Impact of Nanoparticle-Based TiO2 Surfaces on Norovirus Capsids and Genome Integrity.

Human noroviruses (HuNoVs) are among the main causes of acute gastroenteritis worldwide. HuNoVs can survive for several days up to weeks at room temperature in the environment, on food, and on food handling and processing surfaces. As a result, this could lead to viral spread through the ingestion of food in contact with contaminated surfaces. The development of stable surface materials with antiviral activity might be useful to reduce viral outbreaks. Metal-based compounds, including photoactivated titanium nanoparticles (TiO2 NPs), are known for their antiviral activity. In this study, we tested the impact of 2000 µg/mL TiO2 NPs, with or without UV activation, on HuNoV GII and murine norovirus. Their recovery rates were reduced by 99.6%. We also evaluated a new TiO2 NP-coating process on a polystyrene surface. This process provided a homogenous coated surface with TiO2 NPs ranging between 5 nm and 15 nm. Without photoactivation, this TiO2 NP-coated polystyrene surface reduced the recovery rates of intact HuNoV GII by more than 94%. When a capsid integrity treatment with PtCl4 or a longer reverse transcription polymerase chain detection approach was used to evaluate virus integrity following contact with the TiO2 NP-coated polystyrene, the HuNoV GII recovery yield reduction varied between 97 and 100%. These results support the hypothesis that TiO2 NP-coated surfaces have the potential to prevent viral transmission associated with contaminated food surfaces.

Two Cases of Primary Spinal Glioblastoma in Adults Treated With Multimodality Therapy.

Primary spinal glioblastoma (GBM) is a rare disease entity with no established standard treatment. We present two cases of primary spinal GBM initially presenting with motor-sensory deficits and back pain. Management varied in that the first patient received subtotal resection followed by radiation therapy, while the second patient underwent gross total resection followed by radiation therapy and temozolomide. The first patient died from hypoxemia secondary to disease progression affecting diaphragmatic motion three months after diagnosis. The second patient progressed intracranially and died 7.4 months after diagnosis. There is no standard of care for primary spinal GBM, so treatment should follow a multidisciplinary discussion focused on patient-specific goals. These cases highlight the poor prognosis of primary spinal GBM despite different treatment approaches, necessitating accurate reporting of all similar cases to help improve knowledge and management of this rare malignancy.

The Effect of Bolus on Local Control for Patients Treated With Mastectomy and Radiation Therapy.

PURPOSE: Bolus use during postmastectomy radiation therapy doubles the risk of grade 2 and 3 skin toxicity. Despite its unknown benefit, bolus is often prescribed during postmastectomy radiation therapy for patients without skin involvement. METHODS AND MATERIALS: For women with breast cancer receiving photon 3-dimensional conformal radiation therapy, bolus was used routinely for chest walls but was omitted for breast reconstructions by about half of radiation oncologists from 2007 to 2011. Eligible patients had newly diagnosed invasive breast cancers without skin involvement (pT1-4a, any-N, M0) treated with adjuvant or neoadjuvant radiation therapy. For the bolus and no-bolus groups, we compared the cumulative incidence of local recurrence (LR) and locoregional recurrence (LRR) with distant recurrence and death as competing risks and breast cancer mortality (BCM). Multivariable analysis of LR and BCM included stage, subtype, lymphovascular invasion, grade, margin status, beam energy, bolus use, hormone therapy, chemotherapy, and reconstruction. RESULTS: Systemic therapy was used for 98% of the 1887 patients. The bolus group had 1569 patients and the no-bolus group had 318 patients. Bolus was used in 51% (281/550) of patients treated with reconstruction and 96% (1288/1337) of patients treated without reconstruction. The 10-year outcomes (95% confidence interval) in patients treated with and without bolus were, respectively: LR 1.9% (1.3-2.7) versus 0.9% (0.3-2.6), LRR 3.1% (2.3-4.0) versus 3.2% (1.6-5.5), and BCM 19.4% (17.3-21.6) versus 18.3% (13.9-23.2). On multivariable analysis, bolus use was not associated with better LR (hazard ratio = 1.4 [0.3-6.4]) or BCM (hazard ratio = 0.8 [0.5-1.2]). CONCLUSIONS: For patients treated with mastectomy, radiation therapy, and modern systemic therapy, the cumulative incidence of LR was low, with or without bolus. Because bolus use increases toxicity and does not reduce LR or BCM, it should no longer be used routinely for patients without skin involvement who receive systemic therapy.

