A case-matched study of imatinib mesylate between different formulations on plasma trough concentration, adverse events, quality of life and outcomes in gastrointestinal stromal tumor patients.

Genike, the imatinib (IM)-alpha form is widely used in the treatment of gastrointestinal stromal tumor (GIST) patients in China. We wanted to investigate whether there are differences in IM plasma concentrations, adverse events, health-related quality of life (QOL) and outcomes between patients treated with Genike and Glivec. Thirty included GIST patients receiving IM treatment were matched to either Genike or Glivec according to gastrectomy, body weight, body surface area and sex. There was no statistically significant difference in IM trough plasma levels between the two groups. There were no significant differences in very common adverse events of IM between the Genike and Glivec groups. IM was well tolerated, although it was associated with a significant change in cognitive function (P < 0.001), fatigue (P = 0.015), pain (P = 0.015), nausea/vomiting (P = 0.029), insomnia (P = 0.019), diarrhea (P = 0.003) and financial difficulties (P < 0.001). Physical functioning, financial burden and insomnia were significantly different between the two groups (P = 0.026). Until Aug. 2022, there was no significant difference in time to imatinib treatment failure (TTF) between the two groups. In conclusion, there was no difference in IM plasma concentration and adverse events between Genike and Glivec. Both Genike and Glivec could partially decrease the QOL of GIST patients. Physical functioning was worse in Genike group than in Glivec group, while the economic burden and symptoms of insomnia in Glivec patients were worse. There was no significant difference in TTF between the two groups.

Correlation Between N-Demethyl Imatinib Trough Concentration and Serious Adverse Reactions in Patients with Gastrointestinal Stromal Tumors: A Retrospective Cohort Study.

BACKGROUND: Imatinib is the first-line treatment for gastrointestinal stromal tumors; however, the clinical prognosis and adverse reactions of patients vary owing to individualized discrepancies in plasma exposure. METHODS: To determine the safe interval for steady-state plasma trough concentrations (C min ) of imatinib and its active metabolite, N-demethyl imatinib (NDI), 328 plasma samples from 273 patients treated with imatinib were retrospectively analyzed. Imatinib C min and NDI C min were tested, and adverse reactions were recorded. The association between imatinib C min , NDI C min , and serious adverse reactions was evaluated. RESULTS: The C min range of imatinib was 209.5-4950.0 ng/mL, with the mean value and SD of 1491.8 ± 731.4 ng/mL. The C min range of NDI was 80.0-2390.0 ng/mL with the mean value and SD of 610.8 ± 281.5 ng/mL. NDI C min was positively correlated with imatinib C min , whereas the ratio of NDI C min to imatinib C min (NDI C min /imatinib C min ) was negatively correlated with imatinib C min . Univariate logistic regression analysis demonstrated that the treatment objective, daily dose, imatinib C min , NDI C min , and imatinib C min + NDI C min were significantly associated with serious adverse reactions. Multivariate logistic regression analysis showed that NDI C min was an independent risk factor for serious adverse reactions, with a threshold of 665 ng/mL. CONCLUSIONS: NDI C min was an independent risk factor for serious adverse reactions, with a threshold of 665 ng/mL. Monitoring NDI C min was beneficial for the rational application of imatinib and individualized treatment of patients with gastrointestinal stromal tumors.

Expression of DOG1 in peripheral blood cells of patients with gastrointestinal stromal tumor.

BACKGROUND AND STUDY AIMS: The diagnosis and surveillance of gastrointestinal stromal tumor (GIST) rely on pathology and immunochemistry (IHC), making it complicated and invasive. Noninvasive and convenient biomarkers of this disease need to be explored. The high specificity and sensitivity of IHC in detecting GIST 1 (DOG1) in biopsy indicate that it is also expressed in circulating tumor cells of the blood and may be an ideal biomarker for GIST. This aimed to detect the expression of DOG1 in peripheral blood cells (PBCs) and determine the relationship between DOG1 expression and clinical factors. PATIENTS AND METHODS: A total of 45 patients with GIST and 46 healthy controls (HCs) were recruited from the Second Affiliated Hospital of Nanchang University between December 2015 and June 2018. PBCs were isolated from peripheral venous blood by density gradient centrifugation. RNA was extracted from PBCs, and DOG1 mRNA was detected by quantitative reverse transcription polymerase chain reaction. DOG1 mRNA expression between GIST and HC was compared, and the relationship between clinical factors and DOG1 was also analyzed. RESULTS: DOG1 mRNA expression in PBCs was significantly higher in patients with GIST than that in HCs (3.326 [1.942-5.328] versus 0.744 [0.269-1.087], p < 0.01). The specificity and sensitivity were 88.9% and 89.1%, respectively (AUC = 0.912). Tumor diameter and risk of aggressive behavior were correlated with DOG1 expression, and other clinical factors (sex, age, location, number of phase-splitting cells, Ki-67 index, metastatic status) did not show any relationship with DOG1 expression. However, clinical factors, including tumor diameter and risk grade, were not independent factors in DOG1 expression when multivariate analysis was conducted. CONCLUSION: DOG1 expressions were significantly higher in patients with GIST than that in HCs. Tumor diameter and risk classification correlated with DOG1 expression but were not independent factors. DOG1 in PBCs is a promising noninvasive biomarker for GIST.

