Priorities for cancer prevention

Page, Jamie; Whaley, Paul; Watterson, Andrew; Clapp, Richard

doi:10.1016/s1470-2045(12)70140-7

Cited by 9 publications

(6 citation statements)

References 2 publications

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“…Similar to solitary neoplasms, multiple sporadic GISTs have a varying potential for malignancy, ranging from virtually indolent tumors to fatal cancers. It was reported that the estimated 5-year RFS rate for GISTs was 70.5% 24. In our study, the 5-year RFS rate for multiple GISTs was 66%, which is comparable to that of patients with only a single tumor.…”

Section: Discussionsupporting

confidence: 71%

Multiple gastrointestinal stromal tumors: analysis of clinicopathologic characteristics and prognosis of 20 patients

Tjhoi

Shou

et al. 2019

CMAR

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Purpose Multiple gastrointestinal stromal tumors (GISTs) are rare. The aim of this study was to investigate the clinicopathologic characteristics and prognosis of multiple GISTs. Patients and methods Between May 2003 and June 2018, patients who underwent surgery for multiple GISTs were retrospectively analyzed. Exons 9, 11, 13, and 17 of the KIT gene, and exons 12, and 18 of the PDGFRA gene were examined in 34 tumors from 20 patients. Results A total of 20 patients with multiple GISTs were enrolled. There were 11 females and nine males with a median age of 59 years (range: 37–80 years). Of these cases, 16 were sporadic cases and four were associated with GIST syndromes (two cases of Carney triad and two cases of neurofibromatosis type 1 [NF1]). The most common presentation was gastrointestinal bleeding. Carney triad GISTs did not exhibit KIT/PDGFRA mutations. One of the NF1 patients was a KIT/PDGFRA wild-type, and the other patient had a PDGFRA mutation. Of the sporadic cases, one shared the same KIT gene mutation within each GIST and one had two lesions that were both wild-type for KIT and PDGFRA. Different KIT mutations among individual tumors were detected in seven patients. During the median follow-up period of 66 months (range: 3–183 months), four patients developed liver or abdominal metastases, three of whom expired due to the disease. The rates of recurrence-free survival and overall surviva at 5 years were 65.8% and 76.7%, respectively. Conclusion Multiple GISTs may occur as sporadic tumors or as an additional component of specific syndromes (eg, Carney triad and NF1) that display different clinicopathologic characteristics based on their particular underlying mechanisms. The overall prognosis of patients with multiple GISTs is comparable to that of patients with only a single GIST.

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Section: Discussionsupporting

confidence: 71%

Multiple gastrointestinal stromal tumors: analysis of clinicopathologic characteristics and prognosis of 20 patients

Tjhoi

Shou

et al. 2019

CMAR

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“…In several Phase I trials with both solid and hematological malignancies, RG7112 showed evidence of on-target activity resulting in p53 activation. After treatment with RG7112, there was an increased expression of downstream pro-apoptotic proteins 50–52. In AML, RG7112 was studied both as monotherapy and in combination with low-dose cytarabine 53.…”

Section: P53 and Mdm2mentioning

confidence: 99%

MDM2 antagonists as a novel treatment option for acute myeloid leukemia: perspectives on the therapeutic potential of idasanutlin (RG7388)

