282 research outputs found

    Individualized IMRT treatment approach for cervical lymph node metastases of unknown primary

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    IMRT using simultaneously integrated boost (SIB) in head and neck cancer patients

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    BACKGROUND: Preliminary very encouraging clinical results of intensity modulated radiation therapy (IMRT) in Head Neck Cancer (HNC) are available from several large centers. Tumor control rates seem to be kept at least at the level of conventional three-dimensional radiation therapy; the benefit of normal tissue preservation with IMRT is proven for salivary function. There is still only limited experience with IMRT using simultaneously integrated boost (SIB-IMRT) in the head and neck region in terms of normal tissue response. The aim of this work was (1) to establish tumor response in HNC patients treated with SIB-IMRT, and (2) to assess tissue tolerance following different SIB-IMRT schedules. RESULTS: Between 1/2002 and 12/2004, 115 HNC patients have been curatively treated with IMRT. 70% received definitive IMRT (dIMRT), 30% were postoperatively irradiated. In 78% concomitant chemotherapy was given. SIB radiation schedules with 5–6 × 2 Gy/week to 60–70 Gy, 5 × 2.2 Gy/week to 66–68.2 Gy (according to the RTOG protocol H-0022), or 5 × 2.11 Gy/week to 69.6 Gy were used. After mean 18 months (10–44), 77% of patients were alive with no disease. Actuarial 2-year local, nodal, and distant disease free survival was 77%, 87%, and 78%, respectively. 10% were alive with disease, 10% died of disease. 20/21 locoregional failures occurred inside the high dose area. Mean tumor volume was significantly larger in locally failed (63 cc) vs controlled tumors (32 cc, p <0.01), and in definitive (43 cc) vs postoperative IMRT (25 cc, p <0.05); the locoregional failure rate was twofold higher in definitively irradiated patients. Acute reactions were mild to moderate and limited to the boost area, the persisting grade 3/4 late toxicity rate was low with 6%. The two grade 4 reactions (dysphagia, laryngeal fibrosis) were observed following the SIB schedule with 2.2 Gy per session. CONCLUSION: SIB-IMRT in HNC using 2.0, 2.11 or 2.2 Gy per session is highly effective and safe with respect to tumor response and tolerance. SIB with 2.2 Gy is not recommended for large tumors involving laryngeal structures

    Volumetric stratification of cT4 stage head and neck cancer

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    BACKGROUND: Locoregionally advanced stage head and neck cancer (HNC) is known for unfavorable outcome with only ~ 40–50 % 3-year overall survival (OS). Clinical T4 stage includes a wide range of tumor burden. The lack of further nonsurgical subgrouping of cT4 stage makes intercenter outcome of irradiated cohorts difficult. Aim of this analysis was to further stratify cT4 stage HNC using volumetric staging. MATERIAL AND METHODS: Between January 2002 and January 2013, a total of 201 cT4 stage squamous cell cancer (SCC) HNC patients referred to our center for curative definitive radiation were consecutively irradiated. Radiation was performed using modulated techniques. Total gross tumor volumes (tGTV: primary + nodal tumor volume) of all patients have retrospectively been stratified using a prospectively evaluated volumetric staging system which bases on 3 cut-offs (15/70/130 ml), translating into 4 prognostic subgroups [V1: 1–15 ml (n = 15), V2: 16–70 ml (108), V3: 71–130 ml (62), V4: > 130 ml (16)]. OS, disease-free survival (DFS), locoregional control (LRC), and distant metastasis-free survival (DMFS) rates were calculated. RESULTS: The mean/median follow-up was 31/23 months (range 1–116 months). The 3-year OS, DFS, LRC, and DMFS rates of the entire cohort were 63, 44, 48, and 77 %, respectively. Volumetric staging revealed its potential to prognostically statistically significantly divide the cT4 cohort into 4 volume subgroups (V1/2/3/4): OS: 90 %/72 %/58 %/18 %; DFS: 83 %/50 %/39 %/10 %; LRC: 81 %/53 %/47 %/15 %; DMFS: 93 %/90 %/70 %/41 %, all p < 0.0001. CONCLUSION: Volumetric staging allowed a highly statistically significant stratification of cT4 HNC stages into prognostic subgroups, which offers the chance of better intercenter comparability of irradiated advanced stage HNC cohorts

