Selective type II TRK inhibitors overcome xDFG mutation mediated acquired resistance to the second-generation inhibitors selitrectinib and repotrectinib

Neurotrophic receptor kinase (NTRK) fusions are actionable oncogenic drivers of multiple pediatric and adult solid tumors, and tropomyosin receptor kinase (TRK) has been considered as an attractive therapeutic target for "pan-cancer" harboring these fusions. Currently, two generations TRK inhibitors have been developed. The representative second-generation inhibitors selitrectinib and repotrectinib were designed to overcome clinic acquired resistance of the first-generation inhibitors larotrectinib or entrectinib resulted from solvent-front and gatekeeper on-target mutations. However, xDFG (TRKAG667C/A/S, homologous TRKCG696C/A/S) and some double mutations still confer resistance to selitrectinib and repotrectinib, and overcoming these resistances represents a major unmet clinical need. In this review, we summarize the acquired resistance mechanism of the first- and second-generation TRK inhibitors, and firstly put forward the emerging selective type II TRK inhibitors to overcome xDFG mutations mediated resistance. Additionally, we concluded our perspectives on new challenges and future directions in this field.

Biological Implication of Chimeric RNAs in Cancer / 中国生物化学与分子生物学报

Chimeric RNA is a fusion transcript composed of exons from two or more different genes and generated by chromosome rearrangement or RNA splicing. Chimeric RNAs have the potential to encode novel proteins or function as non-coding RNAs. Chimeric RNAs were ubiquitously expressed across different cancers and normal tissues. To date, mechanistic and functional studies of chimeric RNAs still remain unclear. Precise definition and terminology in the research field of chimeric RNA will be discussed in this review. The formation, classification and clinical significance of chimeric RNAs in cancer progression will be summarized. Previous studies showed that products of chimeric RNAs may play important roles in regulating cell proliferation, motility, invasion and apoptosis through encoded fusion proteins or long non-coding chimeric RNAs. In cancer, chimeric RNA and its encoded specific protein or non-coding RNA can regulate tumorigenesis by changing cell phenotypes or directly affecting gene expression or regulatory pathways, which have the potential to be important diagnostic biomarkers and therapeutic targets. In recent years, more and more cancer-specific chimeric RNAs have been discovered from multiple types of cancers and used as therapeutic targets due to their vital roles in disease prognosis. Therefore, this review will focus on the functions and applications of chimeric RNAs in different tumors, which can shed a light on cancer diagnosis and therapeutics from the new perspective.

Role of NTRK gene fusions and TRK inhibitors in non-small cell lung cancer / 中国肿瘤临床

Lung cancer is one of the major causes of cancer related deaths, and 80%–85% of lung cacer cases are non-small cell lung cancer (NSCLC). Most patients with NSCLC are already in the advanced stages when they are initially diagnosed. Despite remarkable advances in traditional chemotherapy, immunotherapy, and other therapies, the overall survival of patients with NSCLC remains poor. New therapeutic targets have been discovered in recent years with the continuous development of precision medicine, and the corresponding targeted drugs have highlighted the promise of targeted therapy. NTRK gene fusions have been closely related to the formation and progression of a variety of solid tumors. In patients with NSCLC, the incidence of NTRK gene fusions, which usually does not overlap with other common oncogene drivers, is approximately 0.2%. Clinical trials have demonstrated the good efficacy and safety of TRK inhibitors in solid tumors with NTRK gene fusions. In addition, patients with refractory NSCLC can benefit significantly from TRK inhibitors. This article reviews the role of NTRK gene fusions and TRK inhibitors in NSCLC.

Analysis of c-MET, ALK, ROS1 variants in non-small cell lung cancer and its clinical significance / 临床与实验病理学杂志

Purpose The aim was to examine c-MET,ALK,ROS1 variants in advanced non-small cell lung cancer (NSCLC) patients,and to analysis the association of c-MET,ALK,ROS1 variants with the clinical and pathological features.Methods The c-MET,ALK,ROS1 were detected by fluorescence in situ hybridization (FISH) in the 91 cases of NSCLC specimens.The correlation of c-MET gene amplification with clinicopathological features and the ALK,ROS1 fusions was analyzed.Results The positive rate of c-MET gene amplification was 8.79％ (8/91),the positive rates on male and female were 1.82％ and 19.4％,respectively.In ＜ 60-years-old and ≥60-years-old NSCLC patients,the positive rates were 7.5％ and 8.89％,resepectively.The positive rate was higher in stage Ⅲ than stage Ⅳ (9.62％ vs 7.69％),the c-MET gene amplification was detected in 9.2％ adenocarcinoma patients but none in squamous carcinoma patients.The detection rates of ALK fusions and ROS1 fusions were 10％ and 13.3％,respectively.One patient was detected the coexistence of MET with ROS1 fusion.Conclusion The c-MET gene amplification is correlated with gender,but not with age,histological types and clinical stages.C-MET amplification,ALK fusions and ROS1 fusions are almost no coexistence,but not completely mutually exclusive.To they knowledge,this is the first case report the coexistence of MET amplification with ROS1 fusion in NSCLC.

