Diagnostic Performance of Magnetic Resonance Imaging and Computed Tomography for Advanced Retinoblastoma: A Systematic Review and Meta-analysis.

PURPOSE: To determine and compare the diagnostic performance of magnetic resonance imaging (MRI) and computed tomography (CT) for the diagnosis of tumor extent in advanced retinoblastoma, using histopathologic analysis as the reference standard. DESIGN: Systematic review and meta-analysis. PARTICIPANTS: Patients with advanced retinoblastoma who underwent MRI, CT, or both for the detection of tumor extent from published diagnostic accuracy studies. METHODS: Medline and Embase were searched for literature published through April 2013 assessing the diagnostic performance of MRI, CT, or both in detecting intraorbital and extraorbital tumor extension of retinoblastoma. Diagnostic accuracy data were extracted from included studies. Summary estimates were based on a random effects model. Intrastudy and interstudy heterogeneity were analyzed. MAIN OUTCOME MEASURES: Sensitivity and specificity of MRI and CT in detecting tumor extent. RESULTS: Data of the following tumor-extent parameters were extracted: anterior eye segment involvement and ciliary body, optic nerve, choroidal, and (extra)scleral invasion. Articles on MRI reported results of 591 eyes from 14 studies, and articles on CT yielded 257 eyes from 4 studies. The summary estimates with their 95% confidence intervals (CIs) of the diagnostic accuracy of conventional MRI at detecting postlaminar optic nerve, choroidal, and scleral invasion showed sensitivities of 59% (95% CI, 37%-78%), 74% (95% CI, 52%-88%), and 88% (95% CI, 20%-100%), respectively, and specificities of 94% (95% CI, 84%-98%), 72% (95% CI, 31%-94%), and 99% (95% CI, 86%-100%), respectively. Magnetic resonance imaging with a high (versus a low) image quality showed higher diagnostic accuracies for detection of prelaminar optic nerve and choroidal invasion, but these differences were not statistically significant. Studies reporting the diagnostic accuracy of CT did not provide enough data to perform any meta-analyses. CONCLUSIONS: Magnetic resonance imaging is an important diagnostic tool for the detection of local tumor extent in advanced retinoblastoma, although its diagnostic accuracy shows room for improvement, especially with regard to sensitivity. With only a few-mostly old-studies, there is very little evidence on the diagnostic accuracy of CT, and generally these studies show low diagnostic accuracy. Future studies assessing the role of MRI in clinical decision making in terms of prognostic value for advanced retinoblastoma are needed.

A phase 1b study of humanized KS-interleukin-2 (huKS-IL2) immunocytokine with cyclophosphamide in patients with EpCAM-positive advanced solid tumors.

BACKGROUND: Humanized KS-interleukin-2 (huKS-IL2), an immunocytokine with specificity for epithelial cell adhesion molecule (EpCAM), has demonstrated favorable tolerability and immunologic activity as a single agent. METHODS: Phase 1b study in patients with EpCAM-positive advanced solid tumors to determine the maximum tolerated dose (MTD) and safety profile of huKS-IL2 in combination with low-dose cyclophosphamide. Treatment consisted of cyclophosphamide (300 mg/m2 on day 1), and escalating doses of huKS-IL2 (0.5-4.0 mg/m2 IV continuous infusion over 4 hours) on days 2, 3, and 4 of each 21-day cycle. Safety, pharmacokinetic profile, immunogenicity, anti-tumor and biologic activity were evaluated. RESULTS: Twenty-seven patients were treated for up to 6 cycles; 26 were evaluable for response. The MTD of huKS-IL2 in combination with 300 mg/m2 cyclophosphamide was 3.0 mg/m2. At higher doses, myelosuppression was dose-limiting. Transient lymphopenia was the most common grade 3/4 adverse event (AE). Other significant AEs included hypotension, hypophosphatemia, and increase in serum creatinine. All patients recovered from these AEs. The huKS-IL2 exposure was dose-dependent, but not dose-proportional, accumulation was negligible, and elimination half-life and systemic clearance were independent of dose and time. Most patients had a transient immune response to huKS-IL2. Immunologic activity was observed at all doses. Ten patients (38%) had stable disease as best response, lasting for ≥ 4 cycles in 3 patients. CONCLUSION: The combination of huKS-IL2 with low-dose cyclophosphamide was well tolerated. Although no objective responses were observed, the combination showed evidence of immunologic activity and 3 patients showed stable disease for ≥ 4 cycles. TRIAL REGISTRATION: http://NCT00132522.

