Volumetric stratification of cT4 stage head and neck cancer

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

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

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

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

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

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

Protein kinase C inhibitor and irradiation-induced apoptosis: Relevance of the cytochrome c-mediated caspase-9 death pathway

Caspases are a family of cysteine proteases that constitute the apoptotic cell death machinery, We report the importance of the cytochrome c-mediated caspase-9 death pathway for radiosensitization by the protein kinase C (PKC) inhibitors staurosporine (STP) and PKC-412. In our genetically defined tumor cells, treatment with low doses of STP or the conventional PKC-specific inhibitor PKC-412 in combination with irradiation (5 Gy) potently reduced viability, enhanced mitochondrial cytochrome c release into the cytosol, and specifically stimulated the initiator caspase-9. Whereas treatment with each agent alone had a minimal effect, combined treatment resulted in enhanced caspase-3 activation. This was prevented by broad-range and specific caspase-9 inhibitors and absent in caspase-9-deficient cells. The tumor suppressor p53 was required for apoptosis induction by combined treatment but was dispensable for dose-dependent STP-induced caspase activation. These results demonstrate the requirement for an intact caspase-9 pathway for apoptosis-based radiosensitization by PKC inhibitors and show that STP induces apoptosis independent of p53

Effect of VEGF receptor inhibitor PTK787/ZK222548 combined with ionizing radiation on endothelial cells and tumour growth

The vascular endothelial growth factor (VEGF) receptor is a major target for anti-angiogenesis-based cancer treatment. Here we report the treatment effect of ionizing radiation in combination with the novel orally bioavailable VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 on endothelial cell proliferation in vitro and with tumour xenografts in vivo. Combined treatment of human umbilical vein endothelial cells with increasing doses of PTK787/ZK222584 and ionizing radiation abrogated VEGF-dependent proliferation in a dose-dependent way, but inhibition of endothelial cell proliferation was not due to apoptosis induction. In vivo, a combined treatment regimen of PTK787/ZK222584 (4 × 100 mg/kg) during 4 consecutive days in combination with ionizing radiation (4 × 3 Gy) exerted a substantial tumour growth delay for radiation-resistant p53-disfunctional tumour xenografts derived from SW480 colon adenocarcinoma cells while each treatment modality alone had only a minimal effect on tumour size and neovascularization. SW480 tumours from animals that received a combined treatment regimen, displayed not only an extended tumour growth delay but also a significant decrease in the number of microvessels in the tumour xenograft. These results support the model of a cooperative antitumoural effect of angiogenesis inhibitor and irradiation and show that the orally bioavailable VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 is suitable for combination therapy with irradiation. © 2001 Cancer Research Campaign http://www.bjcancer.co

Protective films on complex substrates of thermoplastic and cellular elastomers:Prospective applications to rubber, nylon and cork

Deposition of thin films is an appropriate methodology to enhance the performance of a material by modification of its surface, while keeping the properties of the bulk largely unaffected. However, a practical implementation becomes less straightforward when dealing with sensitive or complex substrates, for instance, those which cannot be subjected to harsh treatments, such as cleaning and etching, or extreme deposition conditions, like high temperatures, and ion impingement et cetera. This paper concentrates on deposition processing of complex substrates. In particular, it discusses the deposition of two types of protective coatings (diamond-like carbon (DLC) films against friction and wear, and TiO2 films against UV light) on three types of thermoplastic and cellular elastomers (rubber, nylon and cork). It is demonstrated that a successful protection of thermoplastic elastomers against wear with DLC films can be attained, after a thorough adaptation of the procedure to the characteristics of the specific substrate. In addition, the paper reports the very first depositions on a cellular elastomer like cork by vapor deposition methods, including Atomic Layer Deposition (ALD)

Cost-utility analysis of total shoulder arthroplasty : a prospective health economic study using real-world data

Background: With increasing health care expenditures, knowledge about the benefit and costs of surgical interventions such as total shoulder arthroplasty (TSA) becomes important for orthopedic surgeons, social insurances and health policy decision makers. We examined the impact of TSA on quality of life (QOL), direct medical costs and productivity losses, and evaluated the cost-utility ratio of TSA compared to ongoing nonoperative management using real-world data. Methods: Patients with shoulder osteoarthritis and/or rotator cuff tear arthropathy indicated for anatomical or reverse TSA were included in this prospective study. Quality of life (EQ-5D-5L) and shoulder function (Constant Score, Shoulder Pain and Disability Index, short version of the Disabilities of the Arm, Shoulder and Hand questionnaire, Subjective Shoulder Value) were assessed before (preop) and up to 2 years after surgery (postop). Health insurance companies provided all-diagnoses direct medical costs for 2018 in Swiss francs (CHF), where 1 CHF was equivalent to 1.02 USD. Indirect costs were assessed using the work productivity and activity impairment questionnaire. Baseline data at recruitment and the total costs of the preop year served as a proxy for nonoperative management. The incremental cost-effectiveness ratio (ICER) was calculated as the total costs to gain one extra quality-adjusted life year (QALY) based on both the health care system and societal perspective. The relationship between QOL and shoulder function was assessed by regression analysis. Results: The mean preOP EQ-5D-5L utility index of 0.68 for a total of 150 patients (mean age 71 years; 21% working; 58% female) increased to 0.89 and 0.87 at 1 and 2 years postop, respectively. Mean direct medical costs were 11,771 CHF (preop), 34,176 CHF (1 year postop) and 11,763 CHF (2 years postop). The ICER was 63,299 CHF/QALY (95% confidence interval [CI]: 44,391; 82,206). Mean productivity losses for 30 working patients decreased from 40,574 CHF per patient (preop) to 26,114 CHF at 1 year postop and 10,310 CHF at 2 years postop. When considering these productivity losses, the ICER was 35,549 CHF/QALY (95% CI: 12,076; 59,016). Quality of life was significantly associated with shoulder function (p < 0.001). Conclusion: Using real-world direct medical cost data, we calculated a cost-utility ratio of 63,299 CHF/QALY for TSA in Switzerland, which clearly falls below the often suggested 100,000 CHF/QALY threshold for acceptable cost-effectiveness. In view of productivity losses, TSA becomes highly cost-effective with an ICER of 35,546 CHF/QALY