Ki-67 labelling index is related to the risk classification and prognosis of gastrointestinal stromal tumours: a retrospective study.

BACKGROUND AND AIMS: Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the digestive tract with malignant potential. The current risk classification standard is unable to accurately evaluate the invasiveness and clinical outcomes of GISTs. Ki-67 labelling index (LI) may be an effective indicator in assessing tumour invasiveness and prognosis, however, its exact value in GISTs is still uncertain. The aims of our study were to evaluate the correlation of the Ki-67 LI and clinicopathological features of GISTs and to assess the potential value of the Ki-67 LI in GISTs classification and prognosis. METHODS: The clinical, pathological and prognostic data were collected and analysed to identify the independent influential factors of GISTs risk stratification and the predictors of GISTs prognosis. RESULTS: The Ki-67 LI was significantly associated with the clinicopathological features of tumour progression (P<0.05). It was an independent influential factor of GISTs risk classification (odds ratio: 1.322; 95% confidence interval: 1.031-1.696) (P=0.028), and the area under the curve (AUC) value of the Ki-67 LI on the discrimination ability of GISTs risk stratification was 0.906 (P<0.001). The optimal cutoff value of the Ki-67 LI was 6% (sensitivity of 87.5% and specificity of 76.2%), and patients with Ki-67 LI≥6% exhibited significantly poorer progression-free survival (PFS) than those with Ki-67 LI<6% (P<0.001). The AUC value of the Ki-67 LI for predicting PFS in postoperative patients was 0.813 (P=0.03). CONCLUSIONS: The Ki-67 LI has appreciated value to predict the risk grade and prognosis of GISTs. Patients with Ki-67 LI≥6% are prone to recurrence and metastasis after operation and may need a close follow-up.

[A model to predict the recurrence of middle-high risk gastrointestinal stromal tumors based on preoperative fibrinogen and peripheral blood inflammatory indexes].

Objective: At present, the modified NIH classification commonly used in clinical practice is still insufficient for assessing the risk of postoperative recurrence in some patients with intermediate-high risk gastrointestinal stromal tumors (GIST). Through exploring risk factors for recurrence of intermediate-high risk GIST, this study establishes a predictive model for recurrence with more convenience and more precision in order to guide adjuvant therapy for intermediate-high risk GIST patients. Methods: A retrospective case-control study was carried out. Clinical and pathological data of 432 GIST patients who did not receive preoperative targeted treatment, underwent complete resection in the Union Hospital of Tongji Medical College of Huazhong University of Science and Technology from January 2005 to June 2018, and were diagnosed as intermediate- or high-risk based on modified NIH classification by postopertive pathology, were retrospectively analyzed. Cox regression model was used to idenitify independent risk factors of recurrence, and a recurrence risk scoring model was established. The receiver operating characteristic curve (ROC curve), consistency index (C-index) and calibration curve were used to evaluate the accuracy of the scoring model in predicting the recurrence of moderate-risk and high-risk GIST patients. Results: Among 432 GIST patients, 332 were diagnosed as high-risk and 100 as moderate-risk; 237 were males and 195 females with average age of (57.4±12.4) years. Of 432 patients, 211 cases (48.8%) had fibrinogen (FIB) >3.5 g/L; 85 cases (19.7%) had platelet to lymphocyte ratio (PLR)>272.5; 122 cases (28.2%) had neutrophil to lymphocyte ratio (NLR) > 4.2; 102 cases (23.6%) had systemic inflammatory reaction index (SIRI)> 2.7; 198 cases (45.8%) had tumor long diameter >8 cm and 108 cases (25.0%) had mitotic counts > 8/50 HPF. Cox multivariable analysis showed that FIB (HR=1.789, 95% CI: 1.058-3.027, P=0.030), PLR (HR=1.862, 95% CI: 1.067-3.249, P=0.029), SIRI (HR=1.790, 95% CI: 1.039-3.084, P=0.036), tumor long diameter (HR=1.970, 95% CI: 1.105-2.925, P=0.017) and mitotic counts (HR=2.187, 95% CI:1.211-3.950, P=0.009) were independent risk factors for recurrence in patients with middle-risk and high-risk GIST. These 5 factors were included in the risk scoring model, which was given a weight score of 58 points, 62 points, 58 points, 63 points, and 78 points, respectively. Patients with a total score of ≤ 78 points were classified as moderate-risk recurrence (group I), those of 78 to 136 points as high-risk recurrence (group II) and those of >136 points as very high-risk recurrence (group III). ROC curve showed that the area under the curve (AUC) of the scoring model was 0.730 and the C-index was 0.724 (95% CI:0.687-0.787). The calibration curves and the Kaplan-Meier curves of patients in the three groups revealed that this model had a good predictive accuracy. Conclusions: For intermediate-risk and high-risk GIST patients, the preoperative FIB >3.5 g/L, PLR > 272.5 and SIRI > 2.7 are independent risk factors of recurrence after surgery. The recurrence risk scoring model established by combining tumor long diameter, mitotic counts, FIB, PLR and SIRI can effectively predict the risk of postoperative recurrence and metastasis in moderate-risk and high-risk GIST patients.