External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial.

BACKGROUND: Whole breast irradiation delivered once per day over 3-5 weeks after breast conserving surgery reduces local recurrence with good cosmetic results. Accelerated partial breast irradiation (APBI) delivered over 1 week to the tumour bed was developed to provide a more convenient treatment. In this trial, we investigated if external beam APBI was non-inferior to whole breast irradiation. METHODS: We did this multicentre, randomised, non-inferiority trial in 33 cancer centres in Canada, Australia and New Zealand. Women aged 40 years or older with ductal carcinoma in situ or node-negative breast cancer treated by breast conserving surgery were randomly assigned (1:1) to receive either external beam APBI (38·5 Gy in ten fractions delivered twice per day over 5-8 days) or whole breast irradiation (42·5 Gy in 16 fractions once per day over 21 days, or 50 Gy in 25 fractions once per day over 35 days). Patients and clinicans were not masked to treatment assignment. The primary outcome was ipsilateral breast tumour recurrence (IBTR), analysed by intention to treat. The trial was designed on the basis of an expected 5 year IBTR rate of 1·5% in the whole breast irradiation group with 85% power to exclude a 1·5% increase in the APBI group; non-inferiority was shown if the upper limit of the two-sided 90% CI for the IBTR hazard ratio (HR) was less than 2·02. This trial is registered with ClinicalTrials.gov, NCT00282035. FINDINGS: Between Feb 7, 2006, and July 15, 2011, we enrolled 2135 women. 1070 were randomly assigned to receive APBI and 1065 were assigned to receive whole breast irradiation. Six patients in the APBI group withdrew before treatment, four more did not receive radiotherapy, and 16 patients received whole breast irradiation. In the whole breast irradiation group, 16 patients withdrew, and two more did not receive radiotherapy. In the APBI group, a further 14 patients were lost to follow-up and nine patients withdrew during the follow-up period. In the whole breast irradiation group, 20 patients were lost to follow-up and 35 withdrew during follow-up. Median follow-up was 8·6 years (IQR 7·3-9·9). The 8-year cumulative rates of IBTR were 3·0% (95% CI 1·9-4·0) in the APBI group and 2·8% (1·8-3·9) in the whole breast irradiation group. The HR for APBI versus whole breast radiation was 1·27 (90% CI 0·84-1·91). Acute radiation toxicity (grade ≥2, within 3 months of radiotherapy start) occurred less frequently in patients treated with APBI (300 [28%] of 1070 patients) than whole breast irradiation (484 [45%] of 1065 patients, p<0·0001). Late radiation toxicity (grade ≥2, later than 3 months) was more common in patients treated with APBI (346 [32%] of 1070 patients) than whole breast irradiation (142 [13%] of 1065 patients; p<0·0001). Adverse cosmesis (defined as fair or poor) was more common in patients treated with APBI than in those treated by whole breast irradiation at 3 years (absolute difference, 11·3%, 95% CI 7·5-15·0), 5 years (16·5%, 12·5-20·4), and 7 years (17·7%, 12·9-22·3). INTERPRETATION: External beam APBI was non-inferior to whole breast irradiation in preventing IBTR. Although less acute toxicity was observed, the regimen used was associated with an increase in moderate late toxicity and adverse cosmesis, which might be related to the twice per day treatment. Other approaches, such as treatment once per day, might not adversely affect cosmesis and should be studied. FUNDING: Canadian Institutes for Health Research and Canadian Breast Cancer Research Alliance.

Entropy of aqueous surfaces. Application to polymeric Langmuir films.

Measuring surface (excess) entropies provides a bounty of valuable structural information that is hard to obtain otherwise. In the paper these quantities are defined and procedures of measurements discussed. Mostly they involve measurements at different temperatures. A review is given for interfaces with aqueous solutions in the absence of polymers. This review illustrates how, sometimes unanticipated, pieces of information are obtained, for example with cloud seeding and a possible explanation of the Jones-Ray effect. As a novel extension the procedure is applied to deposited, or Langmuir, monolayers of poly(ethylene oxide)-poly(propylene oxide) block copolymers. It will be shown how the various phase transitions and associated configurations of these polymers can be recognized and monitored.

