Whole exome analysis of patients (pts) with metastatic GIST (mGIST) demonstrating exceptional survival with imatinib (IM) therapy compared to those with short term benefit.

11513 Background: Most patients with mGIST initially benefit from IM therapy with durable disease control (DC), i.e. objective responses and stable disease, with median duration of approximately two years. We reported exceptional long-term benefit (LTB) with DC and overall survival (OS) >14 years in a subset of mGIST pts treated with IM. We aimed to characterize tumor and normal genomes of exceptional LTB pts treated with IM and compare with short-term benefit (STB) pts. Methods: Among 87 mGIST pts enrolled between July 2000 and June 2001 in the B2222 trial of IM and followed prospectively at the Dana Farber Cancer Institute, we identified 10 LTB (>14 years of DC) pts, and 6 STB (<2 years of DC) pts on IM. Targeted genotyping ( KIT/PDGFRA)was performed in all tumors (n=16). Whole exome sequencing (WES) was performed on archival FFPE tumor samples from LTB and STB pts prior to any IM treatment. We compared WES results from LTB with STB pts to identify unique features of long-term DC and OS with IM. Results: KIT mutation in LTB pts were as follows: exon 11(6 pts), exon 9 (3 pts), and SDH-deficient with KIT/PDGFRA wild type (1 pt). In STB pts, mutated KITwas found 4 pts (exon 11) and 2 pts (exon 9). WES was successful in six LTB (five exon 11, one exon 9) and three STB (two exon 11, one exon 9) pts. A total of 1211 somatic mutations were observed (546 missense, 37 nonsense, 256 silent, 285 indels, 36 splice mutations). The mean somatic mutational burden was 3.42 mutations/Mb (range 1.18-4.93) and 3.34 mutations/Mb (range 1.06-6.68) among LTB and STB, respectively. Genes mutated in LTB but not in STB were MUC7 (4 pts), H1F0 (3 pts), ZKSCAN1 (3 pts), SLC24A1 (3 pts) and USP4 (2 pts). Conclusions: KRAB domain containing zinc finger (KRAB-ZNF) gene expression signatures have been associated with prediction of response to IM, and a possible role in response modulation to tyrosine kinase inhibitors in GIST. We found variants in ZKSCAN1, a gene encoding a transcriptional regulator of the KRAB subfamily of zinc finger, to be present in LTB but not in STB. KRAB-ZNF family of genes may be linked to LTB and exceptional survival with IM in mGIST; functional analyses will be important to test such hypotheses.

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Differential response of primary or secondary exon 13/14 and exon 17 c-kit mutant to nilotinib and sunitinib: Findings from a cell-based drug-screening platform

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e15636 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e15636-e15636

Author(s):

C. Chan ◽

L. Chen ◽

Y. Hsueh ◽

W. Chuang ◽

H. Lee ◽

...

Keyword(s):

Double Mutant ◽

Kinase Inhibitors ◽

Acquired Resistance ◽

Differential Response ◽

Imatinib Treatment ◽

Kit Mutation ◽

Mutant Genotype ◽

Exon 9 ◽

Screening Platform ◽

Exon 11

e15636 Background: Gastrointestinal stromal tumors (GIST) are frequently associated with mutation of c-kit oncogene that is accompanied with constitutional activation of c-kit protein. At present, imatinib is the drug of choice for unresectable or metastatic GIST, however, primary or acquired resistance to imatinib is frequently associated with the presence of an exon 13, 14 or 17 c-kit mutation. The current recommendations for GIST refractory to standard (400 mg/day) imatinib treatment include increasing dose of imatinib to 600–800 mg/day for tumors with primary exon 9 mutation or sunitinib. Several molecular targeted agents are also under investigation. With so many potential agents, personalized therapy based on c-kit mutant genotype for imatinib-resistant GIST deserves to explore. Methods: We prepared a series of c-kit cDNA constructs encoding mutant exon 9 (502AY insertion), 11 (V560D substitution and Δ555–576 deletion), 13 (V654A substitution), 14 (T670I substitution) and 17 (D820G and N822K substitutions) either alone or in combination to simulating the frequently occurred primary ± secondary c-kit mutants in GIST. We expressed these constructs in COS-1 cells to study the efficacy of different tyrosine kinase inhibitors (TKIs) on the autophosphorylation of various single or double mutant c- kit. Results: The efficacy of imatinib on single c-kit mutant was V560D > Δ555–576 > 502AY > D820G or N822K, and ineffective for single and double mutants containing V654A or T670I. Sunitinib is a more potent inhibitor for single 502AY, D820G and N822K mutant than imatinib and nilotinib; while single V654A and T670I c-kit mutant are more sensitive to nilotinib. Interestingly, double exon 11 (V560D or Δ555–576)/V654A or T670I mutant c-kit are more sensitive to sunitinib; while exon 11 (V560D or Δ555–576)/D820G or N822K double mutant c-kit are more sensitive to nilotinib. Conclusions: Our system provides a useful platform to select/screen effective TKIs for GIST with single or double mutant c-kit. The findings of differential response of c-kit mutant to nilotinib and sunitinib may help to select therapy for GIST with primary or secondary exon 13 / 14 and exon 17 mutations. [Table: see text]

