Sophie Espenel

Targeting head and neck tumoral stem cells: From biological aspects to therapeutic perspectives.

Head and neck squamous cell cancer (HNSCC) is the sixth most common cancer in the world. Effective therapeutic modalities such as surgery, radiation, chemotherapy and combinations of each are used in the management of the disease. In most cases, treatment fails to obtain total cancer cure. In recent years, it appears that one of the key determinants of treatment failure may be the presence of cancer stem cells (CSCs) that escape currently available therapies. CSCs form a small portion of the total tumor burden but may play a disproportionately important role in determining outcomes. CSCs have stem features such as self-renewal, high migration capacity, drug resistance, high proliferation abilities. A large body of evidence points to the fact that CSCs are particularly resistant to radiotherapy and chemotherapy. In HNSCC, CSCs have been increasingly shown to have an integral role in tumor initiation, disease progression, metastasis and treatment resistance. In the light of such observations, the present review summarizes biological characteristics of CSCs in HNSCC, outlines targeted strategies for the successful eradication of CSCs in HNSCC including targeting the self-renewal controlling pathways, blocking epithelial mesenchymal transition, niche targeting, immunotherapy approaches and highlights the need to better understand CSCs biology for new treatments modalities.

In Vitro Cell Death Determination for Drug Discovery: A Landscape Review of Real Issues

Cell death plays a crucial role for a myriad of physiological processes, and several human diseases such as cancer are characterized by its deregulation. There are many methods available for both quantifying and qualifying the accurate process of cell death which occurs. Choosing the right assay tool is essential to generate meaningful data, provide sufficient information for clinical applications, and understand cell death processes. In vitro cell death assays are important steps in the search for new therapies against cancer as the ultimate goal remains the elaboration of drugs that interfere with specific cell death mechanisms. However, choosing a cell viability or cytotoxicity assay among the many available options is a daunting task. Indeed, cell death can be approached by several viewpoints and require a more holistic approach. This review provides an overview of cell death assays usually used in vitro for assessing cell death so as to elaborate new potential chemotherapeutics and discusses considerations for using each assay.

Melanoma: Last call for radiotherapy

Melanoma is traditionally considered to be a radioresistant tumor. However, radiotherapy and immunotherapy latest developments might upset this radiobiological dogma. Stereotactic radiotherapy allows high dose per fraction delivery, with high dose rate. More DNA lethal damages, less sublethal damages reparation, endothelial cell apoptosis, and finally clonogenic cell dysfunction are produced, resulting in improved local control. Radiotherapy can also enhance immune responses, inducing neoantigens formation, tumor antigen presentation, and cytokines release. A synergic effect of radiotherapy with immunotherapy is expected, and might lead to abscopal effects. If hadrontherapy biological properties seem able to suppress hypoxia-induced radioresistance and increase biological efficacy, ballistic advantages over photon radiations might also improve radiotherapy outcomes on usually poor prognosis locations. The present review addresses biological and clinical effects of high fraction dose, bystander effect, abscopal effect, and hadrontherapy features in melanoma. Clinical trials results are warranted to establish indications of innovative radiotherapy in melanoma.

Preclinical models in HNSCC: A comprehensive review.

Head and neck cancer remains a significant public health concern. About 60% of patients die within 5years due to local recurrence. Head and neck squamous cell carcinoma (HNSCC) cell lines are important preclinical models in the search for new therapies against this disease. Furthermore, there is a need to test novel drugs before introduction into clinical practice. A preclinical model that closely resembles the in vivo situation would be highly valuable. In the last few decades, a multicellular spheroid model has gained attention as its behavior was comparable to in vivo tumors. Basic research is necessary to achieve an understanding of the normal and pathological state but cannot, in itself, provide sufficient information for clinical applications. Indeed, animal models are an inevitable prelude to assess the efficacy of new therapeutic approaches in HNSCC. The present review proposes an overview of HNSCC pre-clinical models in order to further understand the oncogenic properties for HNSCC and translate these findings into clinic for patients.

Real-World Outcomes of Combination Chemotherapy with Trabectedin plus Pegylated Liposomal Doxorubicin in Patients with Recurrent Ovarian Cancer: A Single-Center Experience.

Background: Trabectedin plus pegylated liposomal doxorubicin (PLD) proved efficacious as second-line treatment for patients with recurrent ovarian cancer (ROC). Methods: We report a single-center retrospective analysis of the efficacy and tolerance of trabectedin 1.1 mg/m2 every 3 weeks in a cohort of real-life ROC patients. Results: From February 2012 to January 2014, 17 patients were treated with trabectedin alone or combined with PLD. Median age was 61 years (range: 48-78). Performance status was 0-1 in 16 patients (94%). Disease response rate was 53% and disease control rate was 76%. At the end of the follow-up, 8 patients (47%) were alive. Median overall survival was 17.6 months (95% CI 13.6 to not reached). Median progression-free survival was 6.7 months (95% CI 5.4-10.0). The most frequent grade 3-4 toxicities were neutropenia (n = 4, 24%) and nausea/vomiting (n = 4, 24%). Conclusion: Trabectedin combined with PLD seems efficient in and well tolerated by real-life ROC patients.

Radiosensibilité et/ou résistance des cancers ORL : aspects biologiques

Radiation therapy is a cornerstone of head and neck cancer management. Technological improvements in recent years in radiation therapy, with intensity-modulated techniques, reinforce even more its role. However, both local and locoregional relapses are still observed. Understanding biological mechanisms of treatment resistance is a topic of major interest. From the cancer cell itself, its ability to repair and proliferate, its microenvironment and oxygenation conditions, migratory and invasive capacity, to biological parameters related to the patient, there are many mechanisms involving radiosensitivity and/or radioresistance of head and neck cancer. The present study explores the main biological mechanisms involved in radiation resistance of head and neck cancer, and describes promising therapeutic approaches.

