Circulating tumor DNA to investigate resistance mechanism and clone evolution of ALK TKI treated lung adenocarcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3011-3011
Author(s):  
Gang Hua ◽  
Xiaoxi Chen ◽  
Ruoying Yu ◽  
Hua Bao ◽  
Xue Wu ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
First Generation ◽  
Second Generation ◽  
Circulating Tumor Dna ◽  
Third Generation ◽  
Alk Inhibitors ◽  
Clone Evolution ◽  
Alk Positive ◽  
Tki Treatment ◽  
Tumor Dna

3011 Background: Sequential treatment with first-, second-generation ALK TKI followed by third-generation TKI (lorlatinib) have been widely applied to ALK-positive lung cancer. However, acquired resistance is often driven by secondary ALK mutations, which are needed to be further explored. Circulating tumor DNA, a non-invasive approach, can detect tumor-derived DNA from multiple metastatic sites and has become a promising strategy for assessing the genetic evolution of tumors and analyzing TKI resistance. Methods: Post-progression plasma specimens were collected and sequenced with a targeted gene panel from a total of 116 patients underwent ALK TKI treatment with from February 2014 to April 2020. The ALK TKIs administrated in this cohort included crizotinib (first-generation), ceritinib (second-generation), alectinib (second-generation), brigatinib (second-generation), ensartinib (second-generation) and lorlatinib (third-generation). Results: In this ALK-positive lung adenocarcinoma cohort, 49.1% were female and the rest were male with a median age of 52 (range 20 to 79). More than half of patients received more than one line of ALK TKI treatment. The most frequent ALK fusion type is EML4-ALK including EML4-ALK v1(E13; A20, 37/116, 31.9%) and EML4-ALKv3(E6a/b; A20, 49/116, 42.2%). TP53 (29.1%, 41/141) was the most frequently mutated gene other than ALK. Frequently identified secondary mutations in patients progressing on ALK inhibitors were ALK mutations L1196M and G1202R. ALK G1202R was more common in patient with v3 fusion than in v1 (25.8% vs 0%; P<.001) while ALK L1196M was more common in v1 than in v3 (20.8% vs 3.2%; P=.005). Meanwhile, G1202R was identified at higher ratio in patients progressed on second-generation ALK TKI than first- and third-generation ALK TKI (11.3% vs 0% and 9.1%) whereas L1196M was more found in patients progressed on first-generation ALK TKI (9.1% vs 1.9% and 4.5%). Other identified secondary mutations were ALK F1174C/V/L, E1210K/Q, D1269A, D1203N and L1122M/V. Compound ALK mutations (≥2 concurrent ALK mutations) were more common in patients relapsed on third-generation ALK TKI lorlatinib (36.4%) compared to first- (12.1%) and second-generation (20.8%) ALK TKIs. Using serial plasma specimens, clone evolution analysis showed that five patients developed compound ALK mutations after sequential ALK TKI treatments and two novel ALK compound lorlatinib-resistant mutations D1203N+I1171N and F1174C+G1202R were identified. Conclusions: Genotyping of sequential post-progression plasma specimens reveals that treatment with sequential first-, second-, and third-generation ALK inhibitors can accelerate the accumulation of ALK resistance mutations and may lead to treatment-refractory compound ALK mutations. The selection for optimal first-line TKI is very important to achieve a more efficacious long-term strategy and prevent the emergence of on-target resistance.

