Pre- and post-weaning nutrition status affects sheep mammary gland morphology and promotes differential gene expression.

Little is known about how varying the plane of nutrition before and after weaning can influence gene expression that drives mammary gland development (MGD). Therefore, the aim of this study was to investigate this paradigm in a seasonal sheep breed. Forty pre-weaning 30-day old Kurdish female lambs were fed either a low-nutrient and protein (L; 2.0 Mcal ME/kg DM; 8.70% crude protein [CP]) or high-nutrient and protein diet (H; 2.5 Mcal ME/kg DM; 14.80% CP). At d 120 (weaning), lambs were allocated into a 2 × 2 arrangement based on pre- and post-weaning diets, resulting in four groups (LL, LH, HL, HH). On d 210, mammary biopsy samples were taken for histomorphological and gene expression studies. Alveoli were larger in HH compared with all other groups (p < 0.05). Whilst estrogen receptor-alpha, progesterone receptor, growth hormone receptor and insulin-like growth factor binding protein-1 gene expression was modulated depending on pre- or post-weaning nutritional levels (p < 0.01). Overall, a consistent high plane of nutrition promoted MGD, with more a complex relationship evident between the expression of genes critical for mammary gland function and development. These findings provide scope for future tailored nutritional strategies to optimize both liveweight gain and MGD.

Reproductive performance, expression of TRAP6 and TGF-ß4 genes in utero-vaginal junction mucosa, and indicators of liver function in female Chukar partridge (Alectoris chukar) breeders fed with fish oil and calcitriol during the egg-laying period.

Reproductive attributes, expression of TRAP6 and TGF-ß mRNA in the mucosa of the utero-vaginal junction (UVJ) of oviduct, and liver function were evaluated in Chukar partridge (Alectoris chukar) breeders subjected to long-term oral administration of fish oil (FO) and/or calcitriol (CT). A total of forty-eight 1.5-year-old laying Chukar partridges and 16 age-matched males (female:male ratio of 3:1) were randomly allocated to four groups (4 replicates of 3 female birds and one male bird each). Breeder females in groups 1, 2, and 3 were orally administered daily with 0.2 mL (0.24 g)/500 g body weight FO, 0.2 mL solution containing 10 µg CT, or their combination (FO + CT) for 42 successive days, respectively. Pure crystalline calcitriol was dissolved in ethanol (30%) prior to administration. The control group (CON), received a similar volume of a 30% solution of ethanol only. Eggs were collected and incubated to evaluate the reproductive performance. Blood samples were taken on days 0, 21, and 42 of the trial for the quantification of serum alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). On day 43, one bird per replicate was killed by cervical dislocation to assess the expression of TRAP6 and TGF-ß genes in the UVJ mucosa. Administration of CT or FO + CT increased the egg production rate, fertility rate, and hatchability rate of the set eggs. Fertility duration and sperm penetration rate were higher in partridges receiving FO and (or) CT, but chick quality, and embryonic mortality were not affected by the treatment effect. Administration of CT or FO + CT decreased the serum ALT and AST levels. Administration of FO or CT was associated with a lower expression of TGF-ß mRNA in the UVJ mucosa. Oral administration of FO resulted in a reduction in the expression of TRAP6 in the UVJ mucosa. However, the birds fed with CT or FO + CT recorded a higher mRNA expression for TRAP6. Although the reproductive performance and TRAP6 expression were higher following the feeding of FO or FO + CT, expression of TGF-ß was decreased, suggesting plausibly that TGF-ß may not have a determinant effect on the reproductive attributes in female Chukar partridges. Further studies are required to understand the mechanisms underlying the effects of TRAP6 and TGF-ß on other reproductive criteria in partridges.

Rapid effective dose calculation for raster-scanning 4He ion therapy with the modified microdosimetric kinetic model (mMKM).

