From chemotherapy to targeted treatment

Today, melanoma is considered as a spectrum of melanocytic malignancies that can be characterized by clinical and molecular features, including targetable mutations in several kinases. The successful development of therapies, targeting mutated BRaF (v-raf murine sarcoma viral oncogene homolog B1) or c-KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog), has resulted in new treatment options including vemurafenib, imatinib and mitogen-activated protein kinase inhibitors. These molecules are selected if the respective mutation is present. after this first progress in the treatment of advanced melanoma, there is expectation that combinations of kinase inhibitor will additionally improve the overall survival rates and progression-free survival in advanced melanom

Microsaccades reflect the dynamics of misdirected attention in magic

The methods of magicians provide powerful tools for enhancing the ecological validity of laboratory studies of attention. The current research borrows a technique from magic to explore the relationship between microsaccades and covert attention under near-natural viewing conditions. We monitored participants’ eye movements as they viewed a magic trick where a coin placed beneath a napkin vanishes and reappears beneath another napkin. Many participants fail to see the coin move from one location to the other the first time around, thanks to the magician’s misdirection. However, previous research was unable to distinguish whether or not participants were fooled based on their eye movements. Here, we set out to determine if microsaccades may provide a window into the efficacy of the magician’s misdirection. In a multi-trial setting, participants monitored the location of the coin (which changed positions in half of the trials), while engaging in a delayed match-to-sample task at a different spatial location. Microsaccades onset times varied with task difficulty, and microsaccade directions indexed the locus of covert attention. Our com-bined results indicate that microsaccades may be a useful metric of covert attentional processes in applied and ecologically valid settings

First-line temozolomide combined with bevacizumab in metastatic melanoma: a multicentre phase II trial (SAKK 50/07)

Background: Oral temozolomide has shown similar efficacy to dacarbazine in phase III trials with median progression-free survival (PFS) of 2.1 months. Bevacizumab has an inhibitory effect on the proliferation of melanoma and sprouting endothelial cells. We evaluated the addition of bevacizumab to temozolomide to improve efficacy in stage IV melanoma. Patients and methods: Previously untreated metastatic melanoma patients with Eastern Cooperative Oncology Group performance status of two or more were treated with temozolomide 150 mg/m2 days 1-7 orally and bevacizumab 10 mg/kg body weight i.v. day 1 every 2 weeks until disease progression or unacceptable toxicity. The primary end point was disease stabilisation rate [complete response (CR), partial response (PR) or stable disease (SD)] at week 12 (DSR12); secondary end points were best overall response, PFS, overall survival (OS) and adverse events. Results: Sixty-two patients (median age 59 years) enrolled at nine Swiss centres. DSR12 was 52% (PR: 10 patients and SD: 22 patients). Confirmed overall response rate was 16.1% (CR: 1 patient and PR: 9 patients). Median PFS and OS were 4.2 and 9.6 months. OS (12.0 versus 9.2 months; P = 0.014) was higher in BRAF V600E wild-type patients. Conclusions: The primary end point was surpassed showing promising activity of this bevacizumab/temozolomide combination with a favourable toxicity profile. Response and OS were significantly higher in BRAF wild-type patient

Radiosensitization by BRAF inhibitor therapy—mechanism and frequency of toxicity in melanoma patients

This study shows radiosensitization by BRAF inhibitors in clinical practice and ex vivo by fluorescence in situ hybridization of chromosomal breaks. Nevertheless, radiotherapy with concomitant BRAF inhibitor therapy is feasible with an acceptable increase in toxicity. Vemurafenib is a more potent radiosensitizer than dabrafenib in both the patient study and the ex vivo experiment

Analysis of BRAF and NRAS Mutation Status in Advanced Melanoma Patients Treated with Anti-CTLA-4 Antibodies: Association with Overall Survival?