Nasal Colonization Rate of Methicillin Resistant Staphylococcus Aureus among Age Group of Spinal Fusion Surgery

OBJECTIVE: Methicillin resistant Staphylococcus aureus (MRSA) is the most common cause of postoperative infection in instrumented fusion surgery. Although MRSA is well-known cause of nosocomial infection, emerging evidence supports that there could be MRSA infection from community. This study evaluated the nasal colonization rate of MRSA among healthy adults within the age range of spinal fusion surgery in Korea. METHODS: Nasal swabs were collected from 99 participants who visited health promotion center. A structured questionnaire regarding healthcare-associated MRSA risk factors was collected simultaneously. Staphylococcus aureus was confirmed by latex agglutination. The resistance to methicillin was identified by oxacillin screening test. RESULTS: Of the 99 participants, 12 (12.1%) had S. aureus isolates. The nasal carriage rate of methicillin susceptible S. aureus (MSSA) was 9 (9.1%). MRSA was identified in 3 participants (3.0%). CONCLUSION: Among the age range of possible spinal fusion surgery, nasal colonization study revealed substantial rate of preoperative MRSA carriers even in healthy adults. A postoperative MRSA infection should not be exclusively considered to be due to surgery-related contamination.

The Incidence of Potential Candidates for Total Disc Replacement among Lumbar and Cervical Fusion Patient Populations

STUDY DESIGN: Retrospective chart review. PURPOSE: To evaluate the incidence of potential total disc replacement (TDR) candidates among cervical and lumbar fusion patient populations using strict Food and Drug Administration (FDA) criteria and with relative exclusion criteria removed. OVERVIEW OF LITERATURE: Recent studies suggest that the potential percentage of patients that are candidates for TDR ranges from 0-5% in lumbar fusions and 43% in cervical fusions. METHODS: We performed a retrospective chart review of 280 consecutive patients who had lumbar (n = 174) and cervical (n = 106) fusion or TDR performed by one of four independent adult orthopaedic spine surgeons. Charts were screened for investigational device exemption (IDE) inclusion/exclusion criteria and later reanalyzed excluding relative exclusion criteria, such as history of chronic medical illness, twolevel disease (cervical cases), and history of prior fusion surgery in the anatomic region. RESULTS: Of the 174 lumbar surgeries, 10 were TDR with Prodisc-L and 164 were lumbar fusions. The most common TDR exclusion criteria were lytic spondylolisthesis or spinal stenosis (47.7% of patients) and more than 2 level degenerative disc disease (37.9%). 14.9% had no IDE exclusion criteria and would be considered candidates for TDR. After excluding the relative lumbar exclusion criteria, this percentage increased to 25.8%. Of the 106 cervical cases, 3 had a TDR with Prodisc-C and 103 had a cervical fusion. Twenty eight percent had no IDE exclusion criteria and would be considered candidates for cervical TDR. CONCLUSIONS: A larger percentage of cervical fusion candidates are potential candidates for TDR (28%) than lumbar fusion candidates (14.9%) based on the strict IDE criteria.

Chromosome polymorphism in the Brazilian dwarf brocket deer, Mazama nana (Mammalia, Cervidae)

The Brazilian dwarf brocket deer (Mazama nana) is the smallest deer species in Brazil and is considered threatened due to the reduction and alteration of its habitat, the Atlantic Rainforest. Moreover, previous work suggested the presence of intraspecific chromosome polymorphisms which may contribute to further population instability because of the reduced fertility arising from the deleterious effects of chromosome rearrangements during meiosis. We used G- and C-banding, and nucleolus organizer regions localization by silver-nitrate staining (Ag-NOR) to investigate the causes of this variation. Mazama nana exhibited eight different karyotypes (2n = 36 through 39 and FN = 58) resulting from centric fusions and from inter and intraindividual variation in the number of B chromosomes (one to six). Most of the animals were heterozygous for a single fusion, suggesting one or several of the following: a) genetic instability in a species that has not reached its optimal karyotypic evolutionary state yet; b) negative selective pressure acting on accumulated rearrangements; and c) probable positive selection pressure for heterozygous individuals which maintains the polymorphism in the population (in contrast with the negative selection for many rearrangements within a single individual).

The Changes of Adjacent Segments after Fusions (above 3-levels to L5) in Degenerative Lumbar Spinal Disorders / 대한척추외과학회지

STUDY DESIGN: A retrospective study. OBJECTIVE: To evaluate the usefulness of MRI grading of disc degeneration in determining whether L5-S1 fusion is necessary in degenerative lumbar spinal disorders. SUMMARY OF LITERATURE REVIEW: Changes in adjacent segments are not well understood, after floating fusion has been performed. MATERIALS AND METHODS: We reviewed 16 surgical cases of degenerative lumbar spinal disorders from July 1996 to February 2000 with an average follow-up of 41 months. Fusion was done in patients without instability, pathology and narrowing of L5-S1. We measured the disc degeneration of adjacent segments in preoperative MRIs using the Modified Pearce classification. In spine AP, lateral and flexion-extension radiographs, we measured disc height, angular motion and instability changes and correlated these with disc degeneration. RESULTS: Disc height changes decreased in the upper and lower adjacent segments and preoperative disc degeneration above grade IV, decreased more in lower adjacent segment. A statistical correlation was found between disc degeneration and disc height changes in the lower segment (P=0.046), but not in the upper segment (P=0.649). The angular-motion was unchanged in the upper and lower adjacent segments, and no statistical correlation was found between disc degeneration and angular-motion changes (P=0.819, 0.208). Postoperative instability was found in the upper adjacent segment in 2 patients, but no statistical cor-relation was found between disc degeneration and instability (P=0.083, P=1.000). CONCLUSION: L5-S1 might be saved when free of pathology, and when disc degeneration is below grade III and balanced sagit-tally. However, further study is needed because of the short-term follow up and low number of cases in this study.

Wrist fusions in children

Sixteen wrist fusions in children are reviewed with one pseudoarthrosis. There was no significant growth disturbance. (Conclusion)