PURPOSE: To develop and verify effective dose (DRBE) calculation in 4He ion beam therapy based on the modified microdosimetric kinetic model (mMKM) and evaluate the bio-sensitivity of mMKM-based plans to clinical parameters using a fast analytical dose engine. METHODS: Mixed radiation field particle spectra (MRFS) databases have been generated with Monte-Carlo (MC) simulations for 4He-ion beams. Relative biological effectiveness (RBE) and DRBE calculation using MRFS were established within a fast analytical engine. Spread-out Bragg-Peaks (SOBPs) in water were optimized for two dose levels and two tissue types with photon linear-quadratic model parameters αph, ßph, and (α/ß)ph to verify MRFS-derived database implementation against computations with MC-generated mixed-field α and ß databases. Bio-sensitivity of the SOBPs was investigated by varying absolute values of ßph, while keeping (α/ß)ph constant. Additionally, dose, dose-averaged linear energy transfer, and bio-sensitivity were investigated for two patient cases. RESULTS: Using MRFS-derived databases, dose differences ≲2% in the plateau and SOBP are observed compared to computations with MC-generated databases. Bio-sensitivity studies show larger deviations when altering the absolute ßph value, with maximum D50% changes of ~5%, with similar results for patient cases. Bio-sensitivity analysis indicates a greater impact on DRBE varying (α/ß)ph than ßph in mMKM. CONCLUSIONS: The MRSF approach yielded negligible differences in the target and small differences in the plateau compared to MC-generated databases. The presented analyses provide guidance for proper implementation of RBE-weighted 4He ion dose prescription and planning with mMKM. The MRFS-DRBE calculation approach using mMKM will be implemented in a clinical treatment planning system.

High frequency of BRAF V600E mutation in Iranian population ameloblastomas.

BACKGROUND: Ameloblastoma is a common locally invasive but slow-growing neoplasm of the jaws with an odontogenic origin. Association between BRAF V600E mutation and clinicopathologic features and behavior of ameloblastoma remains controversial. This study aimed to evaluate BRAF V600E gene mutation and expression of its related proteins with clinicopathologic parameters in conventional ameloblastoma. MATERIAL AND METHODS: 50 Formalin-fixed paraffin-embedded blocks were included in this study. Immunohistochemistry was done using rabbit monoclonal BRAF V600E mutation-specific antibody VE1. Quantitative real-time polymerase chain reaction assay was used for evaluating of BRAF V600E mutation. RESULTS: Expression of BRAF V600E antibody was Positive in 42 out of 50 cases (84%). 46 (92%) out of 50 specimens showed BRAF V600E mutation. There were 13 cases of recurrence (26%). 3 out of 4 cases with negative mutations did not show recurrence. CONCLUSIONS: We report the highest frequency (92%) of BRAF V600E mutation in ameloblastomas in the Iranian population. Although there was not a significant association between BRAF V600E­positive immunoexpression and recurrence and clinicopathologic parameters, its high frequency could emphasize its role as a therapeutic marker in the future.

Study of the intracellular nanoparticle-based radiosensitization mechanisms in F98 glioma cells treated with charged particle therapy through synchrotron-based infrared microspectroscopy.

The use of nanoparticles (NP) as dose enhancers in radiotherapy (RT) is a growing research field. Recently, the use of NP has been extended to charged particle therapy in order to improve the performance in radioresistant tumors. However, the biological mechanisms underlying the synergistic effects involved in NP-RT approaches are not clearly understood. Here, we used the capabilities of synchrotron-based Fourier Transform Infrared Microspectroscopy (SR-FTIRM) as a bio-analytical tool to elucidate the NP-induced cellular damage at the molecular level and at a single-cell scale. F98 glioma cells doped with AuNP and GdNP were irradiated using several types of medical ion beams (proton, helium, carbon and oxygen). Differences in cell composition were analyzed in the nucleic acids, protein and lipid spectral regions using multivariate methods (Principal Component Analysis, PCA). Several NP-induced cellular modifications were detected, such as conformational changes in secondary protein structures, intensity variations in the lipid CHx stretching bands, as well as complex DNA rearrangements following charged particle therapy irradiations. These spectral features seem to be correlated with the already shown enhancement both in the DNA damage response and in the reactive oxygen species (ROS) production by the NP, which causes cell damage in the form of protein, lipid, and/or DNA oxidations. Vibrational features were NP-dependent due to the NP heterogeneous radiosensitization capability. Our results provided new insights into the molecular changes in response to NP-based RT treatments using ion beams, and highlighted the relevance of SR-FTIRM as a useful and precise technique for assessing cell response to innovative radiotherapy approaches.

