Response Of Gastrointestinal Stromal Tumors Research Articles

Four and a half LIM domains 2 (FHL2) attenuates tumorigenesis of gastrointestinal stromal tumors (GISTs) by negatively regulating KIT signaling.

Gastrointestinal stromal tumors (GISTs) are predominately induced by KIT mutants. In this study, we found that four and a half LIM domains 2 (FHL2) was highly expressed in GISTs and KIT signaling dramatically increased FHL2 transcription while FHL2 inhibited KIT transcription. In addition, our results showed that FHL2 associated with KIT and increased the ubiquitination of both wild-type KIT and primary KIT mutants in GISTs, leading to decreased expression and activation of KIT although primary KIT mutants were less inhibited by FHL2 than wild-type KIT. In the animal experiments, loss of FHL2 expression in mice carrying germline KIT/V558A mutation which can develop GISTs resulted in increased tumor growth, but increased sensitivity of GISTs to imatinib treatment which is used as the first-line targeted therapy of GISTs, suggesting that FHL2 plays a role in the response of GISTs to KIT inhibitor. Unlike wild-type KIT and primary KIT mutants, we further found that FHL2 didn't alter the expression and activation of drug-resistant secondary KIT mutants. Taken together, our results indicated that FHL2 acts as the negative feedback of KIT signaling in GISTs while primary KIT mutants are less sensitive and secondary KIT mutants are resistant to the inhibition of FHL2.

Identification of New Tumor-Related Gene Mutations in Chinese Gastrointestinal Stromal Tumors.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. As the main GIST drivers, gain-of-function mutations in KIT or PDGFRA are closely associated with not only tumor development and progression but also therapeutic response. In addition to the status of KIT and PDGFRA, little is known about other potential GIST-related genes. In this study, we identified the mutation profiles in 49 KIT-mutated GIST tumors using the whole exome sequencing (WES) method. Furthermore, some representative mutations were further validated in an independent GIST cohort using the SNaPshot SNP assay. We identified extensive and diverse mutations of KIT in GIST, including many undescribed variants. In addition, we revealed some new tumor-related gene mutations with unknown pathogenicity. By enrichment analyses of gene function and protein-protein interaction network construction, we showed that these genes were enriched in several important cancer- or metabolism-related signaling pathways, including PI3K-AKT,RTK-RAS, Notch, Wnt, Hippo, mTOR, AMPK, and insulin signaling. In particular, DNA repair-related genes, including MLH1, MSH6, BRCA1, BRCA2, and POLE, are frequently mutated in GISTs, suggesting that immune checkpoint blockade may have promising clinical applications for these GIST subpopulations. In conclusion, in addition to extensive and diverse mutations of KIT, some genes related to DNA-repair and cell metabolism may play important roles in the development, progression and therapeutic response of GIST.

Advances in radiological studies of gastrointestinal stromal tumors

The commonly used radiological examinations for gastrointestinal stromal tumor (GIST) include ultrasound, CT, magnetic resonance imaging and PET, which play important roles in the individualized treatment of GIST through the assistance of the detection, location, diagnose and differential diagnosis, biological behavior and risk evaluation, operation planning, therapeutic effects prediction and follow-up. Standardized predisposal, multi-planar reconstruction and multi-phase enhancement are of great significance in the detection of small GIST lesions. Differences in drainage vessels and enhancement characteristics of tumors are helpful in differentiating small intestinal GIST from pancreatic cancer, neuroendocrine tumors and other abdominal non-GIST tumors. Radiology can provide multiple indicators to qualitatively or quantitatively reflect the risk of GIST. Recent study found that the risk classification of GIST has correlation with necrosis, but not cystic degeneration. The risk stratification of GIST by dual-energy CT showed that CT value and standardized iodine concentration in arterial-venous and delayed phases of high-risk tumors were significantly higher than those of non-high-risk tumors. The correlation between tumor enhancement pattern and risk stratificationwas still controversial. Recently, the rise of radiomics and deep learning techniques provide new direction for risk assessment of GIST. Some studies used various models and parameters to predict the risk classifications of GIST and achieved AUC values above 0.85, and some results were also superior to conventional indicators and radiologists' subjective judgment in the prediction of exon 11 mutations, mitotic counts and survivals. Recent developments in PET and diffusion-weighted MRI provide more precise functional quantitative indicators for the prediction and early evaluation of the response of GIST to targeted therapy. These studies are constantly expanding our field of exploration, and prompting us to stride toward the goal of individualized treatment of GIST.

