Objective
To assess the feasibility and preliminary efficacy of adding cetuximab to standard chemoradiotherapy for muscle‐invasive bladder cancer.
Patients and Methods
TUXEDO was a prospective, ...single‐arm, open‐label, phase I/II trial conducted in six UK hospitals. Cetuximab was administered with an initial loading dose of 400 mg/m2 on Day 1 of Week −1, and then seven weekly doses of 250 mg/m2. The radiotherapy schedule was 64 Gy/32F with Day 1 mitomycin C (12 g/m2) and 5‐fluorouracil (500 mg/m2/day) over Days 1–5 and Days 22–26. Patients with T2‐4aN0M0 urothelial cancer and a performance status of 0–1 were eligible. Prior neoadjuvant therapy was permitted. The Phase I primary outcome was impact on radiotherapy treatment completion and toxicity experienced during treatment. The Phase II primary outcome was local control at 3 months post treatment.
Results
Between September 2012 and October 2016, 33 patients were recruited; seven in Phase I, 26 in Phase II. Three patients in Phase II were subsequently deemed ineligible and received no trial therapy. Eight patients discontinued cetuximab due to adverse effects. The patients’ median (range) age was 70.1 (60.6–75.1) years, 20 had a performance status of 0, 27 were male and 26 had already received neoadjuvant chemotherapy. In Phase I, all patients completed planned radiotherapy, with no delays or dose reductions. Of the 30 evaluable patients in Phase II, 25 had confirmed local control 3 months after treatment (77%, 95% confidence interval 58–90). During the trial there were 18 serious adverse events. The study was halted due to slow accrual.
Conclusion
Phase I data demonstrate it is feasible and safe to add cetuximab to chemoradiotherapy. Exploratory analysis of Phase II data provides evidence to consider further clinical evaluation of cetuximab in this setting.
Protein N-termini provide uniquely reactive motifs for single site protein modification. Though a number of reactions have been developed to target this site, the selectivity, generality, and ...stability of the conjugates formed has not been studied. We have therefore undertaken a comprehensive comparative study of the most promising methods for N-terminal protein modification, and find that there is no one size fits all approach, necessitating reagent screening for a particular protein or application. Moreover, we observed limited stability in all cases, leading to a need for continued innovation and development in the bioconjugation field.
Protein N-termini provide uniquely reactive motifs for single site protein modification. A comprehensive comparative study of the most promising modification reagents is performed, finding that there is no one size fits all approach.
Purpose Systemic Therapy for Advanced or Metastatic Prostate Cancer: Evaluation of Drug Efficacy is a randomized controlled trial using a multiarm, multistage, platform design. It recruits men with ...high-risk, locally advanced or metastatic prostate cancer who were initiating long-term hormone therapy. We report survival data for two celecoxib (Cel)-containing comparisons, which stopped accrual early at interim analysis on the basis of failure-free survival. Patients and Methods Standard of care (SOC) was hormone therapy continuously (metastatic) or for ≥ 2 years (nonmetastatic); prostate (± pelvic node) radiotherapy was encouraged for men without metastases. Cel 400 mg was administered twice a day for 1 year. Zoledronic acid (ZA) 4 mg was administered for six 3-weekly cycles, then 4-weekly for 2 years. Stratified random assignment allocated patients 2:1:1 to SOC (control), SOC + Cel, or SOC + ZA + Cel. The primary outcome measure was all-cause mortality. Results were analyzed with Cox proportional hazards and flexible parametric models adjusted for stratification factors. Results A total of 1,245 men were randomly assigned (Oct 2005 to April 2011). Groups were balanced: median age, 65 years; 61% metastatic, 14% N+/X M0, 25% N0M0; 94% newly diagnosed; median prostate-specific antigen, 66 ng/mL. Median follow-up was 69 months. Grade 3 to 5 adverse events were seen in 36% SOC-only, 33% SOC + Cel, and 32% SOC + ZA + Cel patients. There were 303 control arm deaths (83% prostate cancer), and median survival was 66 months. Compared with SOC, the adjusted hazard ratio was 0.98 (95% CI, 0.80 to 1.20; P = .847; median survival, 70 months) for SOC + Cel and 0.86 (95% CI, 0.70 to 1.05; P =.130; median survival, 76 months) for SOC + ZA + Cel. Preplanned subgroup analyses in men with metastatic disease showed a hazard ratio of 0.78 (95% CI, 0.62 to 0.98; P = .033) for SOC + ZA + Cel. Conclusion These data show no overall evidence of improved survival with Cel. Preplanned subgroup analyses provide hypotheses for future studies.