A combined panel of circulating microRNA as a diagnostic tool for detection of the non-small cell lung cancer.

BACKGROUND: Recently, much attention has been paid to use circulating microRNAs (miRs) as a non-invasive tumor marker. The present study for the first time was designed to evaluate concurrent use of miR-21, miR-638, miR148 and miR-152 as putative diagnostic tool for detection of non-small cell lung carcinoma (NSCLC). METHODS: Forty-three patients diagnosed as primary NSCLC was included in this study. The level of selected miRs was measured in whole blood specimens of patients and controls. The corresponding values were also obtained in stages I-IV. We also assessed possible correlation between selected miRs and the clinicopathological findings of studied individuals. RESULTS: miR-21 was increased in patients compared to controls (P = 0.004). In contrast, circulating miR-638, miR-148 and miR-152 was observed to be down-regulated in NSCLC patients than controls (P = 0.001, 0.003, 0.053, respectively). Rise in miR-21-5p expression and decreased blood level of miR-148a-3p was associated with higher stage of NSCLC. The highest sensitivity (90%) was observed for miR-21 while miR-148 had the highest specificity (71%). The corresponding sensitivity and specificity for combined-miRs-panel was 96.4% and 86.67%, respectively. CONCLUSION: In summary, our data suggested the diagnostic importance of combined-miR-panel including miR-21, miR-638, miR148 and miR-152 for effective discrimination of NSCLC from non-cancerous subjects.

Interference of tumour mutational burden with outcome of patients with head and neck cancer treated with definitive chemoradiation: a multicentre retrospective study of the German Cancer Consortium Radiation Oncology Group.

BACKGROUND: Tumour mutational burden (TMB) estimated from whole exome sequencing or comprehensive gene panels has previously been established as predictive factor of response to immune checkpoint inhibitors (ICIs). Its predictive value for the efficacy of concurrent chemoradiation (cCRTX), a potential combination partner of ICI, remains unknown. METHODS: The accuracy of TMB estimation by an in-house 327-gene panel was established in the Cancer Genome Atlas (TCGA) head and neck squamous cell carcinoma (HNSCC) data set. Interference of TMB with outcome after cCRTX was determined in a multicentre cohort of patients with locally advanced HNSCC uniformly treated with cCRTX. Targeted next-generation sequencing was successfully applied in 101 formalin-fixed, paraffin-embedded pretreatment tumour samples. In a subset of cases (n = 40), tumour RNA was used for immune-related gene expression profiling by the nanoString platform. TMB was correlated with TP53 genotype, human papilloma virus (HPV) status, immune expression signatures and survival parameters. Results were validated in the TCGA HNSCC cohort. RESULTS: A high accuracy of TMB estimation by the 327-gene panel was established. High TMB was significantly associated with an increased prevalence of TP53 mutations and immune gene expression patterns unrelated to T cell-inflamed gene expression profiles. Kaplan-Meier analysis revealed significantly reduced overall survival in the patient group with high TMB (hazard ratio for death: 1.79, 95% confidence interval: 1.02-3.14; P = 0.042) which remained significant after correcting for confounding factors in the multivariate model. The prognostic value of TMB was confirmed in the TCGA HNSCC cohort. CONCLUSION: High TMB identifies HNSCC patients with poor outcome after cCRTX who might preferentially benefit from CRTX-ICI combinations.

Impact of fitting algorithms on errors of parameter estimates in dynamic contrast-enhanced MRI.