    Volumetric stratification of cT4 stage head and neck cancer

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    Background: Locoregionally advanced stage head and neck cancer (HNC) is known for unfavorable outcome with only ~ 40-50 % 3-year overall survival (OS). Clinical T4 stage includes a wide range of tumor burden. The lack of further nonsurgical subgrouping of cT4 stage makes intercenter outcome of irradiated cohorts difficult. Aim of this analysis was to further stratify cT4 stage HNC using volumetric staging. Material and methods: Between January 2002 and January 2013, a total of 201 cT4 stage squamous cell cancer (SCC) HNC patients referred to our center for curative definitive radiation were consecutively irradiated. Radiation was performed using modulated techniques. Total gross tumor volumes (tGTV: primary + nodal tumor volume) of all patients have retrospectively been stratified using a prospectively evaluated volumetric staging system which bases on 3 cut-offs (15/70/130ml), translating into 4 prognostic subgroups [V1: 1-15ml (n = 15), V2: 16-70ml (108), V3: 71-130ml (62), V4: > 130ml (16)]. OS, disease-free survival (DFS), locoregional control (LRC), and distant metastasis-free survival (DMFS) rates were calculated. Results: The mean/median follow-up was 31/23months (range 1-116months). The 3-year OS, DFS, LRC, and DMFS rates of the entire cohort were 63, 44, 48, and 77 %, respectively. Volumetric staging revealed its potential to prognostically statistically significantly divide the cT4 cohort into 4volume subgroups (V1/2/3/4): OS: 90 %/72 %/58 %/18 %; DFS: 83 %/50 %/39 %/10 %; LRC: 81 %/53 %/47 %/15 %; DMFS: 93 %/90 %/70 %/41 %, all p < 0.0001. Conclusion: Volumetric staging allowed a highly statistically significant stratification of cT4 HNC stages into prognostic subgroups, which offers the chance of better intercenter comparability of irradiated advanced stage HNC cohort

    Individualized IMRT treatment approach for cervical lymph node metastases of unknown primary

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    Purpose: The goal of the present study was to evaluate the outcome of risk-adapted planning treatment volumes (PTVs) in patients with cervical lymph node metastases of unknown primary cancer (UPC) treated with intensity-modulated radiotherapy (IMRT). Patients and material: Between January 2006 and November 2012, 28 patients with cervical lymph node metastases of UPC were treated in our institution with IMRT either postoperatively (n = 20) or as definitive treatment (n = 8). Nodal involvement distributed as follows: N1 (n = 2), N2a (8), N2b (10), N2c (4), and N3 (4). Systemic therapy with cisplatin or cetuximab was added concomitantly in 20 of 28patients (71 %). Radiotherapy using simultaneously integrated boost (SIB-IMRT) was carried out with 2.0 or 2.11Gy single doses up to 66/70Gy. Results: Mean/median follow-up was 31.6/30.5months (range 3-78months). In all, 15 of 28patients were treated with unilateral SIB-IMRT (54 %). An elective PTV to the contralateral oropharynx and contralateral levelII-III lymph nodes was carried out in 8patients with PET-CT suspected but not histologically proven involvement, recurrences or former tumor of the oropharynx. More extended treatment fields were reserved for patients with N2c or bilaterally N3 status (n = 5). The 3-year overall survival, mucosal control, neck control and distant metastasis-free survival rates were 76, 100, 93, and 88 %, respectively. No patient suffered from a locoregional recurrence. Two patients treated with radiotherapy alone had persistent nodal disease. No gradeII or higher late sequel has been observed. Conclusion: Our single center approach to treat patients with cervical lymph node metastases of UPC with individualized, risk-adapted SIB-IMRT resulted in high locoregional tumor control and was well tolerated