Wear of two artificial tooth materials in vivo: a 12-month pilot study.

STATEMENT OF PROBLEM: Wear of methacrylate artificial teeth resulting in vertical loss is a problem for both dentists and patients. PURPOSE: The purpose of this study was to quantify wear of artificial teeth in vivo and to relate it to subject and tooth variables. MATERIAL AND METHODS: Twenty-eight subjects treated with complete dentures received 2 artificial tooth materials (polymethyl methacrylate (PMMA)/double-cross linked PMMA fillers; 35%/59% (SR Antaris DCL, SR Postaris DCL); experimental 48%/46%). At baseline and after 12 months, impressions of the dentures were poured with improved stone. After laser scanning, the casts were superimposed and matched. Maximal vertical loss (mm) and volumetric loss (mm(3)) were calculated for each tooth and log-transformed to reduce variability. Volumetric loss was related to the occlusally active surface area. Linear mixed models were used to study the influence of the factors jaw, tooth, and material on adjusted (residual) wear values (alpha=.05). RESULTS: Due to drop outs (n=5) and unmatchable casts (n=3), 69% of all teeth were analyzed. Volumetric loss had a strong linear relationship to surface area (P<.001); this was less pronounced for vertical loss (P=.004). The factor showing the highest influence was the subject. Wear was tooth dependent (increasing from incisors to molars). However, these differences diminished once the wear rates were adjusted for occlusal area, and only a few remained significant (anterior versus posterior maxillary teeth). Another influencing factor was the age of the subject. CONCLUSIONS: Clinical wear of artificial teeth is higher than previously measured or expected. The presented method of analyzing wear of artificial teeth using a laser-scanning device seemed suitable.

Absence of progression as assessed by response evaluation criteria in solid tumors predicts survival in advanced GI stromal tumors treated with imatinib mesylate: the intergroup EORTC-ISG-AGITG phase III trial.

PURPOSE: From February 2001 to February 2002, 946 patients with advanced GI stromal tumors (GISTs) treated with imatinib were included in a controlled EORTC/ISG/AGITG (European Organisation for Research and Treatment of Cancer/Italian Sarcoma Group/Australasian Gastro-Intestinal Trials Group) trial. This analysis investigates whether the response classification assessed by RECIST (Response Evaluation Criteria in Solid Tumors), predicts for time to progression (TTP) and overall survival (OS). PATIENTS AND METHODS: Per protocol, the first three disease assessments were done at 2, 4, and 6 months. For the purpose of the analysis (landmark method), disease response was subclassified in six categories: partial response (PR; > 30% size reduction), minor response (MR; 10% to 30% reduction), no change (NC) as either NC- (0% to 10% reduction) or NC+ (0% to 20% size increase), progressive disease (PD; > 20% increase/new lesions), and subjective PD (clinical progression). RESULTS: A total of 906 patients had measurable disease at entry. At all measurement time points, complete response (CR), PR, and MR resulted in similar TTP and OS; this was also true for NC- and NC+, and for PD and subjective PD. Patients were subsequently classified as responders (CR/PR/MR), NC (NC+/NC-), or PD. This three-class response categorization was found to be highly predictive of further progression or survival for the first two measurement points. After 6 months of imatinib, responders (CR/PR/MR) had the same survival prognosis as patients classified as NC. CONCLUSION: RECIST perfectly enables early discrimination between patients who benefited long term from imatinib and those who did not. After 6 months of imatinib, if the patient is not experiencing PD, the pattern of radiologic response by tumor size criteria has no prognostic value for further outcome. Imatinib needs to be continued as long as there is no progression according to RECIST.

Surface deterioration of dental materials after simulated toothbrushing in relation to brushing time and load.