Parameter estimation in dynamic contrast-enhanced MRI (DCE MRI) is usually performed by non-linear least square (NLLS) fitting of a pharmacokinetic model to a measured concentration-time curve. The two-compartment exchange model (2CXM) describes the compartments 'plasma' and 'interstitial volume' and their exchange in terms of plasma flow and capillary permeability. The model function can be defined by either a system of two coupled differential equations or a closed-form analytical solution. The aim of this study was to compare these two representations in terms of accuracy, robustness and computation speed, depending on parameter combination and temporal sampling. The impact on parameter estimation errors was investigated by fitting the 2CXM to simulated concentration-time curves. Parameter combinations representing five tissue types were used, together with two arterial input functions, a measured and a theoretical population based one, to generate 4D concentration images at three different temporal resolutions. Images were fitted by NLLS techniques, where the sum of squared residuals was calculated by either numeric integration with the Runge-Kutta method or convolution. Furthermore two example cases, a prostate carcinoma and a glioblastoma multiforme patient, were analyzed in order to investigate the validity of our findings in real patient data. The convolution approach yields improved results in precision and robustness of determined parameters. Precision and stability are limited in curves with low blood flow. The model parameter v e shows great instability and little reliability in all cases. Decreased temporal resolution results in significant errors for the differential equation approach in several curve types. The convolution excelled in computational speed by three orders of magnitude. Uncertainties in parameter estimation at low temporal resolution cannot be compensated by usage of the differential equations. Fitting with the convolution approach is superior in computational time, with better stability and accuracy at the same time.

Application of fluorescent nuclear track detectors for cellular dosimetry.

Ion beams radiotherapy with charged particles show greater relative biological effectiveness (RBE) compared to conventional photon therapy. This enhanced RBE is due to a localized energy deposition pattern, which is subject to large fluctuations on cellular scales. Fluorescent nuclear track detectors (FNTDs) based on Al2O3:C,Mg crystals coated with cells (Cell-Fit-HD) can provide information on individual cellular energy deposition. In this study we provide a theoretical framework to obtain the distribution of microscopic energy deposition and ionization density in cells exposed to ion beams and identifies contributions of five different sources of variations to the overall energy fluctuation at different depths of a biologically optimized spread-out Bragg peak. We show that fluctuation in the individual energy loss of the particles is the major source of variability while the fluctuation in particle hits plays a minor role. With the Cell-Fit-HD system the uncertainty arising from four of these sources, namely the nucleus area, the number of nuclear hits, the particle linear energy transfer and the chord length can be reduced and only energy loss straggling remains fundamentally unknown. The ability to quantify these factors results in a reduction of the uncertainty in cellular energy deposition from 24-55% down to only 7-12%. We have also shown current experimental results with FNTDs which show promising results, but need further improvements to reach the ideals predicted in this study.

A phenomenological relative biological effectiveness approach for proton therapy based on an improved description of the mixed radiation field.

Proton therapy treatment planning systems (TPSs) are based on the assumption of a constant relative biological effectiveness (RBE) of 1.1 without taking into account the found in vitro experimental variations of the RBE as a function of tissue type, linear energy transfer (LET) and dose. The phenomenological RBE models available in literature are based on the dose-averaged LET (LET D ) as an indicator of the physical properties of the proton radiation field. The LET D values are typically calculated taking into account primary and secondary protons, neglecting the biological effect of heavier secondaries. In this work, we have introduced a phenomenological RBE approach which considers the biological effect of primary protons, and of secondary protons, deuterons, tritons (Z = 1) and He fragments (3He and 4He, Z = 2). The calculation framework, coupled with a Monte Carlo (MC) code, has been successfully benchmarked against clonogenic in vitro data measured in this work for two cell lines and then applied to determine biological quantities for spread-out Bragg peaks and a prostate and a head case. The introduced RBE formalism, which depends on the mixed radiation field, the dose and the ratio of the linear-quadratic model parameters for the reference radiation [Formula: see text], predicts, when integrated in an MC code, higher RBE values in comparison to LET D -based parameterizations. This effect is particular enhanced in the entrance channel of the proton field and for low [Formula: see text] tissues. For the prostate and the head case, we found higher RBE-weighted dose values up to about 5% in the entrance channel when including or neglecting the Z = 2 secondaries in the RBE calculation. TPSs able to proper account for the mixed radiation field in proton therapy are thus recommended for an accurate determination of the RBE in the whole treatment field.