MRI in predicting the response of gastrointestinal stromal tumor to targeted therapy: a patient-based multi-parameter study

BackgroundTo investigate the performance of quantitative indicators of MRI in early prediction of the response of gastrointestinal stromal tumor (GIST) to targeted therapy in a patient-based study.MethodsMRI examinations were performed on 62 patients with GIST using 1.5 T scanners before and at two and 12 weeks after treatment with targeted agents. The longest diameter (LD) and contrast-to-noise ratio (CNR) of the tumors were measured by T2-weighted imaging (T2WI), and the apparent diffusion coefficient (ADC) was determined using diffusion-weighted imaging (DWI). The pre-therapy and early percentage changes (%Δ) of the three parameters were compared with regard to their abilities to differentiate responder and non- responder patients, using ROC curves.ResultsThere were 42 patients in responder and 20 in non-responder group. After two weeks of therapy, the percentage changes in the ADC and LD were significantly different between the two groups (ADC: responder 30% vs. non- responder 1%, Z = − 4.819, P < 0.001; LD: responder − 7% vs. non- responder − 2%, Z = − 3.238, P = 0.001), but not in T2WI-CNR (responder − 3% vs. non-responder 9%, Z = − 0.663, P = 0.508). The AUCs on ROC for %ΔLD, %ΔT2WI-CNR and %ΔADC after two weeks of therapy were 0.756, 0.552 and 0.881, respectively, for response differentiation. When %ΔADC ≥15% was used to predict responder, the PPV was 93.3%.ConclusionsThe percentage change of the ADC after two weeks of therapy outperformed T2WI-CNR and longest diameter in predicting the early response of GIST to targeted therapy.

Correction to: Imaging therapy response of gastrointestinal stromal tumors (GIST) with FDG PET, CT and MRI: a systematic review

The article “Imaging therapy response of gastrointestinal stromal tumors (GIST) with FDG PET, CT and MRI: a systematic review”, written by Antonia Dimitrakopoulou-Strauss, Ulrich Ronellenfitsch, Caixia Cheng, Leyun Pan, Christos Sachpekidis, Peter Hohenberger, and Thomas Henzler, was originally published Online First without open access. After publication in volume 5, issue 3, pages 183‒197, the author decided to opt for Open Choice and to make the article an open access publication. Therefore, the copyright of the article has been changed to © The Author(s) 2017 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as appropriate credit is given to the original author(s) and the source, a link is provided to the Creative Commons license, and any changes made are indicated.

Early Evaluation of Response Using 18F-FDG PET Influences Management in Gastrointestinal Stromal Tumor Patients Treated with Neoadjuvant Imatinib.

18F-FDG PET has previously been proven effective as an early way to evaluate the response of gastrointestinal stromal tumors (GISTs) to imatinib treatment. However, it is unclear whether early evaluation of response affects treatment decisions in GIST patients treated with neoadjuvant intent. Methods: We retrospectively scored changes in management based on early evaluation of response by 18F-FDG PET in patients in the Dutch GIST registry treated with neoadjuvant imatinib. Results: Seventy 18F-FDG PET scans were obtained for 63 GIST patients to evaluate for an early response to neoadjuvant imatinib. The scans led to a change in management in 27.1% of the patients. Change in management correlated strongly with lack of metabolic response (P < 0.001) and non-KIT exon 11-mutated GISTs (P < 0.001). Conclusion: Performing 18F-FDG PET for early evaluation of response often results in a change of management in GIST patients harboring the non-KIT exon 11 mutation and should be considered the standard of care in GIST patients treated with neoadjuvant intent.