    A Mobile Holistic Enterprise Transformation Framework

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    Mobile phones and tablets shipments are surpassing those of the PC category, as well as in relation to Internet usage as of 2016; all details which have made mobile adoption a priority for many enterprises and a challenge for them as well. Many enterprises have fallen into a paradox of spending on creating and updating mobile services, and gaining less than expected in return. Reasons for this include the lack of vision, and the lack of a clearly defined, well communicated mobile strategy. Enterprise Architecture ‘EA’ facilitates a successful transformation by controlling and managing the transitions in order to arrive at a clearly defined future state. It is regarded as the science of change to many. However, EA frameworks are very comprehensive and require weeks of training and resources, and are often too generic for mobile transformation. Therefore, an EA-based mobile holistic enterprise framework has been developed to support enterprises in making mobile initiatives a priority. The proposed framework ensures a clearly defined, well-communicated, holistic future state that is continually evaluated, as opposed to many of the existing frameworks. The proposed Mobile Holistic Enterprise Architecture Framework - ‘MHETF’ - is based on the realisation of the capabilities of smartphones that are aimed at individual average consumers (the backbone of the current mobile trend). The capabilities are categorised and translated into four sets of services categories for business use. They are linked to another two components of the framework which are: (i) the categorisation of goals and objectives that are incorporated into the Balanced Scorecard for evaluation at a later stage in planning, and continually referred to during transitions and (ii) the categorisation of the implementation forms (categorisation of end solutions’ functionalities). The framework is supported by EA inter-operability and maturity models to ensure continuity and alignment with the existing initiatives, the enterprise’s strategic objectives, and the change required in the scope of transformation. An evaluation for the available enterprise architecture frameworks was carried out and resulted in the selection of The Open Group Architecture Framework (TOGAF). The decision was also commended by the participants in the case study evaluation due to their familiarity with this framework, which is being adopted as the Saudi E Government Standard in contrast to the other major frameworks of Zachman and Federal Enterprise Architecture (FEA). MHETF has been applied to three case studies in the Kingdom of Saudi Arabia; two applications for a leading national outsourcing company, and the third for the outpatient clinics in a large hospital in the capital city of Riyadh. The results have shown major improvements in the four goal areas of mobile transformation; productivity, processes, satisfaction improvement and facilitating new opportunities. Eventually, the final evolution has shown that the participants are satisfied with the framework overall, and indicates that the framework changed their perspective of the power of mobile applications significantly, is relatively easy to understand, and that they are planning to adopt it for future mobile initiatives

    Uptake and localisation of mTHPC (Foscan®) and its14C-labelled form in normal and tumour tissues of the hamster squamous cell carcinoma model: a comparative study

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    The aim of this study was to evaluate the pharmacokinetics of meta(tetrahydroxyphenyl)chlorin (mTHPC) on different tissues of interest in a hamster tumour model and to confirm our earlier animal studies on semi-quantitative fluorescence microscopy. The results obtained by three different evaluation methods were compared: in vivo spectrofluorometry, ex vivo fluorescence microscopy and chemical extraction of 14C-labelled mTHPC. Following intracardiac injection of 0.5 mg kg−1 mTHPC, groups of five tumour-bearing animals were used for in situ light-induced fluorescence spectroscopy. Afterwards, the biopsies were taken and snap frozen for fluorescence microscopy. The presence of radioactivity in serum and tissues was determined after chemical digestion in scintillation fluid using a scintillation counter. For each analysed tissue, a good correlation was observed between the three evaluation methods. The highest fluorescence intensity and quantities of mTHPC were observed between 12 and 24 h in liver, kidney, serum, vascular endothelium and advanced neoplasia. The majority of mTHPC was found at around 48 h in smooth muscle and at 96 h in healthy cheek pouch mucosa and early malignant lesions. The lowest level of mTHPC was noted in striated muscle at all times. No selectivity in dye localisation was observed between early squamous cell carcinoma and healthy mucosa. Soon after the injection, a significant selectivity was noted for advanced squamous cell carcinoma as compared to healthy cheek pouch mucosa or striated muscle. A significant difference in mTHPC localisation and quantity was also observed between striated and smooth muscle during the first 48 h following the injection. Finally, this study demonstrated the usefulness of non-invasive in situ spectroscopic measurements to be performed systematically prior to photodynamic therapy as a real-time monitoring for each treated patient in order to individualise and adapt the light dosimetry and avoid over or under treatments

    Ticagrelor, but not clopidogrel, reduces arterial thrombosis via endothelial tissue factor suppression