Intensity-modulated proton therapy, volumetric-modulated arc therapy, and 3D conformal radiotherapy in anaplastic astrocytoma and glioblastoma : A dosimetric comparison.

PURPOSE: The prognosis for high-grade glioma (HGG) patients is poor; thus, treatment-related side effects need to be minimized to conserve quality of life and functionality. Advanced techniques such as proton radiation therapy (PRT) and volumetric-modulated arc therapy (VMAT) may potentially further reduce the frequency and severity of radiogenic impairment. MATERIALS AND METHODS: We retrospectively assessed 12 HGG patients who had undergone postoperative intensity-modulated proton therapy (IMPT). VMAT and 3D conformal radiotherapy (3D-CRT) plans were generated and optimized for comparison after contouring crucial neuronal structures important for neurogenesis and neurocognitive function. Integral dose (ID), homogeneity index (HI), and inhomogeneity coefficient (IC) were calculated from dose statistics. Toxicity data were evaluated. RESULTS: Target volume coverage was comparable for all three modalities. Compared to 3D-CRT and VMAT, PRT showed statistically significant reductions (p < 0.05) in mean dose to whole brain (-20.2 %, -22.7 %); supratentorial (-14.2 %, -20,8 %) and infratentorial (-91.0 %, -77.0 %) regions; brainstem (-67.6 %, -28.1 %); pituitary gland (-52.9 %, -52.5 %); contralateral hippocampus (-98.9 %, -98.7 %); and contralateral subventricular zone (-62.7 %, -66.7 %, respectively). Fatigue (91.7 %), radiation dermatitis (75.0 %), focal alopecia (100.0 %), nausea (41.7 %), cephalgia (58.3 %), and transient cerebral edema (16.7 %) were the most common acute toxicities. CONCLUSION: Essential dose reduction while maintaining equal target volume coverage was observed using PRT, particularly in contralaterally located critical neuronal structures, areas of neurogenesis, and structures of neurocognitive functions. These findings were supported by preliminary clinical results confirming the safety and feasibility of PRT in HGG.

Biologically optimized helium ion plans: calculation approach and its in vitro validation.

Treatment planning studies on the biological effect of raster-scanned helium ion beams should be performed, together with their experimental verification, before their clinical application at the Heidelberg Ion Beam Therapy Center (HIT). For this purpose, we introduce a novel calculation approach based on integrating data-driven biological models in our Monte Carlo treatment planning (MCTP) tool. Dealing with a mixed radiation field, the biological effect of the primary (4)He ion beams, of the secondary (3)He and (4)He (Z = 2) fragments and of the produced protons, deuterons and tritons (Z = 1) has to be taken into account. A spread-out Bragg peak (SOBP) in water, representative of a clinically-relevant scenario, has been biologically optimized with the MCTP and then delivered at HIT. Predictions of cell survival and RBE for a tumor cell line, characterized by [Formula: see text] Gy, have been successfully compared against measured clonogenic survival data. The mean absolute survival variation ([Formula: see text]) between model predictions and experimental data was 5.3% ± 0.9%. A sensitivity study, i.e. quantifying the variation of the estimations for the studied plan as a function of the applied phenomenological modelling approach, has been performed. The feasibility of a simpler biological modelling based on dose-averaged LET (linear energy transfer) has been tested. Moreover, comparisons with biophysical models such as the local effect model (LEM) and the repair-misrepair-fixation (RMF) model were performed. [Formula: see text] values for the LEM and the RMF model were, respectively, 4.5% ± 0.8% and 5.8% ± 1.1%. The satisfactorily agreement found in this work for the studied SOBP, representative of clinically-relevant scenario, suggests that the introduced approach could be applied for an accurate estimation of the biological effect for helium ion radiotherapy.