[Research advance of liquid biopsy in gastrointestinal stromal tumors].

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumors in the gastrointestinal tract. Surgical resection is the only curative treatment, while imatinib is the first-line therapy for recurrent, metastatic, and unresectable GIST. However, more than half of GIST patients suffer from secondary resistance to imatinib within 2 years after treatment initiation. Therefore, early diagnosis, drug resistance and recurrence surveillance are critical for GIST patients. Liquid biopsy is a new method which utilizes the detection of tumor biomarkers in peripheral blood for early diagnosis and therapeutic efficacy assessment. In recent years, liquid biopsy has achieved significant research progress in several kinds of malignancy. This review aims at presenting an overview on research advance of liquid biopsy in GIST and may provide a new method for early diagnosis and therapeutic efficacy assessment of GIST.

Prognostic significance of preoperative plasma fibrinogen levels in primary gastrointestinal stromal tumours: a retrospective cohort study.

BACKGROUND: Improved prediction of prognosis for gastrointestinal stromal tumours (GISTs) has become increasingly important since the introduction of targeted therapy. Here, we aimed to evaluate the prognostic significance of preoperative plasma fibrinogen (Fib) levels in patients with primary GISTs and to analyse their correlations with clinicopathological characteristics. METHODS: A total of 201 previously untreated patients with primary GISTs who had undergone radical surgery at our institution between October 2004 and July 2018 were enrolled. The optimal cut-off value for Fib levels was calculated using time-dependent receiver-operating characteristic curve analysis. RFS, the primary endpoint, was calculated by the Kaplan-Meier method and compared by the log-rank test. Univariate and multivariate Cox regression models were calculated. RESULTS: High preoperative plasma Fib levels were detected as an independent adverse prognostic factor (p = 0.008, hazard ratio 3.136, 95% CI 1.356‒7.256). Furthermore, high preoperative plasma Fib levels also indicated a poor prognosis within the modified National Institutes of Health (mNIH) high-risk subgroup (p = 0.041). In addition, preoperative plasma Fib levels showed a positive correlation with several prognostic factors and even a linear relationship with tumour size (Spearman correlation coefficient [r] = 0.411, p < 0.001). CONCLUSIONS: Our results suggest that high preoperative plasma Fib levels may indicate a poor prognosis in patients with primary GISTs. As a cost-effective biomarker, preoperative assessment of plasma Fib levels may help to further risk stratify patients with mNIH high-risk GISTs and instruct the application of targeted therapy.

Model-based Dose Individualization of Sunitinib in Gastrointestinal Stromal Tumors.

