Aim: There is considerable interest in approaches that could improve the therapeutic window of radiotherapy. In this study, hafnium oxide nanoparticles were designed that concentrate in tumor cells to achieve intracellular high-energy dose deposit. Materials & methods: Conventional methods were used, implemented in different ways, to explore interactions of these high-atomic-number nanoparticles and ionizing radiation with biological systems. Results: Using the Monte Carlo simulation, these nanoparticles, when exposed to high-energy photons, were shown to demonstrate an approximately ninefold radiation dose enhancement compared with water. Importantly, the nanoparticles show satisfactory dispersion and persistence within the tumor and they form clusters in the cytoplasm of cancer cells. Marked antitumor activity is demonstrated in human cancer models. Safety is similar in treated and control animals as demonstrated by a broad program of toxicology evaluation. Conclusion: These findings, supported by good ...

Nanoscale radiotherapy with hafnium oxide nanoparticles.

The epidermal growth factor receptor (EGFR) plays an important role in tissue homeostasis and tumor progression. However, cancer patients treated with EGFR inhibitors (EGFRIs) frequently develop acneiform skin toxicities, which are a strong predictor of a patient's treatment response. We show that the early inflammatory infiltrate of the skin rash induced by EGFRI is dominated by dendritic cells, macrophages, granulocytes, mast cells, and T cells. EGFRIs induce the expression of chemokines (CCL2, CCL5, CCL27, and CXCL14) in epidermal keratinocytes and impair the production of antimicrobial peptides and skin barrier proteins. Correspondingly, EGFRI-treated keratinocytes facilitate lymphocyte recruitment but show a considerably reduced cytotoxic activity against Staphylococcus aureus. Mice lacking epidermal EGFR (EGFR(Δep)) show a similar phenotype, which is accompanied by chemokine-driven skin inflammation, hair follicle degeneration, decreased host defense, and deficient skin barrier function, as well as early lethality. Skin toxicities were not ameliorated in a Rag2-, MyD88-, and CCL2-deficient background or in mice lacking epidermal Langerhans cells. The skin phenotype was also not rescued in a hairless (hr/hr) background, demonstrating that skin inflammation is not induced by hair follicle degeneration. Treatment with mast cell inhibitors reduced the immigration of T cells, suggesting that mast cells play a role in the EGFRI-mediated skin pathology. Our findings demonstrate that EGFR signaling in keratinocytes regulates key factors involved in skin inflammation, barrier function, and innate host defense, providing insights into the mechanisms underlying EGFRI-induced skin pathologies.

Epidermal EGFR Controls Cutaneous Host Defense and Prevents Inflammation

The role of Human papillomavirus in head and neck cancer and the impact on radiotherapy outcome.

The prognosis of patients with advanced head and neck cancer remain dismal. For this tumor type, elevated levels of EGFR are associated with a shorter disease free survival and time to treatment failure, reflecting a more aggressive phenotype. Nimotuzumab is a humanized monoclonal antibody that recognizes domain III of the extracellular region of the EGFR, within an area that overlaps with both the surface patch recognized by cetuximab and the binding site for EGF. In order to assess the efficacy of nimotuzumab in combination with radiotherapy, a controlled, double blind, randomized clinical trial was conducted in 106 advanced squamous cell carcinoma of the head and neck patients, mostly, unfit for chemoradiotherapy. Control patients received a placebo and radiotherapy. Treatment was safe and the most frequent adverse events consisted on grade I or II asthenia, fever, headache and chills. No skin rash was detected. A significant complete response rate improvement was found in the group of patients treated with nimotuzumab as compared to the placebo. In the intent to treat analysis, a trend towards survival benefit for nimotuzumab treated subjects was found. The survival benefit became significant when applying the Harrington-Fleming test, a weighted log-rank that underscores the detection of differences deferred on time. In addition, a preliminary biomarker investigation showed a significant survival improvement for nimotuzumab treated patients as compared to controls for subjects with EGFR positive tumors. All patients showed a quality of life improvement and a reduction of the general and specific symptoms of the disease.

Nimotuzumab plus radiotherapy for unresectable squamous-cell carcinoma of the head and neck.

Based on its potent capacity to induce tumor cell death and to abrogate clonogenic survival, radiotherapy is a key part of multimodal cancer treatment approaches. Numerous clinical trials have documented the clear correlation between improved local control and increased overall survival. However, despite all progress, the efficacy of radiation-based treatment approaches is still limited by different technological, biological, and clinical constraints. In principle, the following major issues can be distinguished: (1) The intrinsic radiation resistance of several tumors is higher than that of the surrounding normal tissue, (2) the true patho-anatomical borders of tumors or areas at risk are not perfectly identifiable, (3) the treatment volume cannot be adjusted properly during a given treatment series, and (4) the individual heterogeneity in terms of tumor and normal tissue responses toward irradiation is immense. At present, research efforts in radiation oncology follow three major tracks, in order to address these limitations: (1) implementation of molecularly targeted agents and ‘omics’-based screening and stratification procedures, (2) improvement of treatment planning, imaging, and accuracy of dose application, and (3) clinical implementation of other types of radiation, including protons and heavy ions. Several of these strategies have already revealed promising improvements with regard to clinical outcome. Nevertheless, many open questions remain with individualization of treatment approaches being a key problem. In the present review, the current status of radiation-based cancer treatment with particular focus on novel aspects and developments that will influence the field of radiation oncology in the near future is summarized and discussed.