Targeted next-generation sequencing of locally advanced squamous cell carcinomas of the head and neck reveals druggable targets for improving adjuvant chemoradiation.

BACKGROUND: Despite clear differences in clinical presentation and outcome, squamous cell carcinomas of the head and neck (SCCHN) arising from human papilloma virus (HPV) infection or heavy tobacco/alcohol consumption are treated equally. Next-generation sequencing is expected to reveal novel targets for more individualised treatment. PATIENTS AND METHODS: Tumour specimens from 208 patients with locally advanced squamous cell carcinoma of the hypopharynx, oropharynx or oral cavity, all uniformly treated with adjuvant cisplatin-based chemoradiation, were included. A customised panel covering 211 exons from 45 genes frequently altered in SCCHN was used for detection of non-synonymous point and frameshift mutations. Mutations were correlated with HPV status and treatment outcome. RESULTS: Mutational profiles and HPV status were successfully established for 179 cases. HPV- tumours showed an increased frequency of alterations in tumour suppressor genes compared to HPV+ cases (TP53 67% versus 4%, CDKN2A 18% versus 0%). Conversely, HPV+ carcinomas were enriched for activating mutations in driver genes compared to HPV- cases (PIK3CA 30% versus 12%, KRAS 6% versus 1%, and NRAS 4% versus 0%). Hotspot TP53 missense mutations in HPV- carcinomas correlated with an increased risk of locoregional recurrence (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.5-12.1, P=0.006) and death (HR 2.2, 95% CI 1.1-4.4, P=0.021). In HPV+ SCCHN, driver gene mutations were associated per trend with a higher risk of death (HR 3.9, 95% CI 0.7-21.1, P=0.11). CONCLUSIONS: Distinct mutation profiles in HPV- and HPV+ SCCHN identify subgroups with poor outcome after adjuvant chemoradiation. Mutant p53 and the phosphoinositide 3-kinase pathway were identified as potential druggable targets for subgroup-specific treatment optimisation.

Clinical features, diagnosis, and outcomes of rhino-orbito-cerebral mucormycosis- A retrospective analysis.

BACKGROUND AND PURPOSE: Rhino-orbito-cerebral mucormycosis (ROCM) is a rare disease with acute and fulminant manifestation. This infection is associated with high morbidity and mortality rates. Herein, we reviewed the manifestations, underlying conditions, medical treatments, and surgical interventions in ROCM patients admitted to a tertiary referral center in northern Iran over a seven-year period. MATERIALS AND METHODS: In a retrospective analysis, 15 cases of ROCM were identified from 2007 to 2013 in Bu Ali Sina Hospital, Sari, Iran. All the ROCM cases were clinically diagnosed and confirmed by histopathological and/or mycological examination. The relevant demographic data, clinical, ophthalmic, and neurologic manifestations, underlying conditions, medical treatments, and surgical interventions were recorded and analyzed. RESULTS: The mean age of the patients was 54±11 years (age range: 28-70 years); 26.7% of the patients were male and 73.3% female (male: female ratio of 1: 2.7). Uncontrolled diabetes was noted in at least 86.7% (13/15) of the cases. The maxillary sinuses were the most frequently involved sites (66.7% of the cases) followed by the ethmoid sinus. Amphotericin B in combination with surgical debridement was used in the treatment of 80% of the cases. Furthermore, 73.3% of the patients who were diagnosed early and underwent medical and extensive surgical debridement of the infected tissues survived. CONCLUSION: Uncontrolled diabetes mellitus is considered to be the main predisposing factor for ROCM. To prevent and reduce mortality rate of this acute disease, early diagnosis based on clinical findings and biopsy is recommended.

Comparing the biological washout of ß+-activity induced in mice brain after 12C-ion and proton irradiation.

