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PurposeGenomic alterations of BRAF and NRAS are oncogenic drivers in malignant melanoma and other solid tumors. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan‑RAF inhibitor. This first-in-human phase 1 study explored the safety and antitumor activity of tovorafenib.MethodsThis two-part study in adult patients with relapsed or refractory advanced solid tumors included a dose escalation phase and a dose expansion phase including molecularly defined cohorts of patients with melanoma. Primary objectives were to evaluate the safety of tovorafenib administered once every other day (Q2D) or once weekly (QW), and to determine the maximum-tolerated and recommended phase 2 dose (RP2D) on these schedules. Secondary objectives included evaluation of antitumor activity and tovorafenib pharmacokinetics.ResultsTovorafenib was administered to 149 patients (Q2D n = 110, QW n = 39). The RP2D of tovorafenib was defined as 200 mg Q2D or 600 mg QW. In the dose expansion phase, 58 (73%) of 80 patients in Q2D cohorts and 9 (47%) of 19 in the QW cohort had grade ≥ 3 adverse events. The most common of these overall were anemia (14 patients, 14%) and maculo-papular rash (8 patients, 8%). Responses were seen in 10 (15%) of 68 evaluable patients in the Q2D expansion phase, including in 8 of 16 (50%) patients with BRAF mutation-positive melanoma naïve to RAF and MEK inhibitors. In the QW dose expansion phase, there were no responses in 17 evaluable patients with NRAS mutation-positive melanoma naïve to RAF and MEK inhibitors; 9 patients (53%) had a best response of stable disease. QW dose administration was associated with minimal accumulation of tovorafenib in systemic circulation in the dose range of 400-800 mg.ConclusionsThe safety profile of both schedules was acceptable, with QW dosing at the RP2D of 600 mg QW preferred for future clinical studies. Antitumor activity of tovorafenib in BRAF-mutated melanoma was promising and justifies continued clinical development across multiple settings.ClinicaltrialsGov identifierNCT01425008.

Abstract Objective According to a seminal hypothesis stated by Crick and Koch in 1995, one is not aware of neural activity in primary visual cortex (V1) because this region lacks reciprocal connections with prefrontal cortex (PFC). Methods We provide here a neuropsychological illustration of this hypothesis in a patient with a very rare form of cortical blindness: ventral and dorsal cortical pathways were lesioned bilaterally while V1 areas were partially preserved. Results Visual stimuli escaped conscious perception but still activated V1 regions that were functionally disconnected from PFC. Interpretation These results are consistent with the hypothesis of a causal role of PFC in visual awareness.

Background: Inferior glenohumeral subluxation (GHS) can cause disabling pain in hemiplegics. Conservative treatments have not been proven to be effective or maintained over time. A few studies have shown the benefits of surgical treatment. The objective of our study was to evaluate the medium-term clinical and radiological results of arthroscopic glenohumeral suspensioplasty surgery by biceps tenodesis in the setting of painful GHS in hemiplegics. Methods: We conducted a retrospective study of patients who underwent arthroscopic glenohumeral suspensioplasty. The assessment, at a minimum of 1 year, included a clinical evaluation (pectoralis major spasticity, pain, range of motion, satisfaction) and a radiographic evaluation (Dursun classification, height of subacromial space). Results: Five patients with a mean age of 51 years (36-72 years) were included at a mean follow-up of 40 months (12-70). Satisfaction was good in 80% of patients. Pain decreased in all patients, but not significantly. Four patients (80%) would repeat the procedure if it were necessary. In all patients, a reduction in GHS over time was observed, with a reduction in subacromial height, except in 1 patient who suffered a tenodesis rupture during a fall. Conclusion: Our results suggest that arthroscopic glenohumeral suspensioplasty by biceps tenodesis may be a therapeutic option in hemiplegic patients with painful GHS.

Background: Scapulectomy is one of the surgical options in the case of malignant lesions in the scapula with an indication of surgical removal. Very few series in the literature have looked at postoperative quality of life and emotional acceptance, particularly in the case of scapulectomy without reconstruction. The objective is to assess the midterm results of scapulectomies in terms of function, quality of life, and acceptance for the patient. Methods: With a mean follow-up of 85 months (range 42 months-180 months), 11 scapulectomies for malignant tumors were performed with a mean age of 50 years: 5 partial scapulectomies, 4 total scapulectomies, and 2 subtotal scapulectomies. There were 6 chondrosarcomas, 2 high-grade osteosarcomas, 1 malignant peripheral nerve sheath tumor, and 1 low-grade atypical epithelioid sarcoma. The radio-clinical analysis was focused on functional results and mental health evaluation. Results: The mean Musculoskeletal Tumor Society score of 11 scapulectomies was 20 ± 5 at 66% of normal, with the Disabilities of the Arm, Shoulder and Hand (DASH) score of 35 ± 26, and the Toronto Extremity Salvage Score of 76%. Patients had controlled pain (mean visual analog scale 1/10). Mobilities of the 11 scapulectomies were correct: average active anterior elevation of 89.5 ± 43 degrees, average abduction of 81 ± 42 degrees, average external rotation of 30 ± 25 degrees, and average internal rotation was at L5. Scapulectomy results in impaired physical and mental health compared with the general population (PCS-12 = -9; MCS-12 = -7). Partial scapulectomy, compared to total scapulectomy, gave better results: Musculoskeletal Tumor Society score (14 ± 1 vs. 24 ± 1 P = .0175), acceptance (45 ± 9 vs. 92 ± 16, P = .0184), mental health (MCS-12: 29 ± 1 vs. 55 ± 4, P = .0175), and Toronto Extremity Salvage Score (84 ± 5 vs. 68 ± 7, P = .0195). Partial and subtotal scapulectomies were better accepted (45 ± 9 vs. 86 ± 23, P = .0323) and tolerated (MCS-12: 29 ± 1 vs. 52 ± 6, P = .0099) by the patient compared to total scapulectomy. Conclusion: Total or partial scapulectomies without scapula reconstruction remain a disabling procedure performed with consequences on the physical and mental health of the patients. Partial or subtotal scapulectomy should be performed whenever possible because it seems to be associated with a better functional prognosis as well as less poor mental health and emotional acceptance of the patients, even though total scapulectomy may be necessary to obtain a complete curative tumor resection, which is the main goal.