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Down-regulation of protein kinase C and kinase inhibitors dissociate short- and long-term enhancement produced by one-trial conditioning of Hermissenda

Journal of Neurophysiology ◽

10.1152/jn.1993.69.2.636 ◽

1993 ◽

Vol 69 (2) ◽

pp. 636-641 ◽

Cited By ~ 19

Author(s):

T. Crow ◽

J. Forrester

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Kinase Inhibitors ◽

Protein Kinase Inhibitors ◽

Cellular Plasticity ◽

Short Term ◽

Down Regulation ◽

Kinase C ◽

Short And Long Term

1. The visual system of Hermissenda has been studied extensively as a site of cellular plasticity produced by classical conditioning. Previous research has shown that one-trial conditioning, consisting of light paired with serotonin (5-HT) results in short- and long-term enhancement of light-elicited generator potentials in identified type B-photoreceptors. Recent evidence suggests that 5-HT exerts its effects on the induction of short-term enhancement by activation of protein kinase C (PKC), a Ca(2+)-activated and phospholipid-dependent protein kinase. However, the contribution of protein kinases in general, and specifically PKC in long-term enhancement has not been established. 2. The protein kinase inhibitors H-7 and sphingosine blocked the induction of short-term enhancement when applied before one-trial conditioning. However, the conditions that are sufficient to block the induction of short-term enhancement do not block long-term enhancement. Sphingosine and H-7 do not block the induction and expression of long-term enhancement when applied before one-trial conditioning. 3. Pretreatment before conditioning with 12-O-tetradecanoyl-phorbol-13-acetate (TPA), which leads to down-regulation of PKC, also did not block long-term enhancement. Down-regulation by itself did not produce enhancement, although the transient peak of light-elicited generator potentials was reduced by pretreatment with TPA. 4. The results suggest that the induction of short- and long-term enhancement involve parallel processes, and thus the expression of long-term cellular plasticity produced by one-trial conditioning does not depend on the induction or expression of short-term enhancement.

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TLR4 signalling in the intestine in health and disease

Biochemical Society Transactions ◽

10.1042/bst0351473 ◽

2007 ◽

Vol 35 (6) ◽

pp. 1473-1478 ◽

Cited By ~ 94

Author(s):

M. Fukata ◽

M.T. Abreu

Keyword(s):

Mammalian Cells ◽

Metabolic Energy ◽

Short Term ◽

Receptor Signalling ◽

Health And Disease ◽

Inflammatory Bowel ◽

Term Benefit ◽

Tlr Signalling

The colonic epithelium is lined along its apical membrane with ∼1014 bacteria/g of tissue. Commensal bacteria outnumber mammalian cells in the gut severalfold. The reason for this degree of commensalism probably resides in the recent recognition of the microbiome as an important source of metabolic energy in the setting of poorly digestible nutrients. As in many themes in biology, the host may have sacrificed short-term benefit, i.e. nutritional advantages, for long-term consequences, such as chronic inflammation or colon cancer. In the present review, we examine the role of TLR (Toll-like receptor) signalling in the healthy host and the diseased host. We pay particular attention to the role of TLR signalling in idiopathic IBD (inflammatory bowel disease) and colitis-associated carcinogenesis. In general, TLR signalling in health contributes to homoeostatic functions. These include induction of antimicrobial peptides, proliferation and wound healing in the intestine. The pathogenesis of IBD, ulcerative colitis and Crohn's disease may be due to increased TLR or decreased TLR signalling respectively. Finally, we discuss the possible role of TLR signalling in colitis-associated neoplasia.

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Pancreatic cancer surgery in elderly patients: Balancing between short-term harm and long-term benefit. A population-based study in the Netherlands

Acta Oncologica ◽

10.3109/0284186x.2015.1105381 ◽

2015 ◽

Vol 55 (3) ◽

pp. 278-285 ◽

Cited By ~ 28

Author(s):

Lydia G. M. van der Geest ◽

Marc G. H. Besselink ◽

Yvette R. B. M. van Gestel ◽

Olivier R. C. Busch ◽

Ignace H. J. T. de Hingh ◽

...