Non-Gaussian diffusion imaging with a fractional order calculus model to predict response of gastrointestinal stromal tumor to second-line sunitinib therapy.

To demonstrate the clinical value of a non-Gaussian diffusion model using fractional order calculus (FROC) for early prediction of the response of gastrointestinal stromal tumor to second-line sunitinib targeted therapy. Fifteen patients underwent sunitinib treatment after imatinib resistance. Diffusion-weighted imaging with multiple b-values was performed before treatment (baseline) and 2 weeks (for early prediction of response) after initiating sunitinib treatment. Conventional MRI images at 12 weeks were used to determine the good and poor responders according to the modified Choi criteria for MRI. Diffusion coefficient D, fractional order parameter β (which correlates to intravoxel tissue heterogeneity), and a microstructural quantity µ were calculated using the FROC model. The FROC parameters and the longest diameter of the lesion, as well as their changes after 2 weeks of treatment, were compared between the good and poor responders. Additionally, the pretreatment FROC parameters were individually combined with the change in D (ΔD) using a logistic regression model to evaluate response to sunitinib treatment with a receiver operating characteristic analysis. Forty-two good-responding and 32 poor-responding lesions were identified. Significant differences were detected in pretreatment β (0.67 versus 0.74, P = 0.011) and ΔD (45.7% versus 12.4%, P = 0.001) between the two groups. The receiver operating characteristic analysis showed that ΔD had a significantly higher predictive power than the tumor size change (area under the curve: 0.725 versus 0.580; 0.95 confidence interval). When ΔD was combined with pretreatment β, the area under the curve improved to 0.843 with a predictive accuracy of 75.7% (56 of 74). The non-Gaussian FROC diffusion model showed clinical value in early prediction of gastrointestinal stromal tumor response to second-line sunitinib targeted therapy. The pretreatment FROC parameter β can increase the predictive accuracy when combined with the change in diffusion coefficient during treatment. Magn Reson Med 79:1399-1406, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Opposing roles of KIT and ABL1 in the therapeutic response of gastrointestinal stromal tumor (GIST) cells to imatinib mesylate.

Most gastrointestinal stromal tumors (GISTs) are caused by activating mutations of the KIT receptor tyrosine kinase. The small molecule inhibitor imatinib mesylate was initially developed to target the ABL1 kinase, which is constitutively activated through chromosomal translocation in BCR-ABL1-positive chronic myeloid leukemia. Because of cross-reactivity of imatinib against the KIT kinase, the drug is also successfully used for the treatment of GIST. Although inhibition of KIT clearly has a major role in the therapeutic response of GIST to imatinib, the contribution of concomitant inhibition of ABL in this context has never been explored. We show here that ABL1 is expressed in the majority of GISTs, including human GIST cell lines. Using siRNA-mediated knockdown, we demonstrate that depletion of KIT in conjunction with ABL1 – hence mimicking imatinib treatment – leads to reduced apoptosis induction and attenuated inhibition of cellular proliferation when compared to depletion of KIT alone. These results are explained by an increased activity of the AKT survival kinase, which is mediated by the cyclin-dependent kinase CDK2, likely through direct phosphorylation. Our results highlight that distinct inhibitory properties of targeted agents can impede antitumor effects and hence provide insights for rational drug development. Novel KIT-targeted agents to treat GIST should therefore comprise an increased specificity for KIT while at the same time displaying a reduced ability to inhibit ABL1.

The Therapeutic Response of Gastrointestinal Stromal Tumors to Imatinib Treatment Assessed by Intravoxel Incoherent Motion Diffusion-Weighted Magnetic Resonance Imaging with Histopathological Correlation.