Outcomes of first, second, and third-generation anaplastic lymphoma kinase (ALK) inhibitors in non-small cell lung cancer brain metastases (NSCLCBM).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2034-2034
Author(s):  
Vineeth Tatineni ◽  
Patrick Joseph O'Shea ◽  
Yasmeen Rauf ◽  
Xuefei Jia ◽  
Erin Sennett Murphy ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastases ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
First Generation ◽  
Second Generation ◽  
Small Cell ◽  
Third Generation ◽  
Small Cell Lung ◽  
Alk Inhibitors

2034 Background: Non-small cell lung cancer (NSCLC) is the most common cause of brain metastases. ALK, which codes for tyrosine kinase receptors, is rearranged in 4-7% of NSCLC. First-generation ALK inhibitors have restricted efficacy due to poor blood-brain barrier (BBB) penetration and ALK-resistant tumor mutations. Second-generation ALK inhibitors have shown better BBB penetration, while third-generation ALK inhibitors were efficacious even against ALK-resistant mutations. In this retrospective study, we investigated the overall survival (OS) and progression-free survival (PFS) in NSCLCBM patients treated with first, second, and third-generation ALK inhibitors. Methods: NSCLCBM patients between 2010 and 2019 were evaluated. We analyzed data regarding molecular marker status, systemic therapies, and date of progression. OS was defined as the start date of systemic therapy to the date of last follow-up or death. The Cox proportional model was used to estimate OS and PFS. Results: A total of 90 patients had ALK gene rearrangement. 16 ALK positive patients received first-generation ALK inhibitor (crizotinib), with a median age of 59.2 years, 50% of the cohort being female and 83.3% being white. Another 17 patients received second-generation (alectinib, ceritinib, brigatinib) and third-generation ALK inhibitors (lorlatinib), with a combined median age of 52.2 years and a cohort of 52.6% females and 72.2% white patients. The 5-year OS rate was 49% (95% confidence interval (CI) = 24%, 71%) for first-generation ALK inhibitors and 76% (95% CI = 40%, 92%) for second and third-generation ALK inhibitors (p-value (p) = 0.019). The median PFS (mPFS) for patients who received first-generation ALK inhibitors was 45.3 months and for those who received second or third-generation ALK inhibitors was 180.1 months. The respective 5-year PFS rate was 43% (95% CI = 19%, 65%) and 72% (95% CI = 42%, 89%). Conclusions: Newer generations of targeted therapies in NSCLCBM have improved BBB penetration and effectiveness against resistant mutations. We determined that there was a significant 5-year OS benefit in patients who received second and third-generation ALK inhibitors compared to first-generation ALK inhibitors, and a respective trend towards significant PFS benefit in newer-generation ALK inhibitors when compared to first-generation. These results are encouraging, but the effect on intracranial lesion size and response rates should be examined in the future.[Table: see text]

The Brown Mite, Bryobia arborea Morgan and Anderson (Acarina: Tetranychidae), on Apple in Nova Scotia.: I. Influence of Intratree Distribution on the Selection of Sampling Units. II. Differences in Habits and Seasonal Trends in Orchards With Bivoltine and Trivoltine Populations. III. Distribution of Diapause Eggs. IV. Hatching of Diapause Eggs

1965 ◽  
Vol 97 (12) ◽  
pp. 1303-1318 ◽  
Author(s):  
H. J. Herbert
Keyword(s):  
Nova Scotia ◽  
First Generation ◽  
Second Generation ◽  
Central Area ◽  
Third Generation ◽  
Apple Trees ◽  
Seasonal Trends ◽  
Sample Unit ◽  
The Third ◽  
Selection Of

AbstractIn Nova Scotia one leaf cluster with an adjoining 1 inch of twig taken from the inside of each of 10 apple trees replicated four times is an adequate sample unit to measure the density of the brown mite.The brown mite has one generation with a partial second in some orchards and one with a partial second and partial third in others. The first generation adults in the bivoltine and trivoltine populations lay summer eggs on the leaves and twigs, and diapause eggs on tin twigs. The second generation adults in the bivoltine populations lay only diapause eggs; in the trivoltine populations they lay both summer and diapause eggs. The adults of the third generation lay only diapause eggs.The brown mite is found on both the leaves and woody parts of the tree. In orchards with bivoltine populations the proportion of mites on leaves reached a peak of 80% by mid-July, but thereafter gradually decreased to 10% by the end of August. However, in orchards with trivoltine populations the proportion of mites on leaves reached a peak of 80 to 90% by mid-July, remained constant until mid-August, and thereafter decreased to approximately 40% by the end of August.The number of diapause eggs laid by adults of each generation in both the bivoltine and trivoltine populations varies widely. The eggs are deposited on the trunk as well as on the branches, with the heaviest deposition in the central area of the tree. The diapause eggs laid by adults of the first generation are the last to hatch and those laid by the third generation are the first to hatch the following spring.The factors responsible for the differences in the number of generations and in the number of diapause eggs laid are unknown.