In clinical ion beam therapy, protons as well as heavier ions such as carbon are used for treatment. For protons, ß(+)-emitters are only induced by fragmentation reactions in the target (target fragmentation), whereas for heavy ions, they are additionally induced by fragmentations of the projectile (further referred to as autoactivation). An approach utilizing these processes for treatment verification, by comparing measured Positron Emission Tomography (PET) data to predictions from Monte Carlo simulations, has already been clinically implemented. For an accurate simulation, it is important to consider the biological washout of ß(+)-emitters due to vital functions. To date, mathematical expressions for washout have mainly been determined by using radioactive beams of (10)C- and (11)C-ions, both ß(+)-emitters, to enhance the counting statistics in the irradiated area. Still, the question of how the choice of projectile (autoactivating or non-autoactivating) influences the washout coefficients, has not been addressed. In this context, an experiment was carried out at the Heidelberg Ion Beam Therapy Center with the purpose of directly comparing irradiation-induced biological washout coefficients in mice for protons and (12)C-ions. To this aim, mice were irradiated in the brain region with protons and (12)C-ions and measured after irradiation with a PET/CT scanner (Siemens Biograph mCT). After an appropriate waiting time, the mice were sacrificed, then irradiated and measured again under similar conditions. The resulting data were processed and fitted numerically to deduce the main washout parameters. Despite the very low PET counting statistics, a consistent difference could be identified between (12)C-ion and proton irradiated mice, with the (12)C data being described best by a two component fit with a combined medium and slow washout fraction of 0.50 ± 0.05 and the proton mice data being described best by a one component fit with only one (slow) washout fraction of 0.73 ± 0.06.

Differentiation of irradiation and cetuximab induced skin reactions in patients with locally advanced head and neck cancer undergoing radioimmunotherapy: the HICARE protocol (head and neck cancer: immunochemo and radiotherapy with erbitux) - a multicenter phase IV trial.

BACKGROUND: In order to improve the clinical outcome of patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) not being capable to receive platinum-based chemoradiation, radiotherapy can be intensified by addition of cetuximab, a monoclonal antibody that blocks the epidermal growth factor receptor (EGFR). The radioimmunotherapy with cetuximab is a feasible treatment option showing a favourable toxicity profile. The most frequent side effect of radiotherapy is radiation dermatitis, the most common side effect of treatment with cetuximab is acneiform rash. Incidence and severity of these frequent, often overlapping and sometimes limiting skin reactions, however, are not well explored. A clinical and molecular differentiation between radiogenic skin reactions and skin reactions caused by cetuximab which may correlate with outcome, have never been described before. METHODS/DESIGN: The HICARE study is a national, multicenter, prospective phase IV study exploring the different types of skin reactions that occur in patients with LASCCHN undergoing radioimmun(chemo)therapy with the EGFR inhibitor cetuximab. 500 patients with LASCCHN will be enrolled in 40 participating sites in Germany. Primary endpoint is the rate of radiation dermatitis NCI CTCAE grade 3 and 4 (v. 4.02). Radioimmunotherapy will be applied according to SmPC, i.e. cetuximab will be administered as loading dose and then weekly during the radiotherapy. Irradiation will be applied as intensity-modulated radiation therapy (IMRT) or 3D-dimensional radiation therapy. DISCUSSION: The HICARE trial is expected to be one of the largest trials ever conducted in head and neck cancer patients. The goal of the HICARE trial is to differentiate skin reactions caused by radiation from those caused by the monoclonal antibody cetuximab, to evaluate the incidence and severity of these skin reactions and to correlate them with outcome parameters. Besides, the translational research program will help to identify and confirm novel peripheral blood based molecular predictors and surrogates for treatment response and resistance. TRIAL REGISTRATION: Clinical Trial Identifier, NCT01553032 (clinicaltrials.gov)EudraCT number: 2010-019748-38.

Radiosensitization by histone deacetylase inhibition in an osteosarcoma mouse model.