PurposeTo exploit the intravoxel incoherent motion (IVIM) diffusion-weighted (DW) MRI when evaluating the therapeutic response of gastrointestinal stromal tumors (GIST) to Imatinib in a mouse model.Materials and MethodsMice with xenografts bearing cells from the GIST-T1 cell line were randomly divided into a treated group receiving Imatinib and a control group. DWMRI scans with 14 b-values (0–1500 s/mm2) were performed before and after treatment (days 1, 3 and 7). IVIM related parameters perfusion fractions (fp) and perfusion-related diffusion coefficients (D*) and the conventional apparent diffusion coefficients (ADC) were calculated by fitting the DWMRI signal decay. The mean changes from baseline to each post-treatment time point for each measurement (ΔADC, Δfp and ΔD*) were calculated. The differences of mean changes between the two groups were tested for statistical significance. Histopathological analyses including Ki-67, CD31, TUNEL and H&E were conducted in conjunction with the MRI scans.ResultsIncreases in ADC of the treated group were higher than those of the control group after treatment, whereas statistical significances were not observed. Compared to the control group, D* in the treated group decreased significantly (ΔD*treated = -41%, -49%, and -49% with P = 0.0001, 0.0001 and 0.0001), and fp increased significantly (Δfptreated = 79%, 82% and 110%, with P = 0.001, 0.0001 and P = 0.0007) on days 1, 3 and 7 after treatment. Histopathological analyses demonstrated different tumor tissue characteristics between the treated and control groups.ConclusionIVIM measurements may serve as more sensitive imaging biomarkers than ADC when assessing GIST response to Imatinib as early as one day after treatment.

Radiologic assessment of earliest, best, and plateau response of gastrointestinal stromal tumors to neoadjuvant imatinib prior to successful surgical resection

To determine the timing of earliest, best and plateau response to neoadjuvant imatinib in patients with GIST. In this IRB-approved retrospective study, we included all 20 patients (10 women; mean age 61 years, range 30-83 years) with KIT-positive primary GIST who received neoadjuvant imatinib and underwent surgery between January 2001 and December 2012. Earliest (earliest time to partial response), best (percentage reduction in longest axial diameter [LAD] and volume correlated with RECIST 1.1 and volumetric criteria) and plateau (time point when there was <10% change in treatment response between two consecutive scans beyond best response) responses were analyzed on review of imaging. Median tumor size at baseline was 7.2 cm (range, 3.0-31.4 cm). Median duration of neoadjuvant imatinib was 32 weeks (IQR, 16-36 weeks). Partial response was noted in 16/20 patients (median interval = 16 weeks; IQR, 7-26 weeks); 4/20 had stable disease. Median time to earliest PR was 16 weeks (IQR, 7-26 weeks). At best response, median decrease in LAD and volume were 43% (IQR, 31-48%) and 83% (IQR, 63-87%), (median interval = 28 weeks; IQR, 18-37 weeks), at which point 10 tumors were resected. Plateau response (45% [IQR, 35-45%] LAD reduction) was noted in the remaining 10 patients (median interval = 34 weeks; IQR, 26-41 weeks) before resection. Tumor size, location or risk category did not correlate with best response or time to best response. Best response to neoadjuvant imatinib was seen at 28 weeks irrespective of tumor size and location. Plateau response was seen at 34 weeks, beyond which further treatment may not be beneficial.

Molecular targeted therapies in non-GIST soft tissue sarcomas: what the radiologist needs to know.

Non-gastrointestinal stromal soft tissue sarcomas are uncommon neoplasms that have a dismal prognosis due to a high incidence of metastases and a poor response to conventional chemotherapy. The identification of characteristic genetic alterations in several of these tumors has opened the window for molecular targeted therapies in patients who have failed conventional chemotherapy. Imaging plays a critical role in assessing the response to these novel therapeutic agents. Just like the response of gastrointestinal stromal tumors to imatinib, the response of non-gastrointestinal stromal soft tissue sarcomas to molecular targeted drugs is better evaluated on imaging by alternate tumor response criteria such as the Choi criteria. In addition, these drugs are associated with distinct class-specific drug toxicities that can come to attention for the first time on imaging. The purpose of this article is to provide a primer for the radiologist on the various molecular targeted therapies in advanced/metastatic non-gastrointestinal stromal soft tissue sarcomas with emphasis on the role of imaging in assessing treatment response and complications.