OBJECTIVES: (1) To evaluate the changes in surface roughness and gloss after simulated toothbrushing of 9 composite materials and 2 ceramic materials in relation to brushing time and load in vitro; (2) to assess the relationship between surface gloss and surface roughness. METHODS: Eight flat specimens of composite materials (microfilled: Adoro, Filtek Supreme, Heliomolar; microhybrid: Four Seasons, Tetric EvoCeram; hybrid: Compoglass F, Targis, Tetric Ceram; macrohybrid: Grandio), two ceramic materials (IPS d.SIGN and IPS Empress polished) were fabricated according to the manufacturer's instructions and optimally polished with up to 4000 grit SiC. The specimens were subjected to a toothbrushing (TB) simulation device (Willytec) with rotating movements, toothpaste slurry and at three different loads (100g/250g/350g). At hourly intervals from 1h to 10h TB, mean surface roughness Ra was measured with an optical sensor and the surface gloss (Gl) with a glossmeter. Statistical analysis was performed for log-transformed Ra data applying two-way ANOVA to evaluate the interaction between load and material and load and brushing time. RESULTS: There was a significant interaction between material and load as well as between load and brushing time (p<0.0001). The microhybrid and hybrid materials demonstrated more surface deterioration with higher loads, whereas with the microfilled resins Heliomolar and Adoro it was vice versa. For ceramic materials, no or little deterioration was observed over time and independent of the load. The ceramic materials and 3 of the composite materials (roughness) showed no further deterioration after 5h of toothbrushing. Mean surface gloss was the parameter which discriminated best between the materials, followed by mean surface roughness Ra. There was a strong correlation between surface gloss and surface roughness for all the materials except the ceramics. The evaluation of the deterioration curves of individual specimens revealed a more or less synchronous course suspecting hinting specific external conditions and not showing the true variability in relation to the tested material. SIGNIFICANCE: The surface roughness and gloss of dental materials changes with brushing time and load and thus results in different material rankings. Apart from Grandio, the hybrid composite resins were more prone to surface changes than microfilled composites. The deterioration potential of a composite material can be quickly assessed by measuring surface gloss. For this purpose, a brushing time of 10h (=72,000 strokes) is needed. In further comparative studies, specimens of different materials should be tested in one series to estimate the true variability.

How Much Chemotherapy Are Patients With Advanced Pancreatic Cancer Receiving at the End of Life?

Background: Advanced pancreatic adenocarcinoma (APC) is a chemoresistant cancer with poor prognosis. We evaluated the use of chemotherapy in the last months of life.Methods: Retrospective analysis of patients with APC treated from 1993 to 2010 at the Oncology Institute of Southern Switzerland. Clinical and laboratory parameters starting from 28 days prior to the last administration of chemotherapy were recorded, including ECOG performance status, presence of ascites, haemoglobin (Hb), white blood cell (WBC) count, platelets, total bilirubin, albumin, LDH, C-reactive protein (C-rp) and Ca 19.9.Results: The characteristics of the 231 patients were: males/females 53%/47%; metastatic/locally advanced disease 80%/20%; median age 66 years (range 32−85). Median overall survival calculated from diagnosis was 6.1 months (95% CI: 5.1−7.2); death was due to disease progression in all cases. At last chemotherapy administration, ECOG performance status was 0−1 in 38% and 2−3 in 62%. Fifty-nine percent of pts received first-line chemotherapy only (gemcitabine in 70%; gemcitabine-based doublets or 5FU in 30%), whilst 32%, 8% and 1% had second- (5FU 37%; oxaliplatinbased doublets 57%; phase I trial 6%), third- and fourth-line therapy (single agent or phase I trial), respectively. The interval between last chemotherapy administration and death was <4 weeks in 24%, _4−12 weeks in 47% and >12 weeks in 29%. Table 1 summarizes the proportion of patients treated according to the interval between last chemotherapy and death refered to chemotherapy line. Median survival from last chemotherapy delivery to death was 7.5 weeks (95% CI 6.7−8.4). In univariate analysis, presence of ascites, elevated WBC, total bilirubin, LDH, C-rp and Ca 19.9, and reduced albumin were found to predict shorter survival (p < 0.05 for each). However, none of them was an independent predictor in the multivariate analysis.Conclusions: A significant proportion of patients with APC received chemotherapy in the last months of life. In our study, none of the clinical and laboratory parameters recorded 28 days priorto the last chemotherapy delivery were found to predict survival.

Ranibizumab in the management of advanced Coats disease Stages 3B and 4: long-term outcomes.