PURPOSE: Various biomarkers have been proposed for sunitinib therapy in gastrointestinal stromal tumor (GIST). However, the lack of "real-life" comparative studies hampers the selection of the most appropriate one. We, therefore, set up a pharmacometric simulation framework to compare each proposed biomarker. EXPERIMENTAL DESIGN: Models describing relations between sunitinib exposure, adverse events (hand-foot syndrome, fatigue, hypertension, and neutropenia), soluble VEGFR (sVEGFR)-3, and overall survival (OS) were connected to evaluate the differences in survival and adverse events under different dosing algorithms. Various fixed dosing regimens [4/2 (weeks on/weeks off) or 2/1 (50 mg), and continuous daily dosing (37.5 mg)] and individualization approaches [concentration-adjusted dosing (CAD), toxicity-adjusted dosing (TAD), and sVEGFR-3-adjusted dosing (VAD)] were explored following earlier suggested blood sampling schedules and dose-reduction criteria. Model-based forecasts of biomarker changes were evaluated for predictive accuracy and the advantage of a model-based dosing algorithm was evaluated for clinical implementation. RESULTS: The continuous daily dosing regimen was predicted to result in the longest survival. TAD (24.5 months) and VAD (25.5 months) increased median OS as compared with a fixed dose schedule (19.9 and 21.5 months, respectively) and CAD (19.7 and 21.3 months, respectively), without markedly raising the risk of intolerable toxicities. Changes in neutrophil count and sVEGFR-3 were accurately forecasted in the majority of subjects (>65%), based on biweekly blood sampling. CONCLUSIONS: Dose adjustments based on the pharmacodynamic biomarkers neutrophil count and sVEGFR-3 can increase OS while retaining drug safety. Future efforts could explore the possibility of incorporating a model-based dose approach in clinical practice to increase dosing accuracy for these biomarkers.

Determination of the absolute bioavailability of oral imatinib using a stable isotopically labeled intravenous imatinib-d8 microdose.

PURPOSE: The aim of this study was to ascertain whether the absolute bioavailability of oral imatinib (Glivec®) during steady state plasma pharmacokinetics in cancer patients could be determined through a concomitant intravenous administration of a single 100 µg microdose of deuterium labeled imatinib (imatinib-d8). Secondly, the usefulness of liquid chromatography-tandem mass spectrometry (LC-MS/MS) was investigated for simultaneous analysis of orally and intravenously administered imatinib. METHODS: Included patients were on a stable daily dose of 400 mg oral imatinib prior to study participation. On day 1, patients received a 100 µg intravenous imatinib-d8 microdose 2.5 h after intake of the oral dose. Plasma samples were collected for 48 h. Imatinib and imatinib-d8 concentrations were simultaneously quantified using a validated LC-MS/MS assay. The absolute bioavailability was calculated by comparing the dose-normalized exposure with unlabeled and stable isotopically labeled imatinib in plasma. RESULTS: A total of six patients were enrolled. All patients had a history of gastrointestinal stromal tumors (GIST). The median absolute bioavailability of oral imatinib at steady state was 76% (range 44-106%). Imatinib and imatinib-d8 plasma concentrations were quantified in all collected plasma samples, with no samples below the limit of quantification for imatinib-d8. CONCLUSION: The absolute bioavailability of imatinib was successfully estimated at steady state plasma pharmacokinetics using the stable isotopically labeled microdose trial design. This study exhibits the use of a stable isotopically labeled intravenous microdose to determine the absolute bioavailability of an oral anticancer agent in patients with LC-MS/MS as the analytical tool.

Elevated preoperative platelet-to-lymphocyte ratio predicts poor prognosis of patients with primary gastrointestinal stromal tumor.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are considered to reflect the systemic inflammatory response and clinical prognosis. However, the independent prognostic values of the NLR and PLR for patients with gastrointestinal stromal tumor (GIST) remain debatable. This study aims to evaluate the prognostic value of preoperative NLR and PLR in GIST patients. METHODS: We retrospectively reviewed all GIST patients diagnosed and surgically treated at Union Hospital between 2005 and 2018. The preoperative NLR and PLR were calculated to evaluate recurrence-free survival (RFS) and overall survival (OS) by Kaplan-Meier analysis. Univariate and multivariate Cox regression analyses were performed to estimate the independent prognostic values. RESULTS: The median follow-up time was 49 months (interquartile range, 22-74 months). The preoperative PLR was significantly increased in the GIST patients with intermediate and high tumor risks. Increases in the NLR (≥2.34) and PLR (≥185.04) were associated with shorter RFS and OS (P < 0.01). Moreover, the multivariate analysis revealed that elevated PLR was an independent factor for shorter RFS (hazard ratio [HR]: 3.041; 95% confidence interval [CI]: 2.001-4.622; P < 0.001) and OS (HR: 1.899; 95% CI: 1.136-3.173; P = 0.014). CONCLUSIONS: The preoperative PLR is a potential biomarker of GIST and is related to the clinical outcome. An elevated preoperative PLR predicts poor prognosis of patients with primary GIST after complete surgical resection.

Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors.

BACKGROUND: Gastrointestinal stromal tumor (GIST) initiation and evolution is commonly framed by KIT/PDGFRA oncogenic activation, and in later stages by the polyclonal expansion of resistant subpopulations harboring KIT secondary mutations after the onset of imatinib resistance. Thus, circulating tumor (ct)DNA determination is expected to be an informative non-invasive dynamic biomarker in GIST patients. METHODS: We performed amplicon-based next-generation sequencing (NGS) across 60 clinically relevant genes in 37 plasma samples from 18 GIST patients collected prospectively. ctDNA alterations were compared with NGS of matched tumor tissue samples (obtained either simultaneously or at the time of diagnosis) and cross-validated with droplet digital PCR (ddPCR). RESULTS: We were able to identify cfDNA mutations in five out of 18 patients had detectable in at least one timepoint. Overall, NGS sensitivity for detection of cell-free (cf)DNA mutations in plasma was 28.6%, showing high concordance with ddPCR confirmation. We found that GIST had relatively low ctDNA shedding, and mutations were at low allele frequencies. ctDNA was detected only in GIST patients with advanced disease after imatinib failure, predicting tumor dynamics in serial monitoring. KIT secondary mutations were the only mechanism of resistance found across 10 imatinib-resistant GIST patients progressing to sunitinib or regorafenib. CONCLUSIONS: ctDNA evaluation with amplicon-based NGS detects KIT primary and secondary mutations in metastatic GIST patients, particularly after imatinib progression. GIST exhibits low ctDNA shedding, but ctDNA monitoring, when positive, reflects tumor dynamics.

Impact of L-carnitine on imatinib-related muscle cramps in patients with gastrointestinal stromal tumor.

Introduction Muscle cramps constitute one of the leading adverse events of imatinib, the standard first-line treatment for advanced gastrointestinal stromal tumor (GIST). This study aims to assess the impact of L-carnitine on relieving cramps in patients with GIST taking imatinib. Materials and methods We reviewed our prospective database for patients with GIST who took L-carnitine (500-mg tablet, 2-3 times daily) for muscle cramps in Asan Medical Center. The assessment tool included severity by the numeric rating scale (NRS), frequency, duration of cramps, and questionnaire for the disturbance in basic activities of daily living (ADL), instrumental ADL (iADL), outdoor activity, or sleeping before and after L-carnitine treatment. Results We examined 42 patients [median age: 60 (range: 17-81) years; males, 52.4%] who received L-carnitine for cramps on NRS ≥ 4 intensity during 2016-2017. In 83.3% of patients (n = 35), the NRS score declined to <4 points, with 8 patients (19.0%) experiencing complete disappearance of symptoms [median response time: 10 (range: 2-30) days]. Moreover, the median duration of each episode and frequency decreased from 5 to 2 min and from 30 to 3 times per month (P < 0.001), respectively. We observed substantial improvement in all quality-of-life aspects after L-carnitine (ADL, 73.2%-14.6%; iADL, 73.2%-17.1%; sleeping, 78.0%-22.0%; outdoor activity, 68.3%-17.1%; P < 0.001). ConclusionL-carnitine could effectively relieve imatinib-related muscle cramps in patients with GIST. Accordingly, a randomized phase 3 study is currently ongoing (NCT03426722).

Development and validation of LC-MS/MS method for imatinib and norimatinib monitoring by finger-prick DBS in gastrointestinal stromal tumor patients.