Khurana¹,

Shafer²

2019

OTT

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Acute myeloid leukemia (AML) is a clonal heterogenous malignancy of the myeloid cells with a poor prognosis lending itself to novel treatment strategies. TP53 is a critical tumor suppressor and plays an essential role in leukemogenesis. Although TP53 is relatively unusual in de novo AML, inactivation of wild-type p53 (WT-p53) is a common event. Murine double minute 2 (MDM2) is a key negative regulator of p53 and its expression; inhibition of MDM2 is postulated to reactivate WT-p53 and its tumor suppressor functions. Nutlins were the first small molecule inhibitors that bind to MDM2 and target its interaction with p53. RG7388 (idasanutlin), a second-generation nutlin, was developed to improve upon the potency and toxicity profile of earlier nutlins. Preliminary data from early phase trials and ongoing studies suggest clinical response with RG7388 (idasanutlin) both in monotherapy and combination strategies in AML. We herein briefly discuss currently approved therapies in AML and review the clinical data for RG7388 (idasanutlin) and MDM2 inhibition as novel treatment strategies in AML. We further describe efficacy and toxicity profile data from completed and ongoing trials of RG7388 (idasanutlin) and other MDM2-p53 inhibitors in development. Many targeted therapies have been approved recently in AML, with a focus on the older and unfit population for intensive induction therapy and in relapsed/refractory disease. The “nutlins”, including RG7388 (idasanutlin), merit continued investigation in such settings.

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“…The reported AEs are consistent with the known toxicity profile of other EGFR-TKIs, such as erlotinib, gefitinib, afatinib, icotinib, and cetuximab, in which rash and gastro-intestinal side-effects are the most frequently reported drug-related AEs 15–18. For example, results of clinical trials showed frequencies of diarrhea at 40.0–67.9% for erlotinib,19,20 27.0–58.2% for gefitinib21–24 and 87.0% for afitinib,25 similar to that observed in this phase I study (56.1%). Mechanisms involved in skin and gastro-intestinal toxicities of EGFR-TKIs are either a reversible or an irreversible tyrosine kinase blockade.…”

Section: Discussionmentioning

confidence: 99%

Safety, tolerability, and pharmacokinetics of simotinib, a novel specific EGFR tyrosine kinase inhibitor, in patients with advanced non-small cell lung cancer: results of a phase Ib trial

Hu¹,

Han²,

Yang³

et al. 2019

CMAR

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Purpose: The aim of this phase Ib study (clinicaltrials.gov: NCT01772732) was to assess safety, tolerability, and pharmacokinetics (PKs) of simotinib (a novel EGFR tyrosine kinase inhibitor) in patients with advanced non-small cell lung cancer (NSCLC) and EGFR gene mutation. Patients and methods: 41 patients with EGFR gene mutations were enrolled and received simotinib orally administered twice daily with dose escalating from 100 to 650 mg in 28 days cycle. Safety and tolerability were assessed through the study. Blood samples were collected for PK analysis on Days 1, 8, 9, 10, 15, 22 and 29. Tumor response was assessed at baseline, on Day 29 and every 8 weeks thereafter. Results: Simotinib was well tolerated, with no dose-limiting toxicities. Maximum tolerated dose (MTD) was not found. 95.1% of patients experienced at least one adverse event (AE), and most of them were mild or moderate. Rash (41.5%) and diarrhea (56.1%) were the most frequently reported AEs. Simotinib was rapidly absorbed and eliminated with average T max ranging from 1 to 4 hrs and T 1/2 ranging between 6.2 and 13.0 hrs after multiple-dose administration. No dose–response relationship between dose and exposure was observed after multiple-dose administration. 39.3% of the enrolled patients achieved a partial response and 46.3% had stable disease. Median progression-free survival and overall survival were 9.9 (CI% 4.7; 12.1) months and 14.6 (95%CI 12.3; 22.5) months, respectively. Conclusion: Simotinib was well tolerated, with manageable AEs at doses of up to 650 mg and MTD was not reached. Further studies to explore higher doses are ongoing.

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Priorities for cancer prevention

Cited by 9 publications

References 2 publications

<p>Multiple gastrointestinal stromal tumors: analysis of clinicopathologic characteristics and prognosis of 20 patients</p>

<p>Multiple gastrointestinal stromal tumors: analysis of clinicopathologic characteristics and prognosis of 20 patients</p>

<p>MDM2 antagonists as a novel treatment option for acute myeloid leukemia: perspectives on the therapeutic potential of idasanutlin (RG7388)</p>

<p>Safety, tolerability, and pharmacokinetics of simotinib, a novel specific EGFR tyrosine kinase inhibitor, in patients with advanced non-small cell lung cancer: results of a phase Ib trial</p>

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