EGFR mutation positive stage IV non small-cell lung cancer: treatment beyond progression

Non-small-cell lung cancer (NSCLC) is the leading cause of death from cancer for both men en women. Chemotherapy is the mainstay of treatment in advanced disease, but is only marginally effective. In about 30% of patients with advanced NSCLC in East Asia and in 10-15% in Western countries, EGFR mutations are found. In this population, first-line treatment with the tyrosine kinase inhibitors (TKI) erlotinib, gefitinib or afatinib is recommended. The treatment beyond progression is less well-defined. In this paper we present 3 patients, EGFR mutation positive, with local progression after an initial treatment with TKI. These patients were treated with local radiotherapy. TKI was temporarily stopped and restarted after radiotherapy. We give an overview of the literature and discuss the different treatment options in case of progression after TKI: TKI continuation with or without chemotherapy, TKI continuation with local therapy, alternative dosing or switch to next-generation TKI or combination therapy. There are different options for treatment beyond progression in EGFR mutation positive metastatic NSCLC, but the optimal strategy is still to be defined. Further research on this topic is ongoing

Differential expression of prolyl hydroxylase 1 in patients with ulcerative colitis versus patients with Crohn's disease/infectious colitis and healthy controls

Background: Inhibition of prolyl hydroxylases (PHDs) leads to the induction of a transcriptional program that, in the gut, promotes intestinal epithelial cell survival. PHD inhibitors have recently been suggested as a promising alternative treatment for inflammatory bowel disease (IBD). In this study, we explored the colonic mucosal expression of the different PHD-isoforms (PHD1, 2 and 3) in order to identify the key isoform(s) involved in the pathogenesis of IBD. Methods: The mRNA expression of inflammatory cytokines (IL-8 and TNF-alpha), an apoptosis marker (caspase 3) and PHD1, 2 and 3 was analysed in biopsies of IBD patients (UC and CD), patients with infectious colitis and healthy controls using qRT-PCR. PHD protein levels were evaluated using western blot. Cellular localization of PHD 1, 2 and 3 was determined by immunohistochemistry. Results: PHD1 was significantly up-regulated in IBD patients, both at the mRNA (UC: p < 0.0001 and CD: p < 0.05) and at the protein level (UC: p < 0.05 and CD: p < 0.05), and showed a very good correlation with the expression of the inflammatory cytokines IL-8 and TNF-alpha and the apoptosis marker caspase 3. Colonic mucosal PHD2 mRNA and protein expressions were not altered in IBD. PHD3 expression was increased in inflamed biopsies from UC patients (p < 0.0001), but only at the mRNA level. PHD1 and PHD2 expression was found both in the colonic lamina propria and the epithelium while PHD3 was mainly located in the endothelium of blood vessels. Conclusions: In this exploratory expression analysis, PHD1 comes forward as the primary therapeutic target for UC and, to a lesser extent, for (colonic) CD

Multifocal cytokeratin expression in a dedifferentiated solitary fibrous tumor with heterologous rhabdomyosarcomatous differentiation : a challenging diagnosis!

We report the case of a dedifferentiated solitary fibrous tumor with heterologous rhabdomyosarcomatous differentiation in a 74-year-old male presenting with a rapidly growing, large soft tissue tumoral mass in the gluteal muscles of the right hip. Dedifferentiation in solitary fibrous tumor had not been recognized until very recently and is an extremely rare phenomenon in this tumor type. In the present case, the diagnosis of dedifferentiated solitary fibrous tumor was difficult because of the absence of areas of conventional solitary fibrous tumor with a predominantly poorly differentiated, anaplastic tumor component in the incision biopsy composed of heterogeneous areas with small blue round cell (Ewing sarcoma-like), rhabdoid, epithelioid, and pleomorphic morphology. Moreover, the unforeseen strong patchy to multifocal positivity for cytokeratin AE1/AE3 and desmin made the diagnosis of a dedifferentiated solitary fibrous tumor even more challenging in this case. The morphology (presence of branching thin-walled, hemangiopericytoma-like blood vessels) and the immunohistochemical profile (including STAT6 and GRIA2 positivity) were very useful to differentiate this very challenging case of a cytokeratin-positive dedifferentiated solitary fibrous tumor with heterologous rhabdomyosarcomatous differentiation from a broad list of differential diagnoses

Immuno-oncological biomarkers for squamous cell cancer of the head and neck : current state of the art and future perspectives

Simple Summary Squamous cell cancer of the head and neck is a common malignancy with poor prognosis. Despite the success of PD-L1 expression, the landscape of diagnostic, prognostic, and predictive biomarkers has delivered limited contributions to the clinic in the last decade. The dissection of the immunological landscape through investigation of the immune infiltrate, blood-based biomarkers, and genetic profiling has shown substantial scientific potential but all are yet to be validated. Further exploration is warranted though implementation of biomarkers. This should ideally be performed through prospective studies using standardized methods with harmonization of technical requirements. This review serves as a comprehensive overview for state-of-the-art knowledge and biomarkers in squamous cell cancer of the head and neck (SCCHN) that may prove their worth in future clinical practice. The era of immune checkpoint inhibitors has altered the therapeutic landscape in squamous cell cancer of the head and neck (SCCHN). Our knowledge about the tumor microenvironment has fueled the research in SCCHN, leading to several well-known and less-known prognostic and predictive biomarkers. The clinical staging, p16/HPV status, and PD-L1 expression are currently the main tools for assessing the patients' diagnosis and prognosis. However, several novel biomarkers have been thoroughly investigated, some reaching actual significant clinical contributions. The untangling of the immune infiltrate with the subtyping of tissue-associated tumor infiltrating lymphocytes, tumor-associated macrophages, and circulating blood-based biomarkers are an interesting avenue to be further explored and prospectively assessed. Although PD-L1 expression remains the most important response predictor for immune checkpoint inhibitors, several flaws impede proper assessment such as technical issues, different scoring protocol, and intra-, inter-, and temporal heterogeneity. In addition, the construction of an immune-related gene panel has been proposed as a prognostic and predictive stratification but lacks consensus. Recently, the role of microbioma have also been explored regarding its systemic and antitumor immunity. This review gives a comprehensive overview of the aforementioned topics in SCCHN. To this end, the integration of these clinically advantageous biomarkers via construction of an immunogram or nomogram could be an invaluable tool for SCCHN in future prospects

Tumor-Infiltrating Lymphocytes in Head and Neck Cancer : Ready for Prime Time?

The evaluation of tumor-infiltrating lymphocytes (TILs) has received global attention as a promising prognostic cancer biomarker that can aid in clinical decision making. Proof of their significance was first shown in breast cancer, where TILs are now recommended in the classification of breast tumors. Emerging evidence indicates that the significance of TILs extends to other cancer types, including head and neck cancer. In the era of immunotherapy as a treatment choice for head and neck cancer, assessment of TILs and immune checkpoints is of high clinical relevance. The availability of the standardized method from the International Immuno-oncology Biomarker Working Group (IIBWG) is an important cornerstone toward standardized assessment. The aim of the current article is to summarize the accumulated evidence and to establish a clear premise for future research toward the implementation of TILs in the personalized management of head and neck squamous cell carcinoma patients