Ipilimumab and tremelimumab are human monoclonal antibodies (Abs) against cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab was the first agent to show a statistically significant benefit in overall survival in advanced melanoma patients. Currently, there is no proven association between the BRAFV600 mutation and the disease control rate in response to ipilimumab. This analysis was carried out to assess if BRAFV600 and NRAS mutation status affects the clinical outcome of anti-CTLA-4-treated melanoma patients. This is a retrospective multi-center analysis of 101 patients, with confirmed BRAF and NRAS mutation status, treated with anti-CTLA-4 antibodies from December 2006 until August 2012. The median overall survival, defined from the treatment start date with the anti-CTLA-4. Abs-treatment to death or till last follow up, of BRAFV600 or NRAS mutant patients (n = 62) was 10.12 months (95% CI 6.78-13.2) compared to 8.26 months (95% CI 6.02-19.9) in BRAFV600/NRASwt subpopulation (n = 39) (p = 0.67). The median OS of NRAS mutated patients (n = 24) was 12.1 months and although was prolonged compared to the median OS of BRAF mutated patients (n = 38, mOS = 8.03 months) or BRAFV600/NRASwt patients (n = 39, mOS = 8.26 months) the difference didn't reach statistical significance (p = 0.56). 69 patients were able to complete 4 cycles of anti-CTLA-4 treatment. Of the 24 patients treated with selected BRAF- or MEK-inhibitors, 16 patients received anti-CTLA 4 Abs following either a BRAF or MEK inhibitor with only 8 of them being able to finish 4 cycles of treatment. Based on our results, there is no difference in the median OS in patients treated with anti-CTLA-4 Abs implying that the BRAF/NRAS mutation status alone is not sufficient to predict the outcome of patients treated with anti-CTLA-4 Abs

Phase I, open-label study of pasireotide in patients with <i>BRAF-</i>wild type and <i>NRAS</i>-wild type, unresectable and/or metastatic melanoma.

Somatostatin analogues exert antitumour activity via direct and indirect mechanisms. The present study was designed to assess the safety and efficacy of pasireotide in patients with &lt;i&gt;BRAF&lt;/i&gt; -wild type (WT) and &lt;i&gt;NRAS&lt;/i&gt; -WT metastatic melanoma. Patients with unresectable and/or metastatic melanoma or Merkel cell carcinoma were eligible. Pasireotide was administered at different doses for ≤8 weeks in dose-escalation phase, followed by long-acting pasireotide 80 mg or lower dose in case of toxicity in follow-up phase up to six additional months. Primary endpoint was safety in the first 8 weeks of dose-escalation phase. The study was terminated early due to slow recruitment. Of the 10 patients with metastatic melanoma enrolled, only four reached the high dose level: two patients reached 3600 µg in dose-escalation and follow-up phases and two patients reached 3600 µg in dose-escalation and long-acting pasireotide 80 mg in follow-up phases and were stable for &gt;5 months. Most common adverse events (AEs) during dose-escalation phase in ≥2 patients (20%) were: diarrhoea (50%), nausea (50%), fatigue (20%), hyperglycaemia (20%), hypophosphatemia (20%), chills (20%) and tumour pain (20%). Grade 3 or 4 study drug-related AEs were diarrhoea and nausea, reported in one patient. Partial response was documented in one patient and stable disease in another. Pasireotide was well tolerated, and safety results were similar to those previously reported in other indications. Further studies are needed to evaluate its antitumour activity alone and in combination with other drugs in melanoma

Discontinuation of anti-PD-1 antibody therapy in the absence of disease progression or treatment limiting toxicity : clinical outcomes in advanced melanoma