Keyword(s):

Pancreatic Cancer ◽

The Netherlands ◽

Elderly Patients ◽

Population Based ◽

Cancer Surgery ◽

Short Term ◽

Population Based Study ◽

Term Benefit ◽

Surgery In Elderly

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Long-term follow-up of a phase II randomized trial in advanced gastrointestinal stromal tumor (GIST) patients (pts) treated with imatinib mesylate

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.9528 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 9528-9528 ◽

Cited By ~ 23

Author(s):

C. D. Blanke ◽

G. D. Demetri ◽

M. Von Mehren ◽

M. C. Heinrich ◽

B. L. Eisenberg ◽

...

Keyword(s):

Phase Ii ◽

Survival Rates ◽

Complete Response ◽

Tumor Control ◽

Term Survival ◽

Mutational Status ◽

Exon 9 ◽

Exon 11

9528 Background: Imatinib achieves tumor control in most pts with advanced GIST, but the durability of remissions has not been well described. We now present an updated long-term analysis of a randomized phase II trial first presented in 2001, with a median follow-up of 52 months. Methods: 147 pts with unresectable or metastatic malignant GIST were randomized to treatment with daily dosing of imatinib, 400 or 600 mg po. Results: Two pts (1%) achieved a complete response, 98 (67%) achieved a partial response (PR), and 23 (16%) exhibited stable disease (SD) as their best response. Median time-to-response was 13 weeks (95% CI; 12–23 weeks), but one quarter of pts responded after 23 weeks. No significant response differences were seen between the two dose levels tested. The median duration of response was 27 months, and median overall survival was 58 months. Pts with SD or PR had similar 4-year survival rates (64% versus 62%). KIT and/or PDGFRA mutational analyses were obtained in 87% of patients, and the mutational status was highly significant in predicting outcome. GISTs harboring KIT mutations in exon 11, exon 9, and with no detectable mutations in KIT or PDGFRA demonstrated PR rates of 87%, 48%, and 0%, respectively. The median survival for pts with exon 11 KIT mutations has not yet been reached, and it was 45 months for those with exon 9 mutations. Conclusions: While late progression can be seen in GIST pts treated with imatinib, the majority of pts derive benefit. Survival in those achieving SD parallels those with PRs. Late responses are often seen in pts with initial SD, and responses in general are of lasting duration. In particular, pts with KIT mutations in exon 11 (the most common exon affected) have very high response rates and favorable long term survival. [Table: see text]

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Investigation of gastrointestinal stromal tumor (GIST) care management in GIST patients (pts) receiving short-term versus long-term imatinib (IM) adjuvant therapy: A chart review analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.34_suppl.195 ◽

2012 ◽

Vol 30 (34_suppl) ◽

pp. 195-195

Author(s):

Anthony Paul Conley ◽

Annie Guérin ◽

Medha Sasane ◽

Geneviève Gauthier ◽

Frances Schwiep ◽

...

Keyword(s):

Risk Assessment ◽

High Risk ◽

Risk Profile ◽

Prescribing Patterns ◽

Community Practice ◽

Short Term ◽

Online Data ◽

Kit Mutation ◽

Nccn Guidelines

195 Background: Although optimal duration of adjuvant IM therapy in Kit+ GIST pts is unknown, the NCCN guidelines recommend treatment for ≥36 months in high-risk pts based on clinical trials showing reduced risk of recurrence and mortality in pts receiving long-term adjuvant IM. The objective of this study was to investigate clinicians’ recurrence risk assessment and GIST management in patients receiving adjuvant IM for short- (6-12 months) vs. long-term (≥24 months) in community practice. Methods: GIST-related and treatment characteristic information on adult pts with primary resectable Kit+ GIST initiating IM ≤84 days after surgery (short-term: 411 pts; long-term: 408 pts) was collected from 320 U.S. oncologists using an online data collection form. In addition, physician prescribing patterns and perception of risk assessment and IM duration were collected. Results: Indicators of risk (tumor size, mitotic count, and tumor location) were significantly associated with IM treatment duration. Tumor rupture status did not impact IM duration, except when unknown, in which case pts had longer IM duration. About 50% of pts had not been tested for Kit mutation; 31% of physicians reported that it would not have changed therapy/management or were not aware of how results should have impacted GIST management. Among short-term pts for whom physicians reported a reason for IM discontinuation, main reasons included non-severe adverse events, completion of the 1-year treatment scheduled, economic constraint/health plan coverage change, and pts’ preference. Overall, 77.8% of surveyed physicians reported that pt risk profile drove their decision of continuing IM over an extended period of time. However, in practice 39.9% of the short-term pts and 48.8% of the long-term pts had a high risk profile as assessed by Fletcher classification; suggesting a lack of consistency between treatment related opinions and practice. Conclusions: These observed discrepancies highlight the need for standardization of risk assessment practices and education among community oncologists and pts.

