Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with demonstrated efficacy across various TRK fusion-positive solid tumours. We assessed the efficacy and safety of ...larotrectinib in patients with TRK fusion-positive thyroid carcinoma (TC).
We pooled data from three phase I/II larotrectinib clinical trials (NCT02576431, NCT02122913, and NCT02637687). The primary endpoint was the investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Data cut-off: July 2020.
Twenty-nine patients (median age: 60; range: 6-80) with TRK fusion-positive TC were treated. Tumour histology was papillary (PTC) in 20 (69%) patients, follicular (FTC) in 2 (7%), and anaplastic (ATC) in 7 (24%) patients. Among 28 evaluable patients, ORR was 71% (95% CI: 51-87); best responses were complete response in 2 (7%) patients, partial response in 18 (64%), stable disease in 4 (14%), progressive disease in 3 (11%), and undetermined in 1 (4%) due to clinical progression prior to the first post-baseline assessment. ORR was 86% (95% CI: 64-97) for PTC/FTC and 29% (95% CI 4-71) for ATC. Median time to response was 1.87 months (range 1.64-3.68). The 24-month DoR, PFS, and OS rates were 81, 69, and 76%, respectively. Treatment-related adverse events were mainly grades 1-2.
In TRK fusion-positive TC, larotrectinib demonstrates rapid and durable disease control and a favourable safety profile in patients with advanced disease requiring systemic therapy.
NTRK gene fusions are known oncogenic drivers and have been identified in various histologies of thyroid carcinoma, most commonly in papillary thyroid carcinoma. This is the first publication specifically studying a TRK inhibitor in a cohort of TRK fusion-positive thyroid carcinoma patients. In the current study, the highly selective TRK inhibitor larotrectinib showed durable antitumour efficacy and a favourable safety profile in patients with TRK fusion-positive thyroid carcinoma. Our findings show that patients with advanced non-medullary thyroid carcinoma who may require systemic therapy could be considered for testing for gene fusions by next-generation sequencing.
Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK ...inhibitor, in adults and children who had tumors with these fusions.
We enrolled patients with consecutively and prospectively identified TRK fusion-positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1-2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety.
A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion-positive tumor types. The overall response rate was 75% (95% confidence interval CI, 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events.
Larotrectinib had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of the age of the patient or of the tumor type. (Funded by Loxo Oncology and others; ClinicalTrials.gov numbers, NCT02122913 , NCT02637687 , and NCT02576431 .).
Larotrectinib is a first-in-class, highly selective, and central nervous system-active tropomyosin receptor kinase (TRK) inhibitor approved for the treatment of adult and pediatric patients with TRK ...fusion cancer. We report the efficacy and safety of larotrectinib in patients with TRK fusion-positive salivary gland cancers.
Patients with TRK fusion-positive salivary gland cancer treated with larotrectinib were identified from two clinical trials (NCT02122913 and NCT02576431). Patients received larotrectinib 100 mg twice daily (BID) except for one patient who received 150 mg BID in the phase I trial. The primary endpoint was objective response rate (ORR) as assessed by the investigator using Response Evaluation Criteria in Solid Tumors version 1.1.
At the data cut-off (July 20, 2020), 24 patients with TRK fusion-positive salivary gland cancer had been treated. The most common histologies were secretory carcinoma (54%), adenocarcinoma (25%), and mucoepidermoid carcinoma (13%). All 24 patients had an ETV6-NTRK3 gene fusion. The ORR was 92% (95% confidence interval, 73-99). Best overall response was complete response in three (13%) patients, partial response in 19 (79%), and progressive disease in two (8%). The rate of progression-free survival at 24 months was 78% (median follow-up 30.9 months). Most treatment-related adverse events (AEs) were grade 1-2, and no patients discontinued treatment due to AEs.
Larotrectinib demonstrated robust and durable efficacy in patients with TRK fusion-positive salivary gland tumors of various histologies, and a favorable safety profile. These findings support NTRK gene fusion testing in patients with advanced salivary gland cancers.
NCT02122913 and NCT02576431.
Bottle Creek Brown, Ian W; Brose, David S; Drooker, Penelope Ballard ...
2003
eBook
This is the first comprehensive study and analysis of the most important Mississippian mound site on the north-central Gulf coast.
Consisting of 18 earthen mounds and numerous additional habitation ...areas dating to A.D. 1250-1550, the Bottle Creek site was first professionally investigated in 1932 when David L. DeJarnette of the Alabama Museum of Natural History began work there to determine if the site had a cultural relationship with Moundville, connected to the north by a river system. Although partially mapped in the 1880s, Bottle Creek's location in the vast Mobile-Tensaw Delta of Baldwin County completely surrounded by swamp made it inaccessible and protected it from most of the plunder experienced by similar sites in the Southeast.