Volumetric Radiosurgery for 1 to 10 Brain Metastases: A Multicenter, Single-Arm, Phase 2 Study.

PURPOSE: Interest is growing in treating multiple brain metastases with radiosurgery. We report on the effectiveness and tolerability of volumetric radiosurgery (VRS). METHODS AND MATERIALS: We enrolled patients with a ≥6-month estimated life expectancy and 1 to 10 brain metastases with a diameter of ≤3 cm at 5 cancer centers. Volumetric radiosurgery was delivered in 5 fractions with 98% target coverage, prescribed as 95% of 50 Gy (47.5 Gy in 5 fractions) to the metastases with no margin and 95% of 40 Gy (38 Gy in 5 fractions) to their 2-mm planning target volumes, concurrent with 20 Gy to the whole brain planning target volume. The treatment was delivered with daily image guidance using conventional linear accelerators and volumetric modulated arc therapy. A magnetic resonance imaging scan was obtained every 3 months. The primary endpoint was the 3-month objective response in the brain according to the Response Evaluation Criteria in Solid Tumors, version 1.1. The principal secondary endpoint was 1-year actuarial control of treated metastases. Toxicities were graded using the Common Terminology Criteria for Adverse Events, version 4.0. The present study is registered with ClinicalTrials.gov (clinicaltrials.gov identifier NCT01046123). RESULTS: From July 2010 to May 2013, 60 patients underwent VRS with 47.5 Gy in 5 fractions for 12 metastases in the thalamus and basal ganglia (deep metastases) and 207 non-deep metastases. The median follow-up period was 30.5 months, and the median survival was 10.1 months. For the 43 patients assessable at 3 months, the objective response in the brain was 56%. The treated metastases were controlled in 88% of patients at 1 year and 84% at 3 years. Overall survival did not differ for patients with 4 to 10 versus 1 to 3 metastases (hazard ratio 1.18, P=.6). The crude incidence of severe radionecrosis (grade 3-5) was 25% (3 of 12) per deep metastasis, 1.9% (4 of 219) per non-deep metastasis, and 10% (6 of 60) per patient. CONCLUSIONS: For non-deep brain metastases, 47.5 Gy in 5 fractions was tolerable. Volumetric radiosurgery was effective for long-term control of treated brain metastases.

Langmuir monolayers of non-ionic polymers: equilibrium or metastability? Case study of PEO and its PPO-PEO diblock copolymers.

Stability and reorganization in Langmuir films of PEO in PEO homopolymers and PPO-PEO block copolymers were investigated using film balance measurements. The apparent fractional losses of EO segments transferred into the subphase resulting from successive compression-expansion cycles have been estimated. The apparent loss is mainly Γ(max), M(n) and time-dependent. At surface concentrations Γ⩽0.32 mg/m(2), PEO films are in equilibrium. For 0.32⩽Γ⩽0.7 mg/m(2), the losses remain modest. Further compression leads to densification of the monolayer, requiring the interplay of thermodynamics and kinetic factors In the plateau regime, the loss is higher and constant for 1⩽Γ(max)⩽2 mg/m(2) upon maintaining the achieved surface area for 15 min. Similar losses were obtained for PEO homopolymers of high Mn and PPO353-PEO2295. It suggests that the PEO remains anchored in a metastable state at the air-water interface at surface concentration well above the onset of the plateau. Additional losses are incurred for PEO homopolymers for monolayers kept compressed in the plateau for 2 h. For the interpretation of these phenomena a combination of elements from self-consistent field theory and scaling is desirable with as a trend an increasing contribution of the latter with increasing surface concentration.

Phase transitions in polymer monolayers: Application of the Clapeyron equation to PEO in PPO-PEO Langmuir films.

In this paper we investigate the application of the two-dimensional Clapeyron law to polymer monolayers. This is a largely unexplored area of research. The main problems are (1) establishing if equilibrium is reached and (2) if so, identifying and defining phases as functions of the temperature. Once this is validated, the Clapeyron law allows us to obtain the entropy and enthalpy differences between two coexisting phases. In turn, this information can be used to obtain insight into the conformational properties of the films and changes therein. This approach has a wide potential for obtaining additional information on polymer adsorption at interfaces and the structure of their monolayer films. The 2D Clapeyron law was applied emphasizing polyethylene oxide (PEO) in polypropylene oxide (PPO)-PEO block copolymers, based on new well-defined data for their Langmuir films. Values for enthalpy per monomer of 0.12 and 0.23 kT were obtained for the phase transition of two different PEO chains (Neo of 2295 and 409, respectively). This enthalpy was estimated to correspond to 1.2±0.4 kT per EO monomer present in train conformation at the air/water interface.

