Combined treatment of malignant salivary gland tumours with intensity-modulated radiation therapy (IMRT) and carbon ions: COSMIC

<p>Abstract</p> <p>Background</p> <p>Local control in malignant salivary gland tumours is dose dependent. High local control rates in adenoid cystic carcinomas could be achieved by highly conformal radiotherapy techniques and particle (neutron/carbon ion) therapy. Considering high doses are needed to achieve local control, all malignant salivary gland tumours probably profit from the use of particle therapy, which in case of carbon ion treatment, has been shown to be accompanied by only mild side-effects.</p> <p>Methods/design</p> <p>The COSMIC trial is a prospective, mono-centric, phase II trial evaluating toxicity (primary endpoint: mucositis ≥ CTCAE°3) and efficacy (secondary endpoint: local control, disease-free survival) in the combined treatment with IMRT and carbon ion boost in 54 patients with histologically proved (≥R1-resected, inoperable or Pn+) salivary gland malignancies. Patients receive 24 GyE carbon ions (8 fractions) and IMRT (50 Gy at 2.0 Gy/fraction).</p> <p>Discussion</p> <p>The primary objective of COSMIC is to evaluate toxicity and feasibility of the proposed treatment in all salivary gland malignancies.</p> <p>Trial Registration</p> <p>Clinical trial identifier NCT 01154270</p

The predictive and prognostic potential of plasma telomerase reverse transcriptase (TERT) RNA in rectal cancer patients

Background: Preoperative chemoradiotherapy (CRT) followed by surgery is the standard care for locally advanced rectal cancer, but tumour response to CRT and disease outcome are variable. The current study aimed to investigate the effectiveness of plasma telomerase reverse transcriptase (TERT) levels in predicting tumour response and clinical outcome. Methods: 176 rectal cancer patients were included. Plasma samples were collected at baseline (before CRT\ubcT0), 2 weeks after CRT was initiated (T1), post-CRT and before surgery (T2), and 4\u20138 months after surgery (T3) time points. Plasma TERT mRNA levels and total cell-free RNA were determined using real-time PCR. Results: Plasma levels of TERT were significantly lower at T2 (Po0.0001) in responders than in non-responders. Post-CRT TERT levels and the differences between pre- and post-CRT TERT levels independently predicted tumour response, and the prediction model had an area under curve of 0.80 (95% confidence interval (CI) 0.73\u20130.87). Multiple analysis demonstrated that patients with detectable TERT levels at T2 and T3 time points had a risk of disease progression 2.13 (95% CI 1.10\u20134.11)-fold and 4.55 (95% CI 1.48\u201313.95)-fold higher, respectively, than those with undetectable plasma TERT levels. Conclusions: Plasma TERT levels are independent markers of tumour response and are prognostic of disease progression in rectal cancer patients who undergo neoadjuvant therapy

Identification of Domains and Amino Acids Essential to the Collagen Galactosyltransferase Activity of GLT25D1

Collagen is modified by hydroxylation and glycosylation of hydroxylysine residues. This glycosylation is initiated by the β1,O galactosyltransferases GLT25D1 and GLT25D2. The structurally similar protein cerebral endothelial cell adhesion molecule CEECAM1 was previously reported to be inactive when assayed for collagen glycosyltransferase activity. To address the cause of the absent galactosyltransferase activity, we have generated several chimeric constructs between the active human GLT25D1 and inactive human CEECAM1 proteins. The assay of these chimeric constructs pointed to a short central region and a large C-terminal region of CEECAM1 leading to the loss of collagen galactosyltransferase activity. Examination of the three DXD motifs of the active GLT25D1 by site-directed mutagenesis confirmed the importance of the first (amino acids 166–168) and second motif (amino acids 461–463) for enzymatic activity, whereas the third one was dispensable. Since the second DXD motif is incomplete in CEECAM1, we have restored the motif by introducing the substitution S461D. This change did not restore the activity of the C-terminal region, thereby showing that additional amino acids were required in this C-terminal region to confer enzymatic activity. Finally, we have introduced the substitution Q471R-V472M-N473Q-P474V in the CEECAM1-C-terminal construct, which is found in most animal GLT25D1 and GLT25D2 isoforms but not in CEECAM1. This substitution was shown to partially restore collagen galactosyltransferase activity, underlining its importance for catalytic activity in the C-terminal domain. Because multiple mutations in different regions of CEECAM1 contribute to the lack of galactosyltransferase activity, we deduced that CEECAM1 is functionally different from the related GLT25D1 protein

RadioImmunotherapy for adenoid cystic carcinoma: a single-institution series of combined treatment with cetuximab