This volume builds on earlier investigations to present extensive recent data from major excavations conducted from 1991 to 1994 and supported in part by an NEH grant. Ten anthropologists examine various aspects of the site, including mound architecture, prehistoric diet, pottery classification, vessel forms, textiles used to make pottery impressions, a microlithic stone tool industry, water travel, the persistence of mound use into historic times, and the position of Bottle Creek in the protohistoric world.
The site is concluded to be the best remaining example of Pensacola culture, an archaeological variant of the widespread Mississippian tradition identified by a shell-tempered pottery complex and by its geographic association with the north-central coast of the Gulf of Mexico. Occupied for three centuries by a thriving native culture, Bottle Creek is an important remnant of North American peoples and as such is designated a National Historic Landmark. This published compilation of the research data should establish a base for future scholarly investigation and interpretation.
Ian W. Brown is Professor of Anthropology at The University of Alabama and Curator of Gulf Coast Archaeology at the Alabama Museum of Natural History. He has numerous publications, including Decorated Pottery of the Lower Mississippi Valley: A Sorting Manual. David S. Brose is Director of the Schiele Museum of Natural History in North Carolina and coeditor of The Northwest Florida Expeditions of Clarence Bloomfield Moore and Societies in Eclipse.
Societies in Eclipse Brose, David S; Smith, Marvin T; Williams, Stephen ...
2010, 2005-01-08
eBook
While contact with explorers, missionaries, and traders made a significant impact on natives of the Eastern Woodlands, Indian peoples cannot be solely understood from the historical record. Here, in ...Societies in Eclipse , archaeologists combine recent research with insights from anthropology, historiography, and oral tradition to examine the cultural landscape preceding and immediately following the arrival of Europeans. The evidence suggests that native societies were in the process of significant cultural transformation prior to contact.  
This collection provides a comprehensive vocabulary for defining the cultural manifestation of the term “Woodland.” The Middle Ohio Valley is an archaeologically rich region that ...stretches from southeastern Indiana, across southern Ohio and northeastern Kentucky, and into northwestern West Virginia. In this area are some of the most spectacular and diverse Woodland Period archaeological sites in North America, but these sites and their rich cultural remains do not fit easily into the traditional Southeastern classification system. This volume, with contributions by most of the senior researchers in the field, represents an important step toward establishing terminology and taxa that are more appropriate to interpreting cultural diversity in the region. The important questions are diverse. What criteria are useful in defining periods and cultural types, and over what spatial and temporal boundaries do those criteria hold? How can we accommodate regional variation in the development and expression of traits used to delineate periods and cultural types? How does the concept of tradition relate to periods and cultural types? Is it prudent to equate culture types with periods? Is it prudent to equate archaeological cultures with ethnographic cultures? How does the available taxonomy hinder research? Contributing authors address these issues and others in the context of their Middle Ohio Valley Woodland Period research.  
Ten scholars whose specialties range from ethnohistory to remote sensing and lithic analysis to bioarchaeology chronicle changes in the way prehistory in the Southeast has been studied since the 19th ...century. Each brings to the task the particular perspective of his or her own subdiscipline in this multifaceted overview of the history of archaeology in a region that has had an important but variable role in the overall development of North American archaeology. Some of the specialties discussed in this book were traditionally relegated to appendixes or ignored completely in site reports more than 20 years old. Today, most are integral parts of such reports, but this integration has been hard won. Other specialties have been and will continue to be of central concern to archaeologists. Each chapter details the way changes in method can be related to changes in theory by reviewing major landmarks in the literature. As a consequence, the reader can compare the development of each subdiscipline. As the first book of this kind to deal specifically with the region, it be will valuable to archaeologists everywhere. The general reader will find the book of interest because the development of southeastern archaeology reflects trends in the development of social science as a whole. Contributors include: Jay K. Johnson, David S. Brose, Jon L. Gibson, Maria O. Smith, Patricia K. Galloway, Elizabeth J. Reitz, Kristen J. Gremillion, Ronald L. Bishop, Veletta Canouts, and W. Fredrick Limp
One challenge in merging community and ecosystem ecology is to integrate the complexity of natural multitrophic communities into concepts of ecosystem functioning. Here, we combine food‐web and ...allometry theories to demonstrate that primary production, as measured by the total nutrient uptake of the multitrophic community, is determined by vertical diversity (i.e. food web's maximum trophic level) and structure (i.e. distributions of species and their abundances and metabolic rates across trophic levels). In natural ecosystems, the community size distribution determines all these vertical patterns and thus the total nutrient uptake. Our model suggests a vertical diversity hypothesis (VDH) for ecosystem functioning in complex food webs. It predicts that, under a given nutrient supply, the total nutrient uptake increases exponentially with the maximum trophic level in the food web and it increases with its maximum body size according to a power law. The VDH highlights the effect of top–down regulation on plant nutrient uptake, which complements traditional paradigms that emphasised the bottom–up effect of nutrient supply on vertical diversity. We conclude that the VDH contributes to a synthetic framework for understanding the relationship between vertical diversity and ecosystem functioning in food webs and predicting the impacts of global changes on multitrophic ecosystems.
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