Bench to Bedside and Back Again: Personalizing Treatment for Patients with GIST

Gastrointestinal stromal tumors (GISTs), defined by the presence of constitutively activated KIT, are the most common gastrointestinal mesenchymal malignancies. This observation has been successfully exploited in clinical trials of Gleevec (also known as imatinib mesylate, STI-571) for patients with unresectable and/or metastatic GISTs. The biological mechanisms of Gleevec as well as its downstream molecular effects are generally unknown. We used a DNA microarray-based approach to identify gene expression patterns and signaling pathways that were altered in response to Gleevec in GIST cells. We identified a total of 148 genes or expressed sequence tags (of 10,367) that were differentially regulated; 7 known genes displayed a durable response after treatment. The significantly down-regulated genes were SPRY4A, FZD8, PDE2A, RTP801, FLJ20898, and ARHGEF2. The only up-regulated gene was MAFbx. On a functional level, we demonstrated that imatinib inhibited phosphorylation of KIT, AKT, and extracellular signal-regulated kinase 1/2 without affecting the total level of these proteins and that differential expression of these response genes involved activation of mitogen-activated protein kinase-dependent and -independent pathways. In an attempt to correlate these in vitro findings to clinical data, we examined GIST needle biopsy specimens taken from patients before and after Gleevec administration according to the CSTI571-B2222 Phase II trial and demonstrated that expression levels of the two gene transcripts evaluated correlated well with clinical response. This study emphasizes the potential value of an in vitro cell model to investigate GIST response to imatinib in vivo, for the purpose of identifying important genetic markers of clinical response, mechanisms of drug action, and possible therapeutic targets.

No Place Like Home? Outpatient Management of Patients With Febrile Neutropenia and Low Risk

and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: Proposal of new computed tomography response criteria. J Clin Oncol 25:1753-1759, 2007 45. Choi H, Charnsangavej C, de Castro Faria S, et al: CT evaluation of the response of gastrointestinal stromal tumors after imatinib mesylate treatment: A quantitative analysis correlated with FDG PET findings. AJR Am J Roentgenol 183:1619-1628, 2004 46. Lencioni R, Llovet JM: Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 30:52-60, 2010 47. Abou-Alfa GK, Schwartz L, Ricci S, et al: Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 24:4293-4300, 2006 48. Abou-Alfa GK, Zhao B, Capanu M, et al: Tumor necrosis as a correlate for response in subgroup of patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. ESMO 2008, Stockholm, Sweden. Ann Oncol 19:viii178, 2008 (suppl 8; abstr 547P)

Tumor volumes measurement (3D) versus Response Evaluation Criteria in Solid Tumors (RECIST version 1.1, 1D) and Choi criteria (C) in assessing response of gastrointestinal stromal tumors (GIST) to imatinib (IM).

10059 Background: Assessing antitumor effect of treatment is particularly important to guide treatment changes and to assess novel treatments in early clinical trials. We compared the sensitivity of 3D and 1D measurements in detecting size changes of liver metastases from GIST and assessing response to treatment. Methods: IM was given until progressive disease (PD) as assessed by RECIST. We evaluated liver metastases from 58 GIST patients (pts) by manual (2 independent readers) and semi-automated measurements on CT-scans at baseline, after 6 and 12 months (mo) of IM. Bland-Altman plots were used to evaluate agreement between readers and techniques. Percentages of cases with size changes ≥20% assessed by 3D and 1D were compared by McNemar's test (Pietanza et al, ASCO 2008). The ability of 3D, 1D and C to evaluate response was based on 2 target lesions. Minimally relevant changes by RECIST (+20/-30%) were related to a volume scale to obtain corresponding change cut-offs of +73/-65% and +20/-30%, considering lesions as sphere- or ellipsoid-like, respectively. Association with overall survival (OS) was determined by log-rank test. Results: Mean inter-observer variability for manual measurements was very low: 0.77% for 3D and 0.06% for 1D. 3D detected a size change ≥20% more frequently than RECIST at 6 mo (82 vs 44%, P=0.0001) and 12 mo (29 vs 12%, P=0.0005). Manual and semi-automated methods provided clinically consistent similar measures (variability 0.55 and 0.28% for 3D and 1D respectively, with R2 = 1.0 and 0.99, respectively). At 6 mo, 3D was more sensitive than RECIST in assessing partial response (PR) (60 vs 14% pts, P<0.0001) by using ellipsoid cut-off. OS correlated with PD at 6 mo (P=0.02 for both 3D and 1D and 0.01 for C) and 12 mo (P=0.001 for 3D, 0.002 for 1D, not significant for C). Conclusions: In detecting PR, 3D (ellipsoid cut-off) and C are superior to RECIST 1.1. 3D is a better discriminator of size changes than RECIST 1.1 in GIST, rendering it an interesting method to apply in early clinical trials.