Real-World Vinflunine Outcomes in Bladder Cancer in a Single-Institution Study: Moving Beyond Clinical Trials

PURPOSE Intravenous vinflunine 320 mg/m(2) every 3 weeks plus best supportive care resulted in better overall survival in comparison with best supportive care alone for eligible patients with failure of prior therapy with locally advanced or metastatic transitional cell cancer of urothelial tract (TCCU). The objective of the present study was to describe our real-life experience of vinflunine for treatment of patients with TCCU. PATIENTS AND METHODS We retrospectively investigated all patients with TCCU who received at least 1 cycle of vinflunine. RESULTS Nineteen patients were treated between May 2010 and March 2014 in a compassionate-use program. Performance status was poor in our real-life cohort, with 6 patients (32%) with an Eastern Cooperative Oncology Group performance status of 2. Median duration of vinflunine treatment was 2.4 months (range, 0-4.3 months), and median number of cycles was 3 (range, 1-6). Total response rate was 32%, with partial responses only. Disease control rate was 53%, with a median duration of 7.7 months (range, 6.0-9.4 months). Median progression-free survival was 87 days, or 2.9 months (range, 0.7-11.7 months). After vinflunine treatment, 42% of patients received from 1 to 3 additional lines of chemotherapy. The most frequent grade 4 toxicities were constipation (26%), with 3 intestinal obstructions (16%) and 1 mechanical ileus (5%); and asthenia and fatigue (21%). CONCLUSION Vinflunine, as a TCCU second-line chemotherapy, brings benefits, particularly in cases where there is no alternative treatment.

Correlation between anthropometric parameters and acute skin toxicity in breast cancer radiotherapy patients: a pilot assessment study

OBJECTIVE The objective of the present study was to identify acute skin toxicity risk factors linked to the anthropometric characteristics of patients with breast cancer treated with radiation therapy. METHODS Consecutive patients with breast cancer were enrolled after breast-conserving surgery and before radiotherapy course. Acute skin toxicity was assessed weekly during the 7 weeks of radiotherapy with the International Classification from National Cancer Institute. Grade 2 defined acute skin toxicity. Patient characteristics and anthropometric measurements were collected. RESULTS 54 patients were enrolled in 2013. Eight patients (14.8%) had grade ≥2 toxicity. The average weight and chest size were 65.5 kg and 93.6 cm, respectively. Bra cup size is significantly associated with a risk of grade 2 dermatitis [odds ratio (OR) 3.46, 95% confidence interval (CI) (1.29-11.92), p = 0.02]. Anthropometric breast fat mass measurements, such as thickness of left [OR 2.72, 95% CI (1.08-8.26), p = 0.04] and right [OR 2.45, 95% CI (0.99-7.27), p = 0.05] axillary fat, are correlated with an increased risk. Distance between the pectoral muscle and nipple is a reproducible measurement of breast size and is associated with acute skin toxicity with significant tendency (OR = 2.21, 95% CI (0.97-5.98), p = 0.07). CONCLUSION Breast size and its different anthropometric measurements (thickness of left and right axillary fat, nipple-to-pectoral muscle distance) are correlated with the risk of skin toxicity. ADVANCES IN KNOWLEDGE The present article analyses several characteristics and anthropomorphic measurements of breast in order to assess breast size. A standardized and reproducible protocol to measure breast volume is described.

Carcinosarcomes gynécologiques : revue générale et principes de prise en charge

Carcinosarcoma, also known as mixed mesodermal tumor or malignant mixed Mullerian tumor (MMMT) is a pathological entity combining a sarcomatous and a carcinomatous component. Found in thoracic, digestive, genitourinary, liver or skin locations, the most common location is the female genital tract. In gynecological tumors, carcinosarcoma accounts for about 2-5% of endometrial cancers, and 1% of ovarian cancers. To date, there is no consensus on the therapeutic strategy. It relies mostly on maximum cytoreductive surgery. Adjuvant therapy remains controversial, and few prospective studies investigating its interest. Retrospective studies show the benefits of adjuvant chemotherapy based on platinum in most cases. Radiation therapy has a place in the adjuvant situations of endometrial and cervical carcinosarcoma. A more detailed pathological knowledge, and the use of targeted therapies may be promising in this histological subtype whose prognosis remains very poor. The objective of this study is to present the main principles of carcinosarcoma management in female genital tracts, describing pathological and prognostic features at the same time.

Lysophosphatidic acid (LPA) as a pro-fibrotic and pro-oncogenic factor: a pivotal target to improve the radiotherapy therapeutic index

Radiation-induced fibrosis is widely considered as a common but forsaken phenomenon that can lead to clinical sequela and possibly vital impairments. Lysophosphatidic acid is a bioactive lipid involved in fibrosis and probably in radiation-induced fibrosis as suggested in recent studies. Lysophosphatidic acid is also a well-described pro-oncogenic factor, involved in carcinogenesis processes (proliferation, survival, angiogenesis, invasion, migration). The present review highlights and summarizes the links between lysophosphatidic acid and radiation-induced fibrosis, lysophosphatidic acid and radioresistance, and proposes lysophosphatidic acid as a potential central actor of the radiotherapy therapeutic index. Besides, we hypothesize that following radiotherapy, the newly formed tumour micro-environment, with increased extracellular matrix and increased lysophosphatidic acid levels, is a favourable ground to metastasis development. Lysophosphatidic acid could therefore be an exciting therapeutic target, minimizing radio-toxicities and radio-resistance effects.