Intra- and interobserver reproducibility of interpretation of immunohistochemical stains of prostate cancer.

The evaluation of immunohistochemistry (IHC) is usually semiquantitative, and thus subject to observer variability. We analyzed the reproducibility of different IHC measures. Fifty TMA cores of prostate cancer were stained for PDX-1, a transcription factor overexpressed in the cytoplasm of prostate cancer cells. The strongest intensity was scored 0-3 and 1-3 was used for extent (1-33%, 34-66%, and 67-100%). The stains were evaluated twice by four observers: two genitourinary pathologists, and two medical doctors with no formal pathology training. Staining intensity was also measured with automated image analysis. The pathologists read the slides faster than nonpathologists (total time 88 and 178 min, respectively, p = 0.03). Mean weighted kappa for intraobserver agreement was 0.85 (range 0.81-0.89) for intensity and 0.43 (range 0.38-0.51) for extent with similar results among pathologists and nonpathologists. Mean weighted kappa for interobserver agreement was 0.80 (range 0.77-0.84) for intensity and 0.21 (range 0.11-0.26) for extent. The subjective estimations of intensity correlated with results of image analysis (r = 0.61-0.66, p < 0.001), but the correlation between observers was stronger (r = 0.75-0.81) and correlated better with Gleason grade. Thus, subjective assessment of intensity can be done with a high level of reproducibility while estimation of staining extent is less reliable. Although educated pathologists were faster, the level of pathology training is not crucial for obtaining reproducible results in the analysis of TMA-based studies.

Dose escalation in the radiotherapy of non-small-cell lung cancer with aperture-based intensity modulation and photon beam energy optimization for non-preselected patients.

PURPOSE: To verify the potential of aperture-based intensity-modulated radiotherapy (AB-IMRT) to realize dose escalation plans for non-preselected non-small-cell lung cancer (NSCLC) patients, using photon beam energy optimization. METHODS AND MATERIALS: Seven cases of NSCLC were retrospectively studied. Clinical reference plans were made at 60 Gy by an experienced dosimetrist. Dose escalation was applied to PTV2, a subvolume within the main PTV1. Escalation plans were optimized by considering beam angles (table and gantry), energy (6 and 23 MV) and weights, for an increasing dose to the PTV2, starting from 66 Gy and keeping 30 fractions. RESULTS: In five cases, doses over 78 Gy could be achieved before exceeding organs at risk (OARs) standard tolerance. Peripheral overdosages, as well as lung and spinal cord tolerance doses, limited escalation. Means+/-SD V(95%) parameters were (97.3+/-0.9)% for PTV1s and (96.7+/-2.2)% for PTV2s. Doses to OARs were also maintained at acceptable levels. Optimized plans made use of both low- and high-energy beams and had a similar number of monitor units compared to the 60 Gy clinical plans. CONCLUSIONS: The AB-IMRT system can successfully realize dose escalation for a sizeable number of cases. Plans produced contained few large segments, and are applicable to a wide range of tumor volumes and locations.

Intervals longer than 20 weeks from breast-conserving surgery to radiation therapy are associated with inferior outcome for women with early-stage breast cancer who are not receiving chemotherapy.

PURPOSE: To determine the interval from breast-conserving surgery (BCS) to radiation therapy (RT) that affects local control or survival. PATIENTS AND METHODS: The 10-year Kaplan-Meier (KM) local recurrence-free survival (LRFS), distant recurrence-free survival (DRFS), and breast cancer-specific survival (BCSS) were computed for 6,428 women who had T1 to 2, N0 to 1, M0 breast cancer that was diagnosed in British Columbia between 1989 and 2003, and who were treated with BCS and RT without chemotherapy. Intervals from BCS to RT were grouped by weeks as follows: < or = 4 (n = 83), greater than 4 to 8 (n = 2,288; reference group); greater than 8 to 12 (n = 2,606); greater than 12 to 16 (n = 961); greater than 16 to 20 (n = 358); and greater than 20 weeks (n = 132). Cox proportional hazards models and matching were used to control for confounding variables. RESULTS: The median follow-up time was 7.5 years. The 10-year KM outcomes were as follows: LRFS, 95.4%; DRFS, 90.5%; and BCSS, 92.5%. Compared with the greater than 4 to 8 weeks group, hazard ratios (HR) were not significantly different for any outcome among patients who were treated up to 20 weeks after BCS. However, LRFS (hazard ratio [HR], 2.00; P = .15), DRFS (HR, 1.86; P = .02) and BCSS (HR, 2.15; P = .009) were inferior for women with BCS-to-RT intervals greater than 20 weeks compared with those greater than 4 to 8 weeks. The matched analysis yielded similar results. CONCLUSION: Outcomes were statistically similar for BCS-to-RT intervals up to 20 weeks, but they were inferior for intervals beyond 20 weeks. Time can be reasonably allowed for the breast to heal and for patients to consider treatment options, but RT should start within 20 weeks of BCS.