Distillery Configurations

2019 ◽  
pp. 47-64
Author(s):  
Karl Raitz
Keyword(s):  
Nineteenth Century ◽  
Labor Force ◽  
First Generation ◽  
Second Generation ◽  
High Capacity ◽  
Third Generation ◽  
Early Nineteenth Century ◽  
Railroad Tracks ◽  
Urban Rail ◽  
Capacity Output

Early-nineteenth-century farmers and millers were often craft distillers, mashing and fermenting grain meal in wooden barrels before distilling the liquid in small copper pot stills. Waterwheels powered the first-generation creek-side mills and distilleries. Wood fueled early steam engines; the use of coal required access to better transportation. Second-generation distilleries, operating from the 1830s to the 1880s, used traditional pot stills,although some adopted new column stills, perfected in Scotland, when they began to mechanize. Old still buildings were often modified to accommodate new machinery. Distillers stored whiskey-filled wooden barrels in stack warehouses to age. Industrialization required a larger labor force. By 1880, businesses in Louisville and other river cities were producing steam engines, boilers, and related equipment. Third-generation distilleries operated from the 1880s to 1920; their high-capacity output required more grain and fuel, mandating locations near railroad tracks or navigable rivers. Complementary industries such as cooperages, metal fabricators, slaughterhouses, and tanneries were attracted to urban, rail-side distilleries.

Failure properties of 352 explanted silicone-gel breast implants

1996 ◽  
Vol 4 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Walter Peters ◽  
Dennis Smith ◽  
Stanley Lugowski
Keyword(s):  
First Generation ◽  
Second Generation ◽  
Survival Curve ◽  
Breast Implants ◽  
Thick Wall ◽  
Thin Wall ◽  
Third Generation ◽  
Silicone Gel ◽  
Failure Properties

There have been three generations of silicone-gel breast implants. First generation implants (thick wall – thick gel with Dacron patches) were made from 1963 to 1972. Second generation implants (thin wall-thin gel) were made from 1972 until the mid 1980s. The introduction of third generation implants (stronger wall, low-bleed) was geographically dependent. In Canada, Dow Corning Silastic II implants were introduced in 1986, and Surgitek SCL implants were introduced in 1988. In the present study, a total of 352 silicone-gel breast implants were removed from 239 patients between 1981 and 1995. Their failure properties were dependent upon their generation (year of manufacture) and, for second generation implants, their duration in situ. Of the 352 implants, 20 were first generation, and all were fully intact. Twenty-eight were third generation implants, and 27 were fully intact. Failure properties of the 302 second generation implants were dependent upon their duration of implantation. A survival curve indicated that these implants began to fail (by leaking or rupturing) after four years in situ. By six years, 40% had failed. After 12 years, 95% had failed. Of the 171 second generation implants removed between 1991 and 1995, 77% had failed. The failure properties were similar for the three main manufacturers: Dow Corning, Heyer-Schulte and Surgitek. The failure rate for second generation implants is much higher than was previously believed. This is particularly significant in view of the current difficulty in diagnosing implant failure.