The natural history of patients with newly diagnosed high-risk nonmetastatic (M0) prostate cancer receiving hormone therapy (HT) either alone or with standard-of-care radiotherapy (RT) is not well ...documented. Furthermore, no clinical trial has assessed the role of RT in patients with node-positive (N+) M0 disease. The STAMPEDE Trial includes such individuals, allowing an exploratory multivariate analysis of the impact of radical RT.
To describe survival and the impact on failure-free survival of RT by nodal involvement in these patients.
Cohort study using data collected for patients allocated to the control arm (standard-of-care only) of the STAMPEDE Trial between October 5, 2005, and May 1, 2014. Outcomes are presented as hazard ratios (HRs) with 95% CIs derived from adjusted Cox models; survival estimates are reported at 2 and 5 years. Participants were high-risk, hormone-naive patients with newly diagnosed M0 prostate cancer starting long-term HT for the first time. Radiotherapy is encouraged in this group, but mandated for patients with node-negative (N0) M0 disease only since November 2011.
Long-term HT either alone or with RT, as per local standard. Planned RT use was recorded at entry.
Failure-free survival (FFS) and overall survival.
A total of 721 men with newly diagnosed M0 disease were included: median age at entry, 66 (interquartile range IQR, 61-72) years, median (IQR) prostate-specific antigen level of 43 (18-88) ng/mL. There were 40 deaths (31 owing to prostate cancer) with 17 months' median follow-up. Two-year survival was 96% (95% CI, 93%-97%) and 2-year FFS, 77% (95% CI, 73%-81%). Median (IQR) FFS was 63 (26 to not reached) months. Time to FFS was worse in patients with N+ disease (HR, 2.02 95% CI, 1.46-2.81) than in those with N0 disease. Failure-free survival outcomes favored planned use of RT for patients with both N0M0 (HR, 0.33 95% CI, 0.18-0.61) and N+M0 disease (HR, 0.48 95% CI, 0.29-0.79).
Survival for men entering the cohort with high-risk M0 disease was higher than anticipated at study inception. These nonrandomized data were consistent with previous trials that support routine use of RT with HT in patients with N0M0 disease. Additionally, the data suggest that the benefits of RT extend to men with N+M0 disease.
clinicaltrials.gov Identifier: NCT00268476; ISRCTN78818544.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra. This loss leads to complete dopamine depletion in the ...striatum and severe motor impairment. It has been demonstrated previously that a lentiviral vector system based on equine infectious anemia virus (EIAV) gives rise to highly efficient and sustained transduction of neurons in the rat brain. Therefore, a dopamine replacement strategy using EIAV has been investigated as a treatment in the 6-hydroxydopamine (6-OHDA) animal model of PD. A self-inactivating EIAV minimal lentiviral vector that expresses tyrosine hydroxylase (TH), aromatic amino acid dopa decarboxylase (AADC), and GTP cyclohydrolase 1 (CH1) in a single transcription unit has been generated. In cultured striatal neurons transduced with this vector, TH, AADC, and CH1 proteins can all be detected. After stereotactic delivery into the dopamine-denervated striatum of the 6-OHDA-lesioned rat, sustained expression of each enzyme and effective production of catecholamines were detected, resulting in significant reduction of apomorphine-induced motor asymmetry compared with control animals (p < 0.003). Expression of each enzyme in the striatum was observed for up to 5 months after injection. These data indicate that the delivery of three catecholaminergic synthetic enzymes by a single lentiviral vector can achieve functional improvement and thus open the potential for the use of this vector for gene therapy of late-stage PD patients.
Abstract
Alkaline magmatism develops in the rear arc area of Java, Sunda Arc, at different range of slab depth; ~270-580 km in central section and ~150 km in the east. We collate published ...geochemical data of volcanic rocks from four alkaline volcanoes (Muria, Lasem, Bawean, and Ringgit-Beser) and perform statistical analysis to evaluate geochemical characteristics of each suite. A set of major and trace elements is scaled and transformed using principal component analysis (PCA) and then followed by implementation of k-means algorithm to cluster the data points based on Euclidian distances. K-means clustering of the dataset suggests that Central Java alkalines are most elevated in K
2
O and total alkali. The algorithm further suggests that Muria samples can be clustered into two, owing to these components. These two clusters, however, are not well reflected on trace element-based clustering. Lasem volcanics show distinct cluster high in Na
2
O/K
2
O and SiO
2
, while Bawean samples are mixed into both Muria clusters. Ringgit-Beser alkalines show two distinct clusters tied to MgO and enrichment in Ba, Rb, and Sr. Our findings suggest that the potassium and LILE enrichment in these alkaline rocks is independent of slab depth and is most likely regulated by tectonic-related arc segmentation in Java subduction zone.