Brain metastasis is an early manifestation of distant failure in stage III nonsmall cell lung cancer patients treated with radical chemoradiation therapy.

OBJECTIVES: To evaluate the patterns of distant relapse, focusing on brain metastasis, in patients with stage III nonsmall cell lung cancer (NSCLC) treated with radical chemoradiation therapy (CRT). METHODS: The British Columbia Cancer Agency provincial database identified 2268 patients presenting with stage III NSCLC between January 1, 1990 and December 31, 2000. Of these, 120 patients received radical CRT, forming the study cohort. Variables analyzed included gender, age, Eastern Cooperative Oncology Group performance status, stage, histology, sites of metastasis, and survival. Univariate and multivariate analyses were performed. RESULTS: The study cohort comprised 59 men and 61 women, median age 54.5 years. There were 74 stage IIIA and 46 stage IIIB cases. Histologic subtypes were squamous cell carcinoma (n = 29), adenocarcinoma (n = 53), and other non-squamous histologies (n = 38). Median follow-up time was 17.7 months. Median overall survival time was 19.2 months. Thirty-two patients (27%) developed brain metastasis. Non-brain metastases occurred in 51 patients (42%). No variables were statistically significantly associated with the risk of developing brain metastasis. Trends for higher risks of brain metastasis were observed with younger age (P = 0.09), and poor performance status (P = 0.07). Brain metastasis risk was highest during the first 10 months, progressively declining thereafter. CONCLUSIONS: Stage III NSCLC patients treated with CRT have high risks of brain metastasis which persist during the first 10 months after diagnosis. Studies evaluating cranial prophylaxis will be relevant for these patients, particularly during this early period. Novel systemic therapies continue to be needed because non-brain metastases still represent the majority of distant recurrences.

Individualized margins in 3D conformal radiotherapy planning for lung cancer: analysis of physiological movements and their dosimetric impacts.

In conformal radiotherapy planning for lung cancer, respiratory movements are not taken into account when a single computed tomography (CT) scan is performed. This study examines tumor movements to design individualized margins to account for these movements and evaluates their dosimetric impacts on planning volume. Fifteen patients undergoing CT-based planning for radical radiotherapy for localized lung cancer formed the study cohort. A reference plan was constructed based on reference gross, clinical, and planning target volumes (rGTV, rCTV, and rPTV, respectively). The reference plans were compared with individualized plans using individualized margins obtained by using 5 serial CT scans to generate individualized target volumes (iGTV, iCTV, and iPTV). Three-dimensional conformal radiation therapy was used for plan generation using 6- and 23-MV photon beams. Ten plans for each patient were generated and dose-volume histograms (DVHs) were calculated. Comparisons of volumetric and dosimetric parameters were performed using paired Student t-tests. Relative to the rGTV, the total volume occupied by the superimposed GTVs increased progressively with each additional CT scans. With the use of all 5 scans, the average increase in GTV was 52.1%. For the plans with closest dosimetric coverage, target volume was smaller (iPTV/rPTV ratio 0.808) but lung irradiation was only slightly decreased. Reduction in the proportion of lung tissue that received 20 Gy or more outside the PTV (V20) was observed both for 6-MV plans (-0.73%) and 23-MV plans (-0.65%), with p = 0.02 and p = 0.04, respectively. In conformal RT planning for the treatment of lung cancer, the use of serial CT scans to evaluate respiratory motion and to generate individualized margins to account for these motions produced only a limited lung sparing advantage.