Contemporary treatment approaches for metastatic colorectal cancer driven by BRAF V600 mutations

The treatment of metastatic colorectal cancer (mCRC) harboring BRAF V600 mutations is challenging. These tumors are often refractory to standard treatment. Therefore, the patients may exhibit rapid clinical deterioration, depriving them of the chance to receive salvage therapy. In newly diagnosed patients with good performance status, the administration of an intensive chemotherapy regimen like FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin, and irinotecan) along with the antiangiogenic agent bevacizumab can modify this aggressive behavior of the disease and improve patient clinical outcomes. The recently published results of the BEACON (Binimetinib, Encorafenib, and Cetuximab Combined to Treat BRAF-Mutant Colorectal Cancer) study demonstrated that a combination therapy consisting of BRAF, epidermal growth factor receptor, and mitogen-activated protein kinase kinase inhibitors could be a useful second-or third-line alternative. This review summarizes the current treatment strategies for BRAF-mutant mCRC.     

Donepezil improves obstructive sleep apnea in Alzheimer disease: a double-blind, placebo-controlled study

BACKGROUND: There is an association between Alzheimer disease and sleep-disordered breathing. Donepezil is the drug most frequently used to treat cognitive symptoms in Alzheimer disease. This study evaluates the effects of donepezil on obstructive sleep apnea in patients with Alzheimer disease. METHODS: Randomized, double-blind, placebo-controlled design. Twenty-three patients with mild-to-moderate Alzheimer disease and apnea-hypopnea index (AHI) > 5/h were allocated to two groups: donepezil treated (n = 11) and placebo treated (n = 12). Polysomnography and cognitive evaluation using Alzheimer disease assessment scale-cognitive (ADAS-cog) subscale were performed at baseline and after 3 months. Cognitive and sleep data were analyzed using analysis of variance. RESULTS: AHI and oxygen saturation improved significantly after donepezil treatment compared to baseline and placebo (p < 0.05). Rapid eye movement (REM) sleep duration increased after donepezil treatment (p < 0.05). ADAS-cog scores improved after donepezil treatment, although they did not correlate with REM sleep increase and sleep apnea improvement (p < 0.01). CONCLUSIONS: Donepezil treatment improved AHI and oxygen saturation in patients with Alzheimer disease. Treatment also increased REM sleep duration and reduced ADAS-cog scores. Trial registration: ClinicalTrials.gov Identifier: NCT00480870.     

基于固体培养基的金黄色葡萄球菌计数方法的相关性研究

目的 基于固体培养条件下对金黄色葡萄球菌传统计数方法 的比较研究,并探讨A600值和金黄色葡萄球菌活菌数二者之间的关系.方法金黄色葡萄球菌在固体条件下培养至对数生长期,无菌生理盐水制成菌悬液,采用平板计数法、麦氏比浊法、显微计数法检测菌悬液,同时记录3种方法计数结果 ;在相同培养条件下初步稀释后检测菌液的吸光度(A600)值,取A600值在0.2～1间的菌液进一步稀释并检测A600,同时对各个稀释度的菌液进行平板菌落计数.结果在固体培养条件下,传统细菌计数方法计数结果:显微计数法>平板计数法>比浊法;同时A600值和金黄色葡萄球菌活菌数二者之间呈线性相关,线性回归方程为Y=28.98601X-0.17331,A600值(X),菌液浓度(Y×107cfu/mL).结论 基于固体培养条件下,3种传统计数方法之间存在各自的特点.同时,金葡菌菌液的吸光度与金黄色葡萄球菌活菌数之间呈良好的相关性,适用于金黄色葡萄球菌浓度的测定.     

Clinicopathologic features and immunohistochemical spectrum of 11 cases of epithelioid malignant peripheral nerve sheath tumors,including INI1/SMARCB1 results and BRAF V600E analysis