Atypical fibroxanthoma and malignant fibrous histiocytoma Withers, Aaron H.J; Brougham, Nicholas D.L; Barber, Rachel M ...
Journal of plastic, reconstructive & aesthetic surgery,
11/2011, Letnik:
64, Številka:
11
Journal Article
Recenzirano
Summary Background Atypical fibroxanthoma (AFX) and malignant fibrous histiocytoma (MFH) are soft-tissue tumours with variable aggressiveness. There is considerable debate about the relationship ...between these lesions, as histological and immunochemical differentiation is difficult. Methods Current opinions and evidence for diagnostic differences between AFX and MFH were reviewed. Consecutive cases of AFX and MFH were identified from our non-melanoma skin cancer (NMSC) database 1996–2007 for the Central Region of New Zealand. Results Of the 50 411 NMSC lesions excised surgically from 26 138 patients, there were 101 AFX and 15 MFH cases. Three MFH cases were originally diagnosed as AFX. AFX and MFH share similar patient demographics, size and location and histological and immunohistochemical features. Most diagnostic biopsies of AFX were not followed by formal excision. Incomplete excision occurred in a large proportion of patients with AFX, which often did not proceed to re-excision, resulting in local recurrence. Cases of MFH generally underwent definitive treatment including re-excision if incompletely excised, and postoperative adjuvant radiotherapy. Conclusions The failure to treat AFX adequately may have resulted from the lack of appreciation of its aggressiveness. Contrary to the literature, we found few clinical differences between AFX and MFH. AFX and MFH also share similar histologic features and there are no immunohistochemical markers that reliably distinguish them. AFX is best considered a distinct entity with MFH, now reclassified as an undifferentiated pleomorphic sarcoma.
In this report it is demonstrated for the first time that rabies-G envelope of the rabies virus is sufficient to confer retrograde axonal transport to a heterologous virus/vector. After delivery of ...rabies-G pseudotyped equine infectious anaemia virus (EIAV) based vectors encoding a marker gene to the rat striatum, neurons in regions distal from but projecting to the injection site, such as the dopaminergic neurons of the substantia nigra pars compacta, become transduced. This retrograde transport to appropriate distal neurons was also demonstrated after delivery to substantia nigra, hippocampus and spinal cord and did not occur when vesicular stomatitis virus glycoprotein (VSV-G) pseudotyped vectors were delivered to these sites. In addition, peripheral administration of rabies-G pseudotyped vectors to the rat gastrocnemius muscle leads to gene transfer in motoneurons of lumbar spinal cord. In contrast the same vector pseudotyped with VSV-G transduced muscle cells surrounding the injection site, but did not result in expression in any cells in the spinal cord. Long-term expression was observed after gene transfer in the nervous system and a minimal immune response which, together with the possibility of non-invasive administration, greatly extends the utility of lentiviral vectors for gene therapy of human neurological disease.
Copper, obtained from porphyry deposits formed in arc settings, is a critical resource, and is primarily sourced from magmas. However, the processes that shape the copper contents of arc magmas are ...up for debate. Existing models place emphasis on different petrological agents that explain large-scale trends in copper systematics. Previous studies have noted the ’Cu paradox,’ where the magmas with high Sr/Y ratios, indicative of ore-forming potential, have the lowest copper concentrations. Here we compile a multidimensional database of volcanic whole rock compositions and couple it with simple petrological models to elucidate the controls on volcanic whole rock compositions with respect to Cu. We show that calc-alkaline, high Sr/Y magmas undergo major element modification caused by extensive amphibole and/or garnet fractionation, which promotes sulphide precipitation and copper depletion. We demonstrate the importance of amphibole fractionation as a globally important process that promotes both calc-alkaline differentiation and sulphide fractionation in arc magmas, as well as its role in signalling the right set of chemical conditions in magmas that ultimately feed copper porphyry deposits. This work also raises the possibility of amphibole as a geochemical and petrological indicator of potential porphyry-forming conditions in a magma, which we show should be readily detectable by a combination of different geochemical metrics. Despite their paucity in copper, high Sr/Y magmas are associated with porphyry deposits, implying that the propensity of magmas to form such deposits depends on factors other than a magma’s bulk copper content.
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