A dose-escalation study of bi-daily once weekly oral docetaxel either as ModraDoc001 or ModraDoc006 combined with ritonavir

IntroductionTwo solid dispersions of docetaxel (denoted ModraDoc001 capsule and ModraDoc006 tablet (both 10 mg)) were co-administered with 100 mg ritonavir (/r) and investigated in a bi-daily once weekly (BIDW) schedule. Safety, maximum tolerated dose (MTD), pharmacokinetics (PK) and preliminary activity were explored.MethodsAdult patients with metastatic solid tumours were included in two dose-escalation arms. PK sampling was performed during the first week and the second or third week. Safety was evaluated using US National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. Antitumour activity was assessed every 6 weeks according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0.ResultsModraDoc001 capsule/r and ModraDoc006 tablet/r were administered to 17 and 28 patients, respectively. The most common adverse events were nausea, vomiting, diarrhoea and fatigue, mostly of grade 1–2 severity. Grade 3/4 neutropenia/neutropenic fever was observed in 2 patients (4%). The MTD was determined as 20/20 mg ModraDoc001/r and 30/20 mg ModraDoc006/r (morning/afternoon dose) once weekly. The mean area under the plasma concentration–time curve (AUC_0–48) ± standard deviation at the MTD for ModraDoc001/r and ModraDoc006/r were 686 ± 388 ng/ml*h and 1126 ± 382 ng/ml*h, respectively. Five partial responses were reported as best response to treatment.ConclusionOral administration of BIDW ModraDoc001/r or ModraDoc006/r is feasible. The once weekly 30/20 mg ModraDoc006 tablet/r dose-level was selected for future clinical development. Antitumour activity is promising.     

BRAF V600E mutation as a novel mechanism of acquired resistance to ALK inhibition in ALK-rearranged lung adenocarcinoma: A case report

Rationale:Patients with lung adenocarcinoma harboring EML4-ALK rearrangements respond well to multiple ALK tyrosine kinase inhibitors (TKIs). However, the tumor will invariably progress due to acquired resistance. Comprehensive genomic profiling appears to be a promising strategy to reveal the underlying molecular mechanisms of ALK-TKIs resistance.Patient concerns:A patient with right lung adenocarcinoma harboring an ALK rearrangement received targeted therapy with multiple ALK-TKIs. He sought for follow-up treatment after his disease progressed again.Diagnosis:The patient had a tumor diagnosed with stage I (T1bN0M0) lung adenocarcinoma.Interventions:Due to the surgical contraindication, the patient did not undergo surgical resection. Instead, he received crizotinib as the first-line therapy with the progression-free survival of 20 months. Then he switched to alectinib treatment, however the disease rapidly progressed again.Outcomes:Next-generation sequencing was performed and revealed that 7 somatic mutations were identified. Among them, 2 mutations, ALK I1171T and BRAF V600E, may be responsible for the resistance of this patient to ALK-TKIs. BRAF V600E mutation may explain the patient''s resistance to lorlatinib.Lessons:We present a case of ALK-rearranged lung adenocarcinoma with acquired resistance to ALK inhibition, in which the BRAF V600E mutation is a novel resistance mechanism. This provides evidence that BRAF V600E mutation is one mechanism of ALK-TKI resistance.     

Inheritance of the mitral valve prolapse syndrome. Discussion of a three-dimensional penetrance model

The families of 12 probands with classic mitral valve prolapse were studied for evidence of mitral valve prolapse. Seventy parents, sibs, and progeny were included in the analysis. Forty-seven percent (16 of 34) of progeny were affected compared with 30 percent (3 of 10) of parents. Thirty-eight percent (10 of 26) of sibs were affected. A three-compartmental penetrance model was devised to account for the variation in expression with age. This includes a latent stage (time before onset of signs), an affected stage, and a stage in which the subjects are withdrawn (because of treatment, regression, or death). The implications of this model are discussed.     

VE1 immunohistochemistry is an adjunct tool for detection of BRAF V600E mutation: Validation in thyroid cancer patients

Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy among other endocrine tumors, and BRAF ^V600E is a frequent genetic mutation occurring in the disease. Although different molecular techniques, most importantly sequencing has been widely recognized as a gold standard but molecular diagnosis remains an expensive, laborious, and time‐intensive process. Recently, immunohistochemistry (IHC) with anti‐BRAF V600E (VE1) antibody has increased practical utility and implemented clinically for the detection of BRAF ^V600E mutation. Therefore, the study aimed to evaluate diagnostic accuracy of VE1 IHC for detecting the BRAF ^V600E mutation frequency and clinical implementation in diagnostic laboratories. In this study, 72 formalin fixed paraffin‐embedded tissues (FFPE) were used to determine the BRAF ^V600E mutation status using IHC and Sanger sequencing. The mutation was found in 29% and 28% cases using IHC and Sanger sequencing, respectively. Furthermore, the results showed 100% sensitivity, 98.07% specificity, 95.2% positive predictive value, and 100% negative predictive value. Notably, significant associations were found between BRAF ^V600E status and tumor stage, tumor focality, and extrathyroidal extensions, respectively. VE1 IHC was found to be a highly sensitive, specific, and diagnostically accurate method in this cohort. Therefore, BRAF ^V600E detection through IHC has been considered as the best tailored technique for routine pathology laboratories.     