Background Programmed cell death protein 1 (PD-1) blocking monoclonal antibodies improve the overall survival of patients with advanced melanoma but the optimal duration of treatment has not been established. Patients and Methods This academic real-world cohort study investigated the outcome of 185 advanced melanoma patients who electively discontinued anti-PD-1 therapy with pembrolizumab (N=167) or nivolumab (N=18) in the absence of disease progression (PD) or treatment limiting toxicity (TLT) at 14 medical centres across Europe and Australia. Results Median time on treatment was 12months (range 0.7-43). The best objective tumour response at the time of treatment discontinuation was complete response (CR) in 117 (63%) patients, partial response (PR) in 44 (24%) patients and stable disease (SD) in 16 (9%) patients; 8 (4%) patients had no evaluable disease (NE). After a median follow-up of 18months (range 0.7-48) after treatment discontinuation, 78% of patients remained free of progression. Median time to progression was 12months (range 2-23). PD was less frequent in patients with CR (14%) compared with patients with PR (32%) and SD (50%). Six out of 19 (32%) patients who were retreated with an anti-PD-1 at the time of PD obtained a new antitumour response. Conclusions In this real-world cohort of advanced melanoma patients discontinuing anti-PD-1 therapy in the absence of TLT or PD, the duration of anti-PD-1 therapy was shorter when compared with clinical trials. In patients obtaining a CR, and being treated for >6months, the risk of relapse after treatment discontinuation was low. Patients achieving a PR or SD as best tumour response were at higher risk for progression after discontinuing therapy, and defining optimal treatment duration in such patients deserves further study. Retreatment with an anti-PD-1 at the time of progression may lead to renewed antitumour activity in some patients. Clinical trial registration NCT02673970 (https://clinicaltrials.gov/ct2/show/NCT02673970?cond=melanoma&cntry=BE&city=Jette&rank=3)Peer reviewe

Recognizing Speech in a Novel Accent: The Motor Theory of Speech Perception Reframed

The motor theory of speech perception holds that we perceive the speech of another in terms of a motor representation of that speech. However, when we have learned to recognize a foreign accent, it seems plausible that recognition of a word rarely involves reconstruction of the speech gestures of the speaker rather than the listener. To better assess the motor theory and this observation, we proceed in three stages. Part 1 places the motor theory of speech perception in a larger framework based on our earlier models of the adaptive formation of mirror neurons for grasping, and for viewing extensions of that mirror system as part of a larger system for neuro-linguistic processing, augmented by the present consideration of recognizing speech in a novel accent. Part 2 then offers a novel computational model of how a listener comes to understand the speech of someone speaking the listener's native language with a foreign accent. The core tenet of the model is that the listener uses hypotheses about the word the speaker is currently uttering to update probabilities linking the sound produced by the speaker to phonemes in the native language repertoire of the listener. This, on average, improves the recognition of later words. This model is neutral regarding the nature of the representations it uses (motor vs. auditory). It serve as a reference point for the discussion in Part 3, which proposes a dual-stream neuro-linguistic architecture to revisits claims for and against the motor theory of speech perception and the relevance of mirror neurons, and extracts some implications for the reframing of the motor theory

Methods for Minimizing the Confounding Effects of Word Length in the Analysis of Phonotactic Probability and Neighborhood Density

This is the author's accepted manuscript. The original is available at http://jslhr.pubs.asha.org/article.aspx?articleid=1781521&resultClick=3Recent research suggests that phonotactic probability (the likelihood of occurrence of a sound sequence) and neighborhood density (the number of words phonologically similar to a given word) influence spoken language processing and acquisition across the lifespan in both normal and clinical populations. The majority of research in this area has tended to focus on controlled laboratory studies rather than naturalistic data such as spontaneous speech samples or elicited probes. One difficulty in applying current measures of phonotactic probability and neighborhood density to more naturalistic samples is the significant correlation between these variables and word length. This study examines several alternative transformations of phonotactic probability and neighborhood density as a means of reducing or eliminating this correlation with word length. Computational analyses of the words in a large database and reanalysis of archival data supported the use of z scores for the analysis of phonotactic probability as a continuous variable and the use of median transformation scores for the analysis of phonotactic probability as a dichotomous variable. Neighborhood density results were less clear with the conclusion that analysis of neighborhood density as a continuous variable warrants further investigation to differentiate the utility of z scores in comparison to median transformation scores. Furthermore, balanced dichotomous coding of neighborhood density was difficult to achieve, suggesting that analysis of neighborhood density as a dichotomous variable should be approached with caution. Recommendations for future application and analyses are discussed