Mechanism of early radiographic response to imatinib in GIST.

10049 Background: Most gastrointestinal stromal tumors (GISTs) harbor activating mutations of the receptor tyrosine kinase KIT, which is inhibited by imatinib (Novartis, Switzerland). Treatment response of GISTs to imatinib is characterized by decreased contrast uptake or tumor size on computed tomographic (CT) imaging. We sought to elucidate the mechanism by which imatinib decreases contrast enhancement of GISTs during the first 3-7 days of therapy. Methods: As part of an IRB-approved, phase II, prospective, randomized clinical trial of preoperative imatinib for GIST patients, radiographic data from 13 patients pre-/post-imatinib treatment were assessed for tumor blood flow (TBF), perfusion and transit time by perfusion CT and tumor response by positron-emission tomography (PET). Tissue specimens pre-/post-imatinib treatment were analyzed for blood vessel density (TBVD)/caliber, stem cell factor (SCF, KIT ligand) expression, KIT phosphorylation and tumor endothelial cell (TEC) apoptosis. GIST and endothelial cell lines (MVEC/HuVEC) were used to assess whether imatinib influences endothelial cell survival through the SCF/KIT signaling pathway. Results: 7 of 13 patients with PET response to imatinib demonstrated a mean 45% decrease (p=0.02) in TBF, whereas 6/13 non-responders had a mean 19% increase of TBF (p=0.21) by perfusion CT. TBVD/caliber wasn’t affected by imatinib in either group as assessed by immunofluourescence. Imatinib treatment resulted in a 14% increase in TEC apoptosis (p=0.015), compared to only 3% in the non-responders (p=0.52) by immunofluourescent TUNEL assay. Additionally, imatinib significantly blocked KIT phosphorylation of the TECs in imatinib responders but not in non-responders by immunoflourescence. In vitro, imatinib suppressed SCF expression from GIST cells, inhibited SCF-induced KIT phosphorylation by western blot and promoted apoptosis as manifested by increased caspase 3 activation in MVEC. Conclusions: The radiographic response of GISTs to imatinib correlates with decreased TBF, TEC apoptosis and SCF/KIT signaling inhibition of MVEC. These findings provide the first mechanistic support of our recently proposed criteria for evaluation of GIST response to imatinib (Choi et al, JCO 2007, 25:1760).

Quantitative functional imaging by Dynamic Contrast Enhanced Ultrasonography (DCE-US) in GIST patients treated with masatinib

To determine the quantitative parameters of DCE-US for predicting early functional response of patients with metastatic gastrointestinal stromal tumors (GIST). Phase II multicentre clinical trial in patients with metastatic GIST treated with masatinib mesylate (7.5 mg/kg daily by oral route) Patients followed using three different imaging techniques: 1) DCE-US before treatment and on days 1, 7, 15 and after 1, 2, 4, 6 months and every 3 months. 2) CT assessments, using RECIST criteria, before treatment, after 2, 4, 6 months and then every 3 months. 3) FDG PET before treatment and after 1 month. Twenty patients included and followed-up for up to 36 months, with 269 DCE-US examinations performed. No significant changes in the 7 selected DCE-US variables on day 1 and 7 vs baseline. On day 15, significant reductions in all the variables related to blood volume recorded: area under the curve (AUC) (p = 0. 004), area under the wash-in (AUWI) (p = 0.002), area under the wash-out (AUWO) (p = 0.002) and Peak Intensity (p = 0.005). Also slope of wash-in changed significantly (p = 0.003). An important reduction in Standard Uptake Values (SUV) recorded in 7/11 patients (PFS >18 months). Decrease in DCE-US AUC, AUWI and AUWO values on day 7 were predictive of PET-CT results. AUC AUWI, AUWO are the DCE-US parameters related to blood volume that at D 15 can predict the response of GISTs to treatment with masatinib. Additional studies are ongoing.