BACKGROUND: Osteosarcomas (OS) are highly malignant and radioresistant tumors. Histone deacetylase inhibitors (HDACi) constitute a novel class of anticancer agents. We sought to investigate the effect of combined treatment with suberoylanilide hydroxamic acid (SAHA) and radiotherapy in OS in vivo. METHODS: Clonogenic survival of human OS cell lines as well as tumor growth delay of OS xenografts were tested after treatment with either vehicle, radiotherapy (XRT), SAHA, or XRT and SAHA. Tumor proliferation, necrosis, microvascular density, apoptosis, and p53/p21 were monitored by immunohistochemistry. The CD95 pathway was performed by flow cytometry, caspase (3/7/8) activity measurements, and functional inhibition of CD95 death signaling. RESULTS: Combined treatment with SAHA and XRT markedly reduced the surviving fraction of OS cells as compared to XRT alone. Likewise, dual therapy significantly inhibited OS tumor growth in vivo as compared to XRT alone, reflected by reduced tumor proliferation, impaired angiogenesis, and increased apoptosis. Addition of HDACi to XRT led to elevated p53, p21, CD95, and CD95L expression. Inhibition of CD95 signaling reduced HDACi- and XRT-induced apoptosis. CONCLUSION: Our data show that HDACi increases the radiosensitivity of osteosarcoma cells at least in part via ligand-induced apoptosis. HDACi thus emerge as potentially useful treatment components of OS.

Efficacy and necessity of nasojejunal tube after gastrectomy.

BACKGROUND: Nasojejunal tube (NJT) decompression is routinely used for intestinal drainage after total gastrectomy. It is supposed that it would protect anastomosis, but since the stomach should be completely removed, today its efficacy is under question. On the other hand, the tube leads to the discomfort of patients and aspiration disorders or nasopharyngial ulceration. The aim of this study was to evaluate the efficacy and necessity of the nasojejunal tube decompression after gastrectomy. METHODS: In this interventional study, 50 gastric cancer patients who underwent gastrectomy in Ghaem and Omid hospitals, which are affiliated with the Mashhad University of Medical Sciences, from 2001 to 2008 were enrolled. The patients were randomly divided into two groups of with NJT (25 cases) and without NJT (25 cases). The rate of complications, hospital stay duration and the time of beginning their diet were evaluated. RESULTS: The two groups were similar in age, sex, state of the disease, bleeding volume and length of removed esophagus. There was no significant difference between these two groups considering the initial passing of gas, the beginning of their diet, and hospital stay duration. But the incidence of sore throat, nasal discomfort, speech disorders, and patients' dissatisfation were higher in the group with NJT. CONCLUSION: It seems that patients without NJT were more comfortable and satisfied after total gastrectomy. Thus, there is no need for the insertion of the NJT after gastrectomy.

Prosthetic incisional hernioplasty: clinical experience with 354 cases.

BACKGROUND: The use of prosthetic materials has become the standard of care in the management of incisional hernias because of its association with a low rate of recurrence. In this paper, the results of the treatment of incisional hernias is reported. METHODS: Over a 15-year period, 354 open abdominal wall incisional hernia repairs were performed using the Rives-Stoppa, onlay and inlay techniques. The prosthetic materials used were polypropylene and Mersilene mesh. Using a questionnaire, the individual characteristics, type of operation (technique), type of prosthesis, complications and surgical outcome were recorded and analysed by SPSS software. RESULTS: A total of 354 patients underwent prosthetic incisional hernioplasty, comprising 265 women and 89 men, with a mean age of 52.1 years, using three techniques that included Rives-Stoppa (312), onlay (33) and underlay (9). The majority of complications included seroma (10), infection (8), intestinal fistula (2), mesh removal (2) and respiratory complication (4). Eighty percent of the patients used abdominal belts after the surgical procedure. Recurrent hernias were observed in four patients with a mean of 98 months follow up. All patients received pre-operative intravenous antibiotics and were discharged with oral antibiotics. CONCLUSION: In this series, the prosthetic incisional hernioplasty approaches, especially the Rives-Stoppa method, yielded excellent long-term results, with minimal morbidity in patients and large primary or recurrent incisional repair.