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Current concepts in clinical radiation oncology.

High rate of severe radiation dermatitis during radiation therapy with concurrent cetuximab in head and neck cancer: Results of a survey in EORTC institutes

The concurrent administration of cetuximab to radiotherapy has recently been shown to improve the clinical outcome of head-and-neck cancer (HNC) patients An aggravation of the radiation-induced skin toxicity was not described Here, however, two cases with severe skin toxicity during the combined treatment are reported In a small group of five patients with locally advanced HNC treated with irradiation and concurrent cetuximab, two cases of unusually severe radiation dermatitis were observed Both patients developed confluent moist desquamations confined to the irradiation field at a dose of 40 Gy (CTC [Common Toxicity Criteria] grade 3), which progressed into an ulcerative dermatitis (grade 4) at 58 Gy and 46 Gy, respectively Histopathology showed a vacuolic degeneration of basal keratinocytes, subepidermal blister formation, and mixed perivascular and interstitial inflammatory infiltrates leading to a complete loss of the epidermis These cutaneous side effects led to the discontinuation of radiotherapy Topical corticosteroids and systemic antibiotic treatment resulted in wound healing, which allowed the continuation of radiotherapy These findings indicate that cetuximab may have the potential to enhance the severity of radiation dermatitis in HNC patients A systematic monitoring of cutaneous side effects during radiotherapy plus cetuximab is advised in order to reliably estimate the frequency of severe (grade 3/4) radiation dermatitis

Development and management of severe cutaneous side effects in head-and-neck cancer patients during concurrent radiotherapy and cetuximab.

13520 Background: Cystatin C has recently been proposed as an ideal marker for glomerular filtration rate (GFR). In this pilot study, cystatin C serum levels were evaluated in comparison to serum creatinine concentrations and plasma clearance of chromium 51-labeled EDTA (Cr-EDTA), in patients with advanced head and neck carcinoma receiving cisplatin-based chemotherapy to assess the validity of cystatin C as an alternative endogenous marker of GFR. Methods: Blood samples for the assessment of cystatin C, creatinine and chromium 51 clearances were collected in patients before and after application of cisplatin. Overall, 35 patients were included in the study, 22 of them were eligible receiving cisplatin -based chemotherapy schedules. Results: A 18% increase of cystatin C serum levels was demonstrated after application of cisplatin. Analysis of chromium 51-labeled EDTA clearance revealed a 21% loss of GFR. In contrast, significant changes could not be detected by analysis of serum creatinine levels. Conclusi...

Cystatin-C a sensitive diagnostic marker for evaluation of the renal function in patients with cisplatin based chemotherapy

BACKGROUND S-100B is a calcium binding acute phase protein and a potential biomarker for brain injury. In prior studies elevated plasma S-100B levels were detected in stroke and severe head trauma. The aim of this study was to evaluate whether S-100 B is elevated during cerebral radiotherapy and whether that is associated with adverse outcomes. MATERIAL AND METHODS In this prospective pilot study, 45 patients (25 males, 20 females, median age 58 (17-81)) underwent cerebral radiation therapy because of a primary or metastaic cerebral malignancy. 39 patients were included in the evaluation. 6 patients died during the study period. S-100 plasma concentrations were measured with an electrochemiluminescence immunoassay on admission and weekly during radiation therapy for the duration of 6 weeks. In 10 healthy young volunteers (5 males, 5 females, median age 32 (28-36)) S-100 B plasma levels were measured weekly for 6 weeks as a negative control. Furthermore, in an active control 10 patients (4 males, 6 females, median age 68 (64-76)) with stroke (7 = major stroke, 3 = lacunar infarct) S- 100 B plasma levels were measured for 7 consecutive days after the event. RESULTS During radiotherapy S-100 B plasma concentrations increased from median baseline values of 0.030 microg/l to 0.044 microg/l. For the time of radiation therapy most patients showed a mild increase, but absolute plasma values were still within the normal range. In the control group of healthy volunteers S-100 B remained unchanged. In stroke patients S-100 B increased to maximum values of 1.7 microg/l three days after the event. In the 3 patients with lacunar infarcts no increase of S-100 B levels could be detected. CONCLUSION Brain irradiation leads to a mild increase of S-100 B plasma levels. However, the absolute rise was far weaker compared to that seen in major brain injuries.

Christian Giro

Papers

High rate of severe radiation dermatitis during radiation therapy with concurrent cetuximab in head and neck cancer: Results of a survey in EORTC institutes

Development and management of severe cutaneous side effects in head-and-neck cancer patients during concurrent radiotherapy and cetuximab.

Cystatin-C a sensitive diagnostic marker for evaluation of the renal function in patients with cisplatin based chemotherapy

Validity of S-100 B in patients after brain radiation.