Final results of a multi-institutional phase II trial of reirradiation with concurrent weekly cisplatin and cetuximab for recurrent or second primary squamous cell carcinoma of the head and neck.

Background: The optimal regimen of chemotherapy and reirradiation (re-XRT) for recurrent head and neck squamous cell carcinoma (HNSCC) is controversial. We report the final outcomes of a multicenter phase II trial evaluating cetuximab and cisplatin-based chemotherapy concurrent with re-XRT for patients with recurrent HNSCC. Materials and methods: Patients with unresectable recurrent disease or positive margins after salvage surgery arising within a previously irradiated field with KPS ≥ 70 were eligible for this trial. Cetuximab 400 mg/m2 was delivered as a loading dose in week 1 followed by weekly cetuximab 250 mg/m2 and cisplatin 30 mg/m2 concurrent with 6 weeks of intensity-modulated radiotherapy to a dose of 60-66 Gy in 30 daily fractions. Patients who previously received both concurrent cetuximab and cisplatin with radiation or who received radiotherapy less than 6 months prior were ineligible. Results: From 2009 to 2013, 48 patients enrolled on this trial, 2 did not receive any protocol treatment. Of the remaining 46 patients, 34 were male and 12 female, with a median age of 62 years (range 36-85). Treatment was feasible and only 1 patient did not complete the treatment course. Common grade 3 or higher acute toxicities were lymphopenia (46%), pain (22%), dysphagia (13%), radiation dermatitis (13%), mucositis (11%) and anorexia (11%). There were no grade 5 acute toxicities. Eight grade 3 late toxicities were observed, four of which were swallowing related. With a median follow-up of 1.38 years, the 1-year overall survival (OS) was 60.4% and 1-year recurrence-free survival was 34.1%. On univariate analysis, OS was significantly improved with young age (P = 0.01). OS was not associated with radiation dose, surgery before re-XRT or interval from prior XRT. Conclusions: Concurrent cisplatin and cetuximab with re-XRT is feasible and offers good treatment outcomes for patients with high-risk features. Younger patients had significantly improved OS. ClinicalTrials.Gov Identifier: NCT00833261.

Numerical investigation of flow and scour around a vertical circular cylinder.

Flow and scour around a vertical cylinder exposed to current are investigated by using a three-dimensional numerical model based on incompressible Reynolds-averaged Navier-Stokes equations. The model incorporates (i) k-ω turbulence closure, (ii) vortex-shedding processes, (iii) sediment transport (both bed and suspended load), as well as (iv) bed morphology. The influence of vortex shedding and suspended load on the scour are specifically investigated. For the selected geometry and flow conditions, it is found that the equilibrium scour depth is decreased by 50% when the suspended sediment transport is not accounted for. Alternatively, the effects of vortex shedding are found to be limited to the very early stage of the scour process. Flow features such as the horseshoe vortex, as well as lee-wake vortices, including their vertical frequency variation, are discussed. Large-scale counter-rotating streamwise phase-averaged vortices in the lee wake are likewise demonstrated via numerical flow visualization. These features are linked to scour around a vertical pile in a steady current.

Impact of mixing on water quality in the Bosphorus - Implications on sustainable management of wastewater marine discharges.

The study established the water quality modelling of the Bosphorus system, based on hydrodynamic data as well as the results of the water quality survey carried out in the last five years. The model revealed significant decrease in the magnitude of pollutant loads in the upper layer at the exit into The Marmara Sea providing numerical proof that no pollutant transport would take place from sewage discharges to the upper layer. A similar modelling approach was implemented at the Bosphorus/Marmara interface, a significant hotspot as it included two major deep marine outfalls. The results asserted that the entire sewage flow would enter the lower flow in The Bosphorus through the interface without an appreciable mixing with the upper flow. This way, the study provided a significant scientific support for the sustainable management of marine discharges in this area, since they have no physical interference with The Marmara Sea.

Pollutant dynamics between The Black Sea and The Marmara Sea: Basis for wastewater management strategy.

The study evaluated pollutant dynamics between The Black Sea and The Marmara Sea using data collected during a marine survey of the region around The Bosphorus strait, in the last five years. A hydraulic model was utilized to define two-layered water exchange in The Bosphorus. Analysis of pollutant exchange indicated The Black Sea as major polluter for the marine environment in The Marmara Sea. Four wastewater outfalls are located along The Bosphorus; Mass balances between the two ends of The Bosphorus indicated losses of 44 t/d total N and 138 t/d COD in the lower layer before reaching The Black Sea. This was explained with a simultaneous nitrification-denitrification process sustained in the low oxygen or anoxic zones around the outfalls, implying that a sustainable wastewater strategy should preclude additional treatment for The Bosphorus discharges, since they do not have an appreciable impact on the water quality of the lower flow.

Exploiting metabolic acidosis in solid cancers using a tumor-agnostic pH-activatable nanoprobe for fluorescence-guided surgery.

Cancer cell metabolism leads to a uniquely acidic microenvironment in solid tumors, but exploiting the labile extracellular pH differences between cancer and normal tissues for clinical use has been challenging. Here we describe the clinical translation of ONM-100, a nanoparticle-based fluorescent imaging agent. This is comprised of an ultra-pH sensitive amphiphilic polymer, conjugated with indocyanine green, which rapidly and irreversibly dissociates to fluoresce in the acidic extracellular tumor microenvironment due to the mechanism of nanoscale macromolecular cooperativity. Primary outcomes were safety, pharmacokinetics and imaging feasilibity of ONM-100. Secondary outcomes were to determine a range of safe doses of ONM-100 for intra-operative imaging using commonly used fluorescence camera systems. In this study (Netherlands National Trial Register #7085), we report that ONM-100 was well tolerated, and four solid tumor types could be visualized both in- and ex vivo in thirty subjects. ONM-100 enables detection of tumor-positive resection margins in 9/9 subjects and four additional otherwise missed occult lesions. Consequently, this pH-activatable optical imaging agent may be clinically beneficial in differentiating previously unexploitable narrow physiologic differences.