Analysis of a case with disappearance of the primary gastrointestinal stromal tumor and progressive liver metastases under long-term treatment with tyrosine kinase inhibitors

The response of gastrointestinal stromal tumors (GISTs) to tyrosine kinase receptor inhibitors (TKR-I) has been a breakthrough for small molecular therapy. We report here on the very different long-term outcome of a synchronous metastatic GIST with complete remission of the primary tumor and progressive liver metastases under TKR-I therapy. In 2003, a 52-year-old patient was diagnosed with gastric GIST and synchronous multiple liver metastases. Therapy with imatinib, 400 mg daily, was started immediately. Fifteen months later, the primary was no longer detectable by endoscopy. In 2006, progression of the liver metastases was observed. Mutation analysis of the initial biopsy specimen from the primary, as well as the biopsy from the three main liver metastases after 3 years of imatinib treatment, revealed the common KIT exon 11 deletion (W557_K558del) in all tumor samples. Two of the metastases had a separate secondary mutation in KIT exon 14 and 17, respectively, while the largest cystic metastatic lesion had no other mutation. Imatinib was then increased to a daily dose of 800 mg, and in April 2007 the treatment was changed to sunitinib. Fifty-two months after initial diagnosis, the patient died of liver failure. At no time point, relapse of the gastric primary tumor was observed. Whilst TKR-Is are commonly very effective in treating GISTs, the present case illustrates their varying effects regarding the clinical behavior and genetic variations within different tumors of the same patient after long-term treatment.

We Should Desist Using RECIST, at Least in GIST

Response Evaluation Criteria in Solid Tumors (RECIST) are insensitive in evaluating imatinib-treated gastrointestinal stromal tumors (GISTs). Response by Choi criteria, a 10% decrease in size or a 15% decrease in density on contrast-enhanced CT, correlated well in a small training set of patients who showed response as measured by positron emission tomography, and was more predictive of time to tumor progression (TTP) than response by RECIST. This study was designed to validate these observations in an independent data set. Fifty-eight patients with imatinib-treated GISTs were evaluated by RECIST and Choi criteria. TTP was compared with TTP in the training set. Patients were analyzed initially with follow-up to 28 months, extended to 60 months for survival analysis. Patients who met Choi response criteria on CT at 2 months had significantly better TTP than those who did not (P = .0002), whereas response group by RECIST was not significantly correlated with TTP. Even when the 98 patients from both sets were analyzed together, the response group by RECIST did not correlate significantly with TTP, whereas response group by Choi criteria did correlate significantly with TTP. Disease-specific survival (DSS) was also significantly correlated with response group by Choi criteria (P = .04), but not with response group by RECIST. Choi response criteria are reproducible, more sensitive, and more precise than RECIST in assessing the response of GISTs to imatinib mesylate. Response by Choi criteria, unlike response by RECIST, correlates significantly with TTP and DSS. Response by Choi criteria should be incorporated routinely into future studies of GIST therapy. We should desist using RECIST, at least in GIST.