Inferior glenohumeral subluxation represents one of the causes of disabling pain in patients with hemiplegia after a stroke. In the case of failure of medical treatment by orthosis or electrical stimulation, surgical treatment of suspensionplasty has been described with good results. We describe here an arthroscopic technique of glenohumeral suspensionplasty by tenodesis of the biceps, proposed in the context of a painful glenohumeral subluxation in patients with hemiplegia.

Cerebrotendinous xanthomatosis is a rare and treatable metabolic disorder related to the accumulation of cholestanol. This disorder is primarily associated with motor and cognitive impairments, although the latter has not been extensively characterized. The objectives of this work were to define the cognitive profile found in cerebrotendinous xanthomatosis patients, investigate the progression of cognitive impairment over time, and search for radio‐clinical correlations. Through a multicentric chart review study, we collected cognitive and radiological data from nine children and eighteen adults with genetically proven cerebrotendinous xanthomatosis. We performed a volumetric and morphological analysis of the brain magnetic resonance imaging. In our cohort, 44% (4/9) of children and 78% (14/18) of adults exhibited cognitive impairment that can be severe. The study revealed a significant impairment in various cognitive domains, specifically executive, attentional, language, and visuo‐spatial. Among adults, 16% (3/18) developed dementia after age 50. These three patients had delayed chenodeoxycholic acid treatment and important cerebral atrophy. Besides these three cases of late‐onset cognitive decline, Mini‐Mental State Evaluation was generally stable, suggesting cognitive impairment due to a neurodevelopmental disorder and persisting in adulthood. Cognitive impairment was less common in children, possibly related to early chenodeoxycholic acid treatment in our cohort. The severity of magnetic resonance imaging abnormalities did not predict cognitive impairment in patients. Overall, in cerebrotendinous xanthomatosis, cognitive impairment can be severe and mainly neurodevelopmental. Early chenodeoxycholic acid treatment might be associated with a reduced risk of cognitive decline. [ABSTRACT FROM AUTHOR]

Abstract Background Pupils in secondary schools do not meet the targets for physical activity levels during physical education (PE) sessions, and there is a lack of data on the vigorous physical activity domain (VPA) in PE known to be positively associated with cardio metabolic health While PE session intensity depends on a variety of factors, the large majority of studies investigating these factors have not taken into account the nested structure of this type of data set. Therefore, the aim of this study was to investigate the relationship between various factors (gender, activity type, class location and class composition) and various activity levels during PE classes in secondary schools, using a multi-level statistical approach. Methods Year eight (12–13 years old) adolescents (201 boys and 106 girls) from six schools were fitted with accelerometers during one PE session each, to determine the percentage (%) of the PE session time spent in sedentary (SPA), light (LPA), moderate (MPA), vigorous (VPA) and moderate-to-vigorous (MVPA) intensity levels. Two- and three-level (pupils, n = 307; classes, n = 13, schools, n = 6) mixed-effect models were used to assess the relationship between accelerometer-measured physical activity levels (% of class time spent in various activity levels) and gender, activity type, class location and composition. Results Participants engaged in MVPA and VPA for 30.7 ± 1.2% and 11.5 ± 0.8% of PE classes, respectively. Overall, no significant association between gender or class composition and PA was shown. A significant relationship between activity type and PA was observed, with Artistic classes significantly less active than Fitness classes for VPA (5.4 ± 4.5 vs. 12.5 ± 7.1%, p = 0.043, d:1.19). We also found a significant association between class location and PA, with significantly less time spent in SPA (24.8 ± 4.8% vs. 30.0 ± 3.4%, p = 0.042, d:0.77) and significantly more time spent in VPA (12.4 ± 3.7% vs. 7.6 ± 2.0%, p = 0.022, d:1.93) and MVPA (32.3 ± 6.7% vs.24.8 ± 3.8%, p = 0.024, d:1.33) in outdoors vs. indoors classes. Conclusions The results suggest that class location and activity type could be associated with the intensity of PA in PE. It is essential to take into account the clustered nature of this type of data in similar studies if the sample size allows it.