<p>Abstract</p> <p>Background</p> <p>Local control in adjuvant/definitive RT of adenoid cystic carcinoma (ACC) is largely dose-dependent. However, some clinical situations do not allow application of tumouricidal doses (i.e. re-irradiation) hence radiation sensitization by exploitation of high endothelial growth factor receptor (EGFR)-expression in ACC seems beneficial. This is a single-institution experience of combined radioimmunotherapy (RIT) with the EGFR-inhibitor cetuximab.</p> <p>Methods</p> <p>Between 2006 and 2010, 9 pts received RIT for advanced/recurrent ACC, 5/9 pts as re-irradiation. Baseline characteristics as well as treatment parameters were retrieved to evaluate efficacy and toxicity of the combination regimen were evaluated. Control rates (local/distant) and overall survival were calculated using Kaplan-Meier estimation.</p> <p>Results</p> <p>Median dose was 65 Gy, pts received a median of 6 cycles cetuximab. RIT was tolerated well with only one °III mucositis/dysphagia. Overall response/remission rates were high (77,8%); 2-year estimate of local control was 80% hence reaching local control levels comparable to high-dose RT. Progression-free survival (PFS) at 2 years and median overall survival were only 62,5% and 22,2 mo respectively.</p> <p>Conclusion</p> <p>While local control and treatment response in RIT seems promising, PFS and overall survival are still hampered by distant failure. The potential benefit of RIT with cetuximab warrants exploration in a prospective controlled clinical trial.</p

Raster-scanned carbon ion therapy for malignant salivary gland tumors: acute toxicity and initial treatment response

<p>Abstract</p> <p>Background and purpose</p> <p>To investigate toxicity and efficacy in high-risk malignant salivary gland tumors (MSGT) of the head and neck. Local control in R2-resected adenoid cystic carcinoma was already improved with a combination of IMRT and carbon ion boost at only mild side-effects, hence this treatment was also offered to patients with MSGT and microscopic residual disease (R1) or perineural spread (Pn+).</p> <p>Methods</p> <p>From November 2009, all patients with MSGT treated with carbon ion therapy were evaluated. Acute side effects were scored according to CTCAE v.4.03. Tumor response was assessed according to RECIST where applicable.</p> <p>Results</p> <p>103 patients were treated from 11/2009 to 03/2011, median follow-up is 6 months. 60 pts received treatment following R2 resections or as definitive radiation, 43 patients received adjuvant radiation for R1 and/or Pn+. 16 patients received carbon ion treatment for re-irradiation. Median total dose was 73.2 GyE (23.9 GyE carbon ions + 49,9 Gy IMRT) for primary treatment and 44.9 GyE carbon ions for re-irradiation. All treatments were completed as planned and generally well tolerated with no > CTC°III toxicity. Rates of CTC°III toxicity (mucositis and dysphagia) were 8.7% with side-effects almost completely resolved at first follow-up.</p> <p>47 patients showed good treatment responses (CR/PR) according to RECIST.</p> <p>Conclusion</p> <p>Acute toxicity remains low in IMRT with carbon ion boost also in R1-resected patients and patients undergoing re-irradiation. R2-resected patients showed high rates of treatment response, though follow-up is too short to assess long-term disease control.</p

Palliative chemotherapy beyond three courses conveys no survival or consistent quality-of-life benefits in advanced non-small-cell lung cancer

This randomised multicentre trial was conducted to establish the optimal duration of palliative chemotherapy in advanced non-small-cell lung cancer (NSCLC). We compared a policy of three vs six courses of new-generation platinum-based combination chemotherapy with regard to effects on quality of life (QoL) and survival. Patients with stage IIIB or IV NSCLC and WHO performance status (PS) 0–2 were randomised to receive three (C3) or six (C6) courses of carboplatin (area under the curve (AUC) 4, Chatelut's formula, equivalent to Calvert's AUC 5) on day 1 and vinorelbine 25 mg m−2 on days 1 and 8 of a 3-week cycle. Key end points were QoL at 18 weeks, measured with EORTC Quality of Life Questionnaire (QLQ)-C30 and QLQ-LC13, and overall survival. Secondary end points were progression-free survival and need of palliative radiotherapy. Two hundred and ninety-seven patients were randomised (C3 150, C6 147). Their median age was 65 years, 30% had PS 2 and 76% stage IV disease. Seventy-eight and 54% of C3 and C6 patients, respectively, completed all scheduled chemotherapy courses. Compliance with QoL questionnaires was 88%. There were no significant group differences in global QoL, pain or fatigue up to 26 weeks. The dyspnoea palliation rate was lower in the C3 arm at 18 and 26 weeks (P<0.05), but this finding was inconsistent across different methods of analysis. Median survival in the C3 group was 28 vs 32 weeks in the C6 group (P=0.75, HR 1.04, 95% CI 0.82–1.31). One- and 2-year survival rates were 25 and 9% vs 25 and 5% in the C3 and C6 arm, respectively. Median progression-free survival was 16 and 21 weeks in the C3 and C6 groups, respectively (P=0.21, HR 0.86, 95% CI 0.68–1.08). In conclusion, palliative chemotherapy with carboplatin and vinorelbine beyond three courses conveys no survival or consistent QoL benefits in advanced NSCLC

Study of the reaction e^{+}e^{-} -->J/psi\pi^{+}\pi^{-} via initial-state radiation at BaBar