Correlation of Computed Tomography and Positron Emission Tomography in Patients With Metastatic Gastrointestinal Stromal Tumor Treated at a Single Institution With Imatinib Mesylate: Proposal of New Computed Tomography Response Criteria

Response Evaluation Criteria in Solid Tumors (RECIST) are insensitive in evaluating gastrointestinal stromal tumors (GISTs) treated with imatinib. This study evaluates whether computed tomography (CT) findings of GIST after imatinib treatment correlate with tumor responses by [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) and develops reliable, quantitative, CT response criteria. A total of 172 lesions selected by RECIST were evaluated in 40 patients with metastatic GISTs treated with imatinib. All patients had pretreatment and 2-month follow-up CTs and FDG-PETs. Multivariate analysis was performed using tumor size and density (Hounsfield unit [HU]) on CT and maximum standardized uptake value (SUVmax) on FDG-PET. Patients were observed up to 28 months. Mean baseline tumor size and density on CT were 5.3 cm and 72.8 HU, respectively, and mean baseline SUVmax on FDG-PET was 5.8. Thirty-three patients had good response on FDG-PET. A decrease in tumor size of more than 10% or a decrease in tumor density of more than 15% on CT had a sensitivity of 97% and a specificity of 100% in identifying PET responders versus 52% and 100% by RECIST. Good responders on CT at 2 months had significantly longer time to progression than those who did not respond (P = .01). Small changes in tumor size or density on CT are sensitive and specific methods of assessing the response of GISTs. If the prognostic value of our proposed CT response criteria can be confirmed prospectively, the criteria should be employed in future studies of patients with GIST.

Neoadjuvant Therapy for Gastrointestinal Stromal Tumor (GIST): Racing Against Resistance

The advent of imatinib mesylate (Gleevec; Novartis Pharmaceuticals, Basel Switzerland) has generated much interest and investigation in gastrointestinal stromal tumor (GIST), a rare and, until recently, poorly understood malignancy. The dramatic responses achieved in a solid tumor with a targeted agent have made GIST a paradigm for the use of new molecular agents. GIST is the most common mesenchymal tumor of the gastrointestinal tract and immunohistochemical reactivity for KIT (CD117) expression is a hallmark of GIST, and is found in nearly all cases. Mutations in KIT, or less commonly, platelet-derived growth factor alpha (PDGFRA) can be identified in over 90% of GISTs. These mutations cause constitutive activation of signaling through the associated tyrosine kinase receptors and are thought to be central to the oncogenesis of GIST. Imatinib is a small molecular inhibitor of KIT and PDGFRA. In the February 2007 issue of the Annals of Surgical Oncology, Haller et al. report their experience with a patient having a large gastric GIST that was markedly reduced in size by neoadjuvant imatinib treatment. This case report highlights several pertinent issues related to imatinib therapy, particularly related to its combined use with surgical resection. While complete response of GIST is rare, partial response occurs in 50% to perhaps as high as 67% of GIST patients treated with imatinib. Prolonged treatment, however, is associated with resistance, which can often be attributed to the development of secondary KIT mutations. In fact, half of patients will become resistant to imatinib by approximately 2 years on treatment. The benefits and limitations of both surgical resection and tyrosine kinase inhibitor therapy for the treatment of GIST make it attractive to explore the combination of these modalities. There are several settings in which this might be advantageous ranging from adjuvant treatment after complete surgical resection of primary localized tumors (up to half of patients might otherwise recur) to surgical resection of residual metastatic disease after initial treatment with a tyrosine kinase inhibitor. The authors specifically address the use of neoadjuvant imatinib treatment prior to surgical resection of a primary GIST. The rationale for neoadjuvant treatment of GIST is similar to that for many other tumors. Most GISTs will respond to imatinib. Resection of responsive tumors may be accomplished with less morbidity and sacrifice of adjacent organs. Some tumors that are deemed unresectable may become resectable. Manipulation of smaller, treated tumors may result in less intraoperative dislodgement of viable tumor cells. Early treatment of distant micrometastatic disease may improve oncologic outcome. Furthermore, progression, particularly distant progression, of patients on neoadjuvant treatment may indicate the futility of surgery in these patients. Several authors have reported their experience with neoadjuvant treatment of GIST prior to surgical Received September 24, 2006; accepted September 27, 2006; published online: January 30, 2007. Address correspondence and reprint requests to: Ronald P. DeMatteo, MD; E-mail: dematter@mskcc.org