BACKGROUND: Laser photocoagulation and cryotherapy to completely destroy telangiectatic vessels and ischemic retina in Coats disease is barely applicable in advanced cases with total retinal detachment, and globe survival is notoriously poor in Stages 3B and 4. Anti-vascular endothelial growth factor intravitreal injections may offer new prospects for these patients. METHODS: This study is a retrospective review of all consecutive patients with Coats disease treated with neoadjuvant or adjuvant intravitreal ranibizumab plus conventional and amblyopia treatment as appropriate. RESULTS: Nine patients (median age, 13 months) presenting Coats Stages 3B and 4 (5 and 4 eyes, respectively) were included. Iris neovascularization resolved within 2 weeks and retinal reapplication within 4 months in all patients. At last follow-up, globe survival was 100% with anatomical success in 8 of the 9 eyes. With a median follow-up of 50 months, fibrotic vitreoretinopathy was developed in 5 of the 9 cases, one leading to tractional retinal detachment and ultimately phthisis bulbi. The remaining 4 of the 9 eyes achieved some vision (range, 0.02-0.063). CONCLUSION: To the best of the authors' knowledge, this is the largest reported series of late-stage Coats undergoing anti-vascular endothelial growth factor therapy, a homogenous cohort of patients treated with a single agent and with the longest follow-up. This study supports the role of ranibizumab in advanced disease by transient restoration of the hemato-retinal barrier and suppression of neovascularization to facilitate classic treatment. At the last follow-up, the authors report unprecedented anatomical success and functional outcome.

High-resolution 3D whole-heart coronary MRA: a study on the combination of data acquisition in multiple breath-holds and 1D residual respiratory motion compensation.

OBJECT: To study a scan protocol for coronary magnetic resonance angiography based on multiple breath-holds featuring 1D motion compensation and to compare the resulting image quality to a navigator-gated free-breathing acquisition. Image reconstruction was performed using L1 regularized iterative SENSE. MATERIALS AND METHODS: The effects of respiratory motion on the Cartesian sampling scheme were minimized by performing data acquisition in multiple breath-holds. During the scan, repetitive readouts through a k-space center were used to detect and correct the respiratory displacement of the heart by exploiting the self-navigation principle in image reconstruction. In vivo experiments were performed in nine healthy volunteers and the resulting image quality was compared to a navigator-gated reference in terms of vessel length and sharpness. RESULTS: Acquisition in breath-hold is an effective method to reduce the scan time by more than 30 % compared to the navigator-gated reference. Although an equivalent mean image quality with respect to the reference was achieved with the proposed method, the 1D motion compensation did not work equally well in all cases. CONCLUSION: In general, the image quality scaled with the robustness of the motion compensation. Nevertheless, the featured setup provides a positive basis for future extension with more advanced motion compensation methods.

Introducing systematic dispatcher-assisted cardiopulmonary resuscitation (telephone-CPR) in a non-Advanced Medical Priority Dispatch System (AMPDS): implementation process and costs.

OBJECTIVE: In order to improve the quality of our Emergency Medical Services (EMS), to raise bystander cardiopulmonary resuscitation rates and thereby meet what is becoming a universal standard in terms of quality of emergency services, we decided to implement systematic dispatcher-assisted or telephone-CPR (T-CPR) in our medical dispatch center, a non-Advanced Medical Priority Dispatch System. The aim of this article is to describe the implementation process, costs and results following the introduction of this new "quality" procedure. METHODS: This was a prospective study. Over an 8-week period, our EMS dispatchers were given new procedures to provide T-CPR. We then collected data on all non-traumatic cardiac arrests within our state (Vaud, Switzerland) for the following 12months. For each event, the dispatchers had to record in writing the reason they either ruled out cardiac arrest (CA) or did not propose T-CPR in the event they did suspect CA. All emergency call recordings were reviewed by the medical director of the EMS. The analysis of the recordings and the dispatchers' written explanations were then compared. RESULTS: During the 12-month study period, a total of 497 patients (both adults and children) were identified as having a non-traumatic cardiac arrest. Out of this total, 203 cases were excluded and 294 cases were eligible for T-CPR. Out of these eligible cases, dispatchers proposed T-CPR on 202 occasions (or 69% of eligible cases). They also erroneously proposed T-CPR on 17 occasions when a CA was wrongly identified (false positive). This represents 7.8% of all T-CPR. No costs were incurred to implement our study protocol and procedures. CONCLUSIONS: This study demonstrates it is possible, using a brief campaign of sensitization but without any specific training, to implement systematic dispatcher-assisted cardiopulmonary resuscitation in a non-Advanced Medical Priority Dispatch System such as our EMS that had no prior experience with systematic T-CPR. The results in terms of T-CPR delivery rate and false positive are similar to those found in previous studies. We found our results satisfying the given short time frame of this study. Our results demonstrate that it is possible to improve the quality of emergency services at moderate or even no additional costs and this should be of interest to all EMS that do not presently benefit from using T-CPR procedures. EMS that currently do not offer T-CPR should consider implementing this technique as soon as possible, and we expect our experience may provide answers to those planning to incorporate T-CPR in their daily practice.