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Long-term results of selective internal radioembolization (SIRT) to control progressive liver metastases of gastro-intestinal stromal tumors (GIST) beyond treatment with tyrosine kinase inhibitors (TKI).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.11538 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 11538-11538

Author(s):

Peter Hohenberger ◽

Nils Rathmann ◽

Karen Buesing ◽

Franka Menge ◽

Steffen Diehl

Keyword(s):

Liver Metastases ◽

Treatment Options ◽

Hepatic Metastases ◽

Progression Free Survival ◽

Long Term Results ◽

Mutational Status ◽

Exon 9 ◽

Exon 11

11538 Background: Liver and peritoneum are the main area of metastatic spread in GIST. Liver resection does not play a role for hepatic metastases in comparison to f.e. colorectal cancer. If hepatic metastases are the only or major area of tumor progression and are resistant to available TKIs due to a missing mutation in KIT/PDGFRA/SDH ( ‘wildtype’) or after treatment with 1st/2nd/3rd/4th line therapy, interventional radioembolization with yttrium-90 (90Y) microspheres are promising treatment options, as radiation doses as high as 200Gy can be applied locally. We analyzed the long-term results of SIRT with respect to hepatic-progression-free survival (HEP-PFS) in a consecutive cohort of patients.. Methods: From 1/2008 to 1/2018, 25 pts (12f, 13m) with biopsy proven liver metastases of GIST which were the only (n = 13) or the dominant site of progression (n = 12) were treated by SIRT. Median age at GIST diagnosis had been 51.8 yrs and when receiving SIRT was 57.6yrs (range, 18–75yrs). The mutational status was ‘wildtype’ (n = 7, 2 NF-1), exon 11 (n = 7), exon 11+2nd mutation (n = 6), exon 9 (n = 3), exon 9+2ndmut (n = 1), and, exon 13 (n = 1). All patients except of two had prior TKI therapy: 1 line n = 3, 2 lines n = 11, 3-4 lines n = 9. Follow-up after SIRT was done via dynamic MRI and contrast-enhanced (CE)-CT, the median follow-up is 30.6 mos (range, 12-100mos) and all patients were followed until death. Results: The median hepatic-progression free survival (HEP-PFS) after SIRT was 17 months (range, 5-53+, 95%CI 11.8-22.1 mos). Of the patients with concomitant extrahepatic disease, the extraHEP-PFS was median 10 months. Twelve patients received next-line TKI therapy for progressive extrahepatic disease, whereas six patients required this for progressive liver metastases. When comparing the results according to the mutational status, patients with a ‘wildtype’ tumor showed a better median HEP-PFS of 19 mos (range, 12-53+, 95%CI 16.7-21.2 mos.) in comparison to KIT exon 9/11/13 mutated patients with only 14 months (range, 4-34 mos., 95%CI 6.5-21.4 mos), p < 0.11 (Wilcoxon). Conclusions: 90Y radioembolization (SIRT) offers a safe and effective treatment for patients with liver metastases of GISTs being the dominant site of tumor progression and with no drug treatment options available. In patients known to have no mutation in KIT/PDGFRA (wt, also NF-1 associated) it looks whether the results might be even more promising and SIRT could be used in early treatment lines.

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Honduras

The Oxford Handbook of Central American History ◽

10.1093/oxfordhb/9780190928360.013.19 ◽

2020 ◽

Author(s):

Dario A. Euraque

Keyword(s):

Well Being ◽

The State ◽

Short Term ◽

National Interests ◽

Lethal Violence ◽

Political Agent ◽

Structural Weakness ◽

Personal Survival ◽

Term Benefit

A fact of Honduran history after the 1840s is the structural weakness of the state as an organized political agent capable of administering a nationally defined territory, managing its constitutionally prescribed monopoly over security, and effectively addressing the most minimal aspects of the population’s economic and social welfare. Various factors explain this. A key problem has been Honduran elites’ lack of cohesion and enlightened commitment to their long-term interests among themselves and beyond their borders. Resorting to lethal violence to secure advantaged and corrupt access to state resources has been the result and norm, even to the detriment of elite unity and hegemony. This has often placed the state and country at the mercy of economic and military forces, local and international, that elites cannot control, and with which they have negotiated for short-term benefit and even personal survival, most often to the detriment of national interests, and Hondurans’ rudimentary well-being.

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