We study the process $e^+e^-\to J/\psi\pi^{+}\pi^{-}$ with initial-state-radiation events produced at the PEP-II asymmetric-energy collider. The data were recorded with the BaBar detector at center-of-mass energies 10.58 and 10.54 GeV, and correspond to an integrated luminosity of 454 $\mathrm{fb^{-1}}$. We investigate the $J/\psi \pi^{+}\pi^{-}$ mass distribution in the region from 3.5 to 5.5 $\mathrm{GeV/c^{2}}$. Below 3.7 $\mathrm{GeV/c^{2}}$ the $\psi(2S)$ signal dominates, and above 4 $\mathrm{GeV/c^{2}}$ there is a significant peak due to the Y(4260). A fit to the data in the range 3.74 -- 5.50 $\mathrm{GeV/c^{2}}$ yields a mass value $4244 \pm 5$ (stat) $\pm 4$ (syst)$\mathrm{MeV/c^{2}}$ and a width value $114 ^{+16}_{-15}$ (stat)$\pm 7$(syst)$\mathrm{MeV}$ for this state. We do not confirm the report from the Belle collaboration of a broad structure at 4.01 $\mathrm{GeV/c^{2}}$. In addition, we investigate the $\pi^{+}\pi^{-}$ system which results from Y(4260) decay

Combined treatment of adenoid cystic carcinoma with cetuximab and IMRT plus C12 heavy ion boost: ACCEPT [ACC, Erbitux® and particle therapy]

<p>Abstract</p> <p>Background</p> <p>Local control in adjuvant/definitive RT of adenoid cystic carcinoma (ACC) is largely dose-dependent leading to the establishment of particle therapy in this indication. However, even modern techniques leave space for improvement of local control by intensification of local treatment. Radiation sensitization by exploitation of high EGFR-expression in ACC with the EGFR receptor antibody cetuximab seems promising.</p> <p>Methods/design</p> <p>The ACCEPT trial is a prospective, mono-centric, phase I/II trial evaluating toxicity (primary endpoint: acute and late effects) and efficacy (secondary endpoint: local control, distant control, disease-free survival, overall survival) of the combined treatment with IMRT/carbon ion boost and weekly cetuximab in 49 patients with histologically proven (≥R1-resected, inoperable or Pn+) ACC. Patients receive 18 GyE carbon ions (6 fractions) and 54 Gy IMRT (2.0 Gy/fraction) in combination with weekly cetuximab throughout radiotherapy.</p> <p>Discussion</p> <p>The primary objective of ACCEPT is to evaluate toxicity and feasibility of cetuximab and particle therapy in adenoid cystic carcinoma.</p> <p>Trial Registration</p> <p>Clinical Trial Identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01192087">NCT 01192087</a></p> <p>EudraCT number: 2010 - 022425 - 15</p

Stoichiometry of Base Excision Repair Proteins Correlates with Increased Somatic CAG Instability in Striatum over Cerebellum in Huntington's Disease Transgenic Mice

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by expansion of an unstable CAG repeat in the coding sequence of the Huntingtin (HTT) gene. Instability affects both germline and somatic cells. Somatic instability increases with age and is tissue-specific. In particular, the CAG repeat sequence in the striatum, the brain region that preferentially degenerates in HD, is highly unstable, whereas it is rather stable in the disease-spared cerebellum. The mechanisms underlying the age-dependence and tissue-specificity of somatic CAG instability remain obscure. Recent studies have suggested that DNA oxidation and OGG1, a glycosylase involved in the repair of 8-oxoguanine lesions, contribute to this process. We show that in HD mice oxidative DNA damage abnormally accumulates at CAG repeats in a length-dependent, but age- and tissue-independent manner, indicating that oxidative DNA damage alone is not sufficient to trigger somatic instability. Protein levels and activities of major base excision repair (BER) enzymes were compared between striatum and cerebellum of HD mice. Strikingly, 5′-flap endonuclease activity was much lower in the striatum than in the cerebellum of HD mice. Accordingly, Flap Endonuclease-1 (FEN1), the main enzyme responsible for 5′-flap endonuclease activity, and the BER cofactor HMGB1, both of which participate in long-patch BER (LP–BER), were also significantly lower in the striatum compared to the cerebellum. Finally, chromatin immunoprecipitation experiments revealed that POLβ was specifically enriched at CAG expansions in the striatum, but not in the cerebellum of HD mice. These in vivo data fit a model in which POLβ strand displacement activity during LP–BER promotes the formation of stable 5′-flap structures at CAG repeats representing pre-expanded intermediate structures, which are not efficiently removed when FEN1 activity is constitutively low. We propose that the stoichiometry of BER enzymes is one critical factor underlying the tissue selectivity of somatic CAG expansion

The Challenges of the External Vote

UID/CPO/04627/2019Over the last few decades, emigrants all over the world have gained expanded voting rights. Despite the normative debates about this issue, there are few empirical studies on why states decide to implement external voting and how electoral systems perform. This chapter seeks to fill this gap by looking at the Portuguese case. Our study suggests that a combination of political and socio-economic factors explains the implementa tion of external voting. On the other hand, the interests of political parties and the low level of civil society engagement are key factors in the failure of both electoral reforms and attempts to overcome the shortcomings of external voting.publishersversionpublishe