How do taxonomic versus thematic relations impact similarity and difference judgments? An ERP study

Taxonomically related concepts like “bee” and “butterfly” and thematically related concepts like “bee” and “honey” have different roles in similarity judgments. We examined the complex impact of taxonomic and thematic relations on similarity and difference judgments via ERPs in a S1–S2 paradigm. Subjects were required to remember a word denoting some object or animal (S1), and compare that to a second word (S2) that was either thematically related, taxonomically related or unrelated to S1, making a “high” or “low” similarity and difference judgments in separate blocks. We found two main differences that suggest thematic and taxonomic relations engage distinct neural processes. The first difference is an N400 effect peaking between 300 ms and 400 ms that is more negative for unrelated words than for thematically and taxonomically related words. The second difference is a frontally distributed P600 peaking between 500 ms and 600 ms that is larger for taxonomically related words than for both unrelated and thematically related words. These results suggest that the dual process model for perceiving similarity is superior to the comparison only model of similarity judgments, and furthermore, provide evidence that the thematic relations are dissociative from taxonomic relations in making similarity and difference judgments.     

BRAFV600E突变对甲状腺乳头状癌HMGB1及MMP-9表达的影响

目的探究BRAF^V600E突变对甲状腺乳头状癌(PTC)高迁移率族蛋白1(HMGB1)及基质金属蛋白酶-9(MMP-9)表达的影响。方法选取2018年1月至2019年11月在本院行甲状腺全切除术或次全切除术的116例PTC患者及匹配癌组织标本作为PTC组,另择同时期体检正常的30例健康人作为对照组。检测PTC患者BRAFV600E基因类型,免疫组化法及Western blot法检测PTC患者甲状腺癌组织中HMGB1、MMP-9表达情况,酶联免疫吸附法检测受试者血清HMGB1、MMP-9水平,并收集PTC患者临床资料。结果 116例PCT患者检出59例BRAF^V600E突变型、57例为BRAFV600E野生型,PTC患者BRAF^V600E突变型为50.86%(59/116)。免疫组化法分析结果显示BRAFV600E突变型HMGB1、MMP-9阳性表达率均显著高于BRAFV600E野生型,差异有统计学意义(P<0.05);Western blot法检测结果显示BRAFV600E突变型HMGB1表达量、MMP-9表达量显著高于BRAF^V600E野生型,差异有统计学意义(P<0.05)。PTC组BRAF^V600E突变型及BRAF^V600E野生型血清HMGB1、MMP-9水平均显著高于对照组,差异有统计学意义(P<0.05),PTC患者BRAFV600E突变型与BRAF^V600E野生型在血清HMGB1、MMP-9水平上比较,差异无统计学意义(P>0.05)。BRAF^V600E突变型TNM分期Ⅲ~Ⅳ期、包膜浸润、多发病灶、淋巴结转移占比显著高于BRAF^V600E野生型,差异有统计学意义(P<0.05)。二元Logistic结果显示,合并包膜浸润、多发病灶、组织HMGB1阳性、组织MMP-9阳性均是BRAF^V600E突变型的影响因素(P<0.05)。结论 PTC患者BRAF^V600E突变型组织HMGB1、MMP-9阳性表达率显著高于BRAF^V600E野生型,且组织HMGB1阳性、MMP-9阳性是BRAF^V600E突变型的影响因素。     

Neurodevelopment for syntactic processing distinguishes childhood stuttering recovery versus persistence

Background

Characterized by the presence of involuntary speech disfluencies, developmental stuttering is a neurodevelopmental disorder of atypical speech-motor coordination. Although the etiology of stuttering is multifactorial, language development during early childhood may influence both the onset of the disorder and the likelihood of recovery. The purpose of this study was to determine whether differences in neural indices mediating language processing are associated with persistence or recovery in school-age children who stutter.

Methods

Event-related brain potentials (ERPs) were obtained from 31 6–7-year-olds, including nine children who do not stutter (CWNS), 11 children who had recovered from stuttering (CWS-Rec), and 11 children who persisted in stuttering (CWS-Per), matched for age, and all with similar socioeconomic status, nonverbal intelligence, and language ability. We examined ERPs elicited by semantic and syntactic (phrase structure) violations within an auditory narrative consisting of English and Jabberwocky sentences. In Jabberwocky sentences, content words were replaced with pseudowords to limit semantic context. A mixed effects repeated measures analysis of variance (ANOVA) was computed for ERP components with four within-subject factors, including condition, hemisphere, anterior/posterior distribution, and laterality.

Results

During the comprehension of English sentences, ERP activity mediating semantic and syntactic (phrase structure) processing did not distinguish CWS-Per, CWS-Rec, and CWNS. Semantic violations elicited a qualitatively similar N400 component across groups. Phrase structure violations within English sentences also elicited a similar P600 component in all groups. However, identical phrase structure violations within Jabberwocky sentences elicited a P600 in CWNS and CWS-Rec, but an N400-like effect in CWS-Per.

Conclusions

The distinguishing neural patterns mediating syntactic, but not semantic, processing provide evidence that specific brain functions for some aspects of language processing may be associated with stuttering persistence. Unlike CWS-Rec and CWNS, the lack of semantic context in Jabberwocky sentences seemed to affect the syntactic processing strategies of CWS-Per, resulting in the elicitation of semantically based N400-like activity during syntactic (phrase structure) violations. This vulnerability suggests neural mechanisms associated with the processing of syntactic structure may be less mature in 6–7-year-old children whose stuttering persisted compared to their fluent or recovered peers.