scholarly journals Development of a Divergent Route to Erythrina Alkaloids

Synlett ◽  
2020 ◽  
Vol 31 (04) ◽  
pp. 327-333 ◽  
Author(s):  
Jesper L. Kristensen ◽  
Sebastian Clementson ◽  
Mikkel Jessing ◽  
Paulo J. Vital
Keyword(s):  
Natural Products ◽  
Total Synthesis ◽  
19Th Century ◽  
First Generation ◽  
Second Generation ◽  
Enantioselective Synthesis ◽  
Third Generation ◽  
Synthetic Strategy ◽  
Erythrina Alkaloids ◽  
The 19Th Century

Erythrina alkaloids were identified at the end of the 19th century and today, more than 100 members of the erythrinane family have been isolated. They are characterized by a unique tetracyclic, α-tertiary spiroamine scaffold. Herein we detail our efforts towards the development of a divergent enantioselective synthesis of (+)-dihydro-β-erythroidine (DHβE) – one of the most prominent members of this intriguing family of natural products.1 Introduction2 Synthetic Strategy2.1 First Generation2.2 Second Generation2.3 Third Generation2.3.1 Radical Endgame2.3.2 Completion of the Total Synthesis3 Conclusion

scholarly journals Novel SPECC1L-MET Fusion Detected in Circulating Tumor DNA in a Patient with Lung Adenocarcinoma following Treatment with Erlotinib and Osimertinib

2019 ◽  
Vol 14 (2) ◽  
pp. e27-e29 ◽  
Author(s):  
Annie W. Nelson ◽  
Alexa B. Schrock ◽  
Dean C. Pavlick ◽  
Siraj M. Ali ◽  
Emily C. Atkinson ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Circulating Tumor Dna ◽  
Tumor Dna

Brominated β-Alkoxyvinyl Trihalomethyl Ketones as Promising Synthons in Heterocyclic Synthesis

Synthesis ◽  
2020 ◽  
Vol 52 (14) ◽  
pp. 2008-2016
Author(s):  
Mateus Mittersteiner ◽  
Nilo Zanatta ◽  
Helio G. Bonacorso ◽  
Marcos A. P. Martins
Keyword(s):  
First Generation ◽  
Second Generation ◽  
Building Blocks ◽  
Third Generation ◽  
Cycloaddition Reactions ◽  
Heterocyclic Synthesis

5-Bromo- and 5,5-dibromo-1,1,1-trihalo-4-methoxypent-3-en-2-ones (brominated enones) have proven to be attractive building blocks for the construction of heterocyclic and polyheterocyclic compounds bearing a trihalomethyl moiety through interesting cyclocondensation, alkylation, and cycloaddition reactions. This review compiles all of the reactions conducted with these brominated enones since they were first disclosed in 2001.1 Introduction2 Synthesis and Initial Applications3 Synthesis Using First-Generation Intermediates4 Synthesis Using Second-Generation Intermediates5 Synthesis Using Third-Generation Intermediates6 Conclusions

Evolution of a Chemical Strategy Toward the Synthesis of Unsymmetrically Oxidized Nuphar Alkaloids

Synlett ◽  
2019 ◽  
Vol 30 (14) ◽  
pp. 1632-1642
Author(s):  
Jacob J. Lacharity ◽  
Armen Zakarian
Keyword(s):  
Total Synthesis ◽  
First Generation ◽  
Second Generation ◽  
Third Generation ◽  
Successful Strategy ◽  
Synthesis Design ◽  
Sulfonium Ylide ◽  
Chemical Strategy

Here we describe the frustrations, joys, and unexpected turns experienced in our journey toward a successful strategy directed at the total synthesis of unsymmetrically oxidized Nuphar thioalkaloids. While many adjustments were made to our initial synthesis plan, our general approach to the construction of the central bis(spirothiolane) moiety remained unchanged. Specifically, each iteration of our synthesis design involved the formation of the thiaspirane motif through the stereodivergent coupling of a thietane with a metal carbenoid, followed by a Stevens-type rearrangement of the resulting sulfonium ylide.1 Introduction2 First-Generation Strategy3 Second-Generation Strategy4 Third-Generation Strategy5 Conclusion

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