An European Organisation for Research and Treatment of Cancer phase I study of lapatinib and docetaxel as neoadjuvant treatment for Human Epidermal Growth Factor Receptor 2 (HER2) positive locally-advanced/inflammatory or large operable breast cancer.

BACKGROUND: Lapatinib is an effective anti-HER2 therapy in advanced breast cancer and docetaxel is one of the most active agents in breast cancer. Combining these agents in pre-treated patients with metastatic disease had previously proved challenging, so the primary objective of this study aimed to determine the maximum tolerated dose (MTD) in treatment-naive patients, by identifying acute dose-limiting toxicities (DLT) during cycle 1 in the first part of a phases 1-2 neoadjuvant European Organisation for Research and Treatment of Cancer (EORTC) trial. PATIENTS AND METHODS: Patients with large operable or locally-advanced HER2 positive breast cancer were treated with continuous lapatinib, and docetaxel every 21days for 4 cycles. Dose levels (DLs) were: 1000/75, 1250/75, 1000/85, 1250/85, 1000/100 and 1250/100 (mg/day)/(mg/m(2)). RESULTS: Twenty-one patients were included. Two DLTs occurred at dose level 5 (1000/100); one grade 4 neutropenia ⩾7days and one febrile neutropenia. A further 3 patients were therefore treated at the same dose with prophylactic granulocyte-colony stimulating factor (G-CSF), and 3 patients at dose level 6. No further DLTs were observed. CONCLUSIONS: Our recommended dose for phase II is lapatinib 1000mg/day and docetaxel 100mg/m(2) with G-CSF in HER2 positive non-metastatic breast cancer. The dose of lapatinib should have been 1250mg/day but we were mindful of the high rate of treatment discontinuation in GeparQuinto with lapatinib 1250mg/day combined with docetaxel. No grade 3-4 diarrhoea was observed. Pharmacodynamics analysis suggests that concomitant medications altering P-glycoprotein activity (in addition to lapatinib) can modify toxicity, including non-haematological toxicities. This needs verification in larger trials, where it may contribute to understanding the sources of variability in clinical toxicity and treatment discontinuation.

KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours.

A recent randomized EORTC phase III trial, comparing two doses of imatinib in patients with advanced gastrointestinal stromal tumours (GISTs), reported dose dependency for progression-free survival. The current analysis of that study aimed to assess if tumour mutational status correlates with clinical response to imatinib. Pre-treatment samples of GISTs from 377 patients enrolled in phase III study were analyzed for mutations of KIT or PDGFRA by combination of D-HPLC and direct sequencing of tumour genomic DNA. Mutation types were correlated with patients' survival data. The presence of exon 9-activating mutations in KIT was the strongest adverse prognostic factor for response to imatinib, increasing the relative risk of progression by 171% (P&lt;0.0001) and the relative risk of death by 190% (P&lt;0.0001) when compared with KIT exon 11 mutants. Similarly, the relative risk of progression was increased by 108% (P&lt;0.0001) and the relative risk of death by 76% (P=0.028) in patients without detectable KIT or PDGFRA mutations. In patients whose tumours expressed an exon 9 KIT oncoprotein, treatment with the high-dose regimen resulted in a significantly superior progression-free survival (P=0.0013), with a reduction of the relative risk of 61%. We conclude that tumour genotype is of major prognostic significance for progression-free survival and overall survival in patients treated with imatinib for advanced GISTs. Our findings suggest the need for differential treatment of patients with GISTs, with KIT exon 9 mutant patients benefiting the most from the 800 mg daily dose of the drug.