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    The P2Y12 antagonist ticagrelor reduces mortality in patients with acute coronary syndrome (ACS), compared with clopidogrel, and the mechanisms underlying this effect are not clearly understood. Arterial thrombosis is the key event in ACS; however, direct vascular effects of either ticagrelor or clopidogrel with focus on arterial thrombosis and its key trigger tissue factor have not been previously investigated.Methods and results: Human aortic endothelial cells were treated with ticagrelor or clopidogrel active metabolite (CAM) and stimulated with tumour necrosis factor-alpha (TNF-α); effects on procoagulant tissue factor (TF) expression and activity, its counter-player TF pathway inhibitor (TFPI) and the underlying mechanisms were determined. Further, arterial thrombosis by photochemical injury of the common carotid artery, and TF expression in the murine endothelium were examined in C57BL/6 mice treated with ticagrelor or clopidogrel. Ticagrelor, but not CAM, reduced TNF-α-induced TF expression via proteasomal degradation and TF activity, independently of the P2Y12 receptor and the equilibrative nucleoside transporter 1 (ENT1), an additional target of ticagrelor. In C57BL/6 mice, ticagrelor prolonged time to arterial occlusion, compared with clopidogrel, despite comparable antiplatelet effects. In line with our in vitro results, ticagrelor, but not clopidogrel, reduced TF expression in the endothelium of murine arteries.Conclusion: Ticagrelor, unlike clopidogrel, exhibits endothelial-specific antithrombotic properties and blunts arterial thrombus formation. The additional antithrombotic properties displayed by ticagrelor may explain its greater efficacy in reducing thrombotic events in clinical trials. These findings may provide the basis for new indications for ticagrelor

    Genetic deletion of the adaptor protein p66Shc increases susceptibility to short-term ischaemic myocardial injury via intracellular salvage pathways

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    Genetic deletion of p66Shc, as shown in the present study, leads to increased myocardial infarction in response to short-term ischaemia and reperfusion. Therefore, heart-specific activation of p66Shc protein may represent a promising novel strategy to prevent ischaemic and reperfusion myocardial injury. In particular, pharmacological modulation of apoptosis via myocardial salvage pathways involving p66Shc might be a promising approach to limit short-term ischaemic injury, for instance in patients with acute coronary syndrome (ACS) from the time of symptom onset to percutaneous coronary intervention. However, the present study also adds complexity to the use of this pathway as a therapeutic target. Indeed, given the different effects of activation and silencing of p66Shc in different cells, tissues and organs, tissue selective inhibition would be required. Indeed, while short-term activation might be protective in the context of an ACS, long-term inhibition may prevent endothelial dysfunction, atherosclerosis, and diabetic vascular disease. Obviously, this complexity also raises safety concerns for the potential use of p66Shc in acute myocardial infarction that need to be clarified by additional researc

    Outcome in recurrent head neck cancer treated with salvage-IMRT

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    BACKGROUND: Recurrent head neck cancer (rHNC) is a known unfavourable prognostic condition. The purpose of this work was to analyse our rHNC subgroup treated with salvage-intensity modulated radiation therapy (IMRT) for curable recurrence after initial surgery alone. Patients Between 4/2003-9/2008, 44 patients with squamous cell rHNC were referred for IMRT, mean/median 33/21 (3-144) months after initial surgery. None had prior head neck radiation. 41% underwent definitive, 59% postoperative IMRT (66-72.6Gy). 70% had simultaneous chemotherapy. METHODS: Retrospective analysis of the outcome following salvage IMRT in rHNC patients was performed. RESULTS: After mean/median 25/21 months (3-67), 22/44 (50%) patients were alive with no disease; 4 (9%) were alive with disease. 18 patients (41%) died of disease. Kaplan Meier 2-year disease specific survival (DSS), disease free survival (DFS), local and nodal control rates of the cohort were 59/49/56 and 68%, respectively. Known risk factors (advanced initial pTN, marginal initial resection, multiple recurrences) showed no significant outcome differences. Risk factors and the presence of macroscopic recurrence gross tumor volume (rGTV) in oral cavity patients vs others resulted in statistically significantly lower DSS (30 vs 70% at 2 years, p=0.03). With respect to the assessed unfavourable outcome following salvage treatment, numbers needed to treat to avoid one recurrence with initial postoperative IMRT have, in addition, been calculated. CONCLUSION: A low salvage rate of only ~50% at 2 years was found. Calculated numbers of patients needed to treat with postoperative radiation after initial surgery, in order to avoid recurrence and tumor-specific death, suggest a rather generous use of adjuvant irradiation, usually with simultaneous chemotherapy
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