disease recurrence and patient mortality is mainly associated with widespread metastasis to serosal surfaces and accompanying peritoneal effusions. Targeted therapies have recently been developed as novel therapeutic options for malignant ascites. The tri-functional anti-epithelial cell adhesion molecule and anti-cluster of differentiation 3 monoclonal antibody catumaxumab has been assessed in the therapy of malignant ascites, and proven to significantly reduce the ascitic flow rate when applied into the peritoneal cavity. The anti-angiogenic targeted agent bevacizumab has also shown good effects in the symptomatic treatment of malignant ascites, significantly prolonging the time until the next paracentesis. Vascular endothelial growth factor (VEGF) Trap, or aflibercept, is a fusion protein that inhibits VEGF-receptor binding. Aflibercept has proven to be effective in reduction of ascites, diminishing clinical symptoms of ascites and prolonging the time to next paracentesis. All three agents we review in the present article are effective in symptomatic control of ascites, leading to a rapid reduction of effusion and prolonging the time interval between paracenteses. However, no improvement in overall survival was observed in any of the clinical trials reported. We, thus, conclude that further investigations on larger patient series are needed to clarify whether the reduction of ascites by these targeted agents leads to a prolongation in tumor-related survival or not.

Targeting signaling pathways in epithelial ovarian cancer.

UNLABELLED: Ovarian carcinoma (OC) is the most lethal gynecological malignancy. Response to platinum-based chemotherapy is poor in some patients and, thus, current research is focusing on new therapy options. The various histological types of OC are characterized by distinctive molecular genetic alterations that are relevant for ovarian tumorigenesis. The understanding of these molecular pathways is essential for the development of novel therapeutic strategies. PURPOSE: We want to give an overview on the molecular genetic changes of the histopathological types of OC and their role as putative therapeutic targets. In Depth Review of Existing Data: In 2012, the vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, was approved for OC treatment. Bevacizumab has shown promising results as single agent and in combination with conventional chemotherapy, but its target is not distinctive when analyzed before treatment. At present, mammalian target of rapamycin (mTOR) inhibitors, poly-ADP-ribose polymerase (PARP) inhibitors and components of the EGFR pathway are in the focus of clinical research. Interestingly, some phytochemical substances show good synergistic effects when used in combination with chemotherapy. CONCLUSION: Ongoing studies of targeted agents in conjunction with chemotherapy will show whether there are alternative options to bevacizumab available for OC patients. Novel targets which can be assessed before therapy to predict efficacy are needed. The assessment of therapeutic targets is continuously improved by molecular pathological analyses on tumor tissue. A careful selection of patients for personalized treatment will help to reduce putative side effects and toxicity.