Epithelioid malignant peripheral nerve sheath tumor (MPNST) is a rare, relatively less chemosensitive sarcoma. We report clinicopathologic features of 11 epithelioid MPNSTs, including rare forms, along with INI1 immunostaining and BRAF V600E mutation results. BRAF V600E mutation was tested by Real‐time polymerase chain reaction (PCR) technique. Eleven tumors occurred in six men and five women (M:F ratio = 0.85:1) within an age range of 5–73 years (average = 44), mostly in lower limbs (five), followed by upper limbs (four). Tumor size (n = 6), varied from 3.1 to 15 cm (average = 8.3). Histopathologically, most tumors were multilobular, characterized by epithelioid to round‐shaped, malignant cells, along with spindle cells (three cases), “rhabdoid‐like” cells (seven cases) and pleomorphic giant cells (single case). By immunohistochemistry, tumor cells were positive for S100 protein (11/11) (100%), EMA (3/7) (42.8%), pan CK(2/7) (28.5%), and HMB45 (1/11) (9%), while these were negative for Melan A (0/11) and INI1 (3/11), including a single tumor, displaying HMB45 positivity. BRAF V600E mutation was positive in 1/8 cases, that lacked melanocytic marker expression. All patients (n = 5) were treated by surgical resection. During follow‐up (n = 8, median duration = 23 months), four patients developed tumor recurrences and four developed metastasis, mostly to lymph nodes (3). Finally, four patients were alive with disease, two were alive with no evidence of disease, and two patients died of disease. Epithelioid MPNSTs have a diverse histopathologic spectrum. Loss of INI1 is useful, including in identifying rare forms of epithelioid MPNST, displaying melanocytic differentiation. Most tumors are treated by surgical resection. Loss of INI1 and the presence of BRAF V600E mutation in some cases raises future possibility of exploring targeted therapy in those, rare epithelioid MPNSTs.     

Neurophysiology of Hungarian subject–verb dependencies with varying intervening complexity

Non-adjacent dependencies are thought to be more costly to process than sentences wherein dependents immediately follow or precede what they depend on. In English locality effects have been revealed, while in languages with rich case marking (German and Hindi) sentence final structures show anti-locality-effects. The motivation of the current study is to test whether locality effects can be directly applied to a typologically different language than those investigated so far. Hungarian is a “topic prominent” language; it permits a variation of possible word sequencing for semantic reasons, including SVO word order. Hungarian also has a rich morphological system (e.g., rich case system) and postpositions to indicate grammatical functions. In the present ERP study, Hungarian subject–verb dependencies were compared by manipulating the mismatch of number agreement between the sentence's initial noun phrase and the sentence's final intransitive verb as well as the complexity of the intervening sentence material, interrupting the dependencies. Possible lexical class and frequency or cloze-probability effects for the first two words of the intervening sentence material were revealed when used separate baseline for each word, while at the third word of the intervening material as well as at the main verb ERPs were not modulated by complexity but at the verb ERPs were enhanced by grammaticality. Ungrammatical sentences enlarged the amplitude of both LAN and P600 components at the main verb. These results are in line with studies suggesting that the retrieval of the first element of a dependency is not influenced by distance from the second element, as the first element is directly accessible when needed for integration (e.g., McElree, 2000).     

Effect of local heat versus ice on blepharoptosis resulting from ocular myasthenia

OBJECTIVE: To determine the effect of heat versus ice application to a ptotic eyelid in patients with ocular or systemic myasthenia. DESIGN: Observational case series. PARTICIPANTS: Three consecutive patients and one subsequent patient with ptosis and clinical or laboratory signs of myasthenia were initially evaluated. METHODS: In all four patients, the heat test and the ice test were performed. In three patients, the modified sleep test was also performed. In the heat or ice test, the patient was asked to hold a heat or ice pack, respectively, over the closed ptotic eye for 10 to 15 minutes. The modified sleep test was performed by having the patient close both eyes for a 10- to 15-minute period. Photographs were taken before and immediately after each test. MAIN OUTCOME MEASURE: The effect of heat or ice on ptosis. RESULTS: Transient complete improvement of ptosis in three patients and marked improvement in one patient was noted after each test. The results of the heat, ice, and modified sleep tests were identical. CONCLUSIONS: Marked improvement of myasthenic ptosis in all four patients occurred regardless of local warming or cooling. The common denominator of all these tests, rest, seems to be the relevant factor in the study as designed.     

Adenoid cystic carcinoma of the supraglottic larynx: report of a case and review of the literature

Although adenoid cystic carcinoma is the most common malignant tumor of the minor salivary glands, it seldom occurs in the larynx. Less than 0.25 per cent of all laryngeal carcinomas are adenoid cystic, and only 15 such cases of supraglottic origin are recorded in the literature. In only four cases the details of treatment and outcome are described. We report another case and review the literature in order to define the entity of adenoid cystic carcinoma of the supraglottic larynx. This case reveals the aggressive nature of the disease, which is often associated with the solid variant histology and also demonstrates the most rapid course of any cases described in the literature. Other histologic variants of adenoid cystic carcinoma of the supraglottic larynx follow a more prolonged course that can extend many years even with persistent local disease. However, development of distant metastases may eventually occur. Therefore, 5-year statistics are not adequate, and 10 or 20 years' follow-up is required to evaluate the curability of this disorder. Evaluation, treatment, and clinical course of adenoid cystic carcinoma of the supraglottic larynx are discussed.