The introduction of imatinib, an oral tyrosine kinase inhibitor, as first-line standard therapy in patients with unresectable, metastatic, or recurrent gastro-intestinal stromal tumor (GIST), strongly improved their treatment outcomes. However, therapeutic drug monitoring (TDM) is recommended for this drug due to the large inter-individual variability in plasma concentration when standard dose is administered. A Cmin higher than 760 ng/mL was associated with a longer progression free survival. Thus, a LC-MS/MS method has been developed and fully validated to quantify imatinib and its active metabolite, norimatinib, in finger-prick dried blood spot (DBS). The influence of hematocrit, sample homogeneity, and spot size and the correlation between finger-prick and venous DBS measurements were also assessed. The method showed a good linearity (R2 > 0,996) between 50-7500 ng/mL for imatinib and 10-1500 ng/mL for norimatinib. Analytes were extracted from DBS samples by simply adding to 3 mm-discs 150 µL of acidified methanol containing IMA-D8. The collected extract was then injected on a LC Nexera system in-house configured for the on-line cleanup, coupled with an API-4000 QT. The chromatographic separation was conducted on a Synergi Fusion-RP column (4 µm, 2x50 mm) while the trapping column was a POROS R1/20 (20 µm, 2x30 mm). The total run time was 8.5 min. DBSs stored at room temperature in plastic envelopes containing a silica-gel drying bag were stable up to 16 months. The proposed method was applied to 67 clinical samples, showing a good correlation between patients' finger-prick DBS and plasma concentrations, measured by the reference LC-MS/MS method, internally validated. Imatinib and norimatinib concentrations found in finger-prick DBS were adjusted by hematocrit or by an experimental correction factor to estimate the corresponding plasma measurements. At the best of our knowledge, the proposed LC-MS/MS method is the first analytical assay to measure imatinib and norimatinib in DBS samples.

[Application of imatinib plasma concentration monitoring in the whole process management of gastrointestinal stromal tumor patients].

Objective: To investigate the significance of monitoring imatinib mesylate (IM) plasma concentrations in patients with gastrointestinal stromal tumor (GIST). Methods: A retrospective descriptive study was carried out. Inclusion criteria: (1) patients with GIST confirmed by postoperative pathology or puncture pathology receiving maintenance therapy of IM; (2) administration of same dose of IM for at least 4 weeks (achieving steady - state plasma concentration). Patients who had severe organ dysfunction, received IM generics, or received IM simultaneously with other drugs significantly affecting IM pharmacokinetic were excluded. A total of 185 patients at the GIST Clinic of Renji Hospital, Shanghai Jiaotong University School of Medicine from August 2018 to May 2019 were enrolled, including 114 males (61.6%) and 71 females (38.4%) with a median age of 60 years old (range, 30-89 years), and 63 advanced cases. Patients receiving preoperative or postoperative adjuvant therapy were given IM 400 mg QD; patients with KIT exon 9 mutation or with disease progression during IM 400 mg QD treatment were given IM 600 mg QD. If the patient had adverse reactions such as myelosuppression during the medication, IM would be reduced or given BID per day. The peripheral venous blood was collected (22 to 24 hours after the last dose for patients who took IM QD and 2 hours before the first dose per day for those who took IM BID). IM plasma concentration was measured through high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). Correlation analysis between IM plasma concentration results and clinical data was performed using linear regression analysis. Results: A total of 241 stable blood samples of IM plasma concentration from 185 patients were finally collected. The IM plasma concentrations were significantly different between the doses of 300 mg/d and 400 mg/d [(942.4±433.5) µg/L vs. (1340.0±500.1) µg/L, t=6.317, P<0.001], and between 400 mg/d and 600 mg/d [(1340.0±500.1) µg/L vs. (2188.0±875.5) µg/L, t=3.557, P=0.004]. Among the blood samples of 57 patients receiving IM 300 mg/d, the IM plasma concentration of the advanced patients was significantly lower than that of the non-advanced patients [(795.6±225.8) µg/L vs. (992.2±484.4) µg/L, t=2.088, P=0.042]. Among the 137 blood samples of patients receiving IM 400 mg/d, the IM plasma concentration was higher in patients aged >60 years than those aged ≤60 years [(1461.0±595.3) µg/L vs. (1240.0±380.9) µg/L, t=2.528, P=0.013] and the IM plasma concentration of cases with diarrhea was significantly lower than that of those without diarrhea [(745.8±249.6) µg/L vs. (1382.0±486.9) µg/L, t=6.794, P<0.001]. Gender, primary location, surgical procedure, mutated gene, mutation type, or time of administration was associated with IM plasma concentration no matter in patients taking IM doses of 400 mg/d or 300 mg/d (all P>0.05). Regression analysis showed that body mass (P=0.004 and P=0.019), body mass index (P=0.016 and P=0.042), and body surface area (P=0.007 and P=0.028) were all negatively correlated with IM plasma concentrations in patients taking IM doses of 300 mg/d and 400 mg/d. Within the 137 patients who received a fixed oral dose of 400 mg/d IM, 17 patients received oral 200 mg BID, whose IM plasma drug concentration was not significantly different compared with that of 120 patients who received 400 mg IM QD [(1488.0±408.3) µg/L vs. (1319.0±509.7) µg/L, t=1.307, P=0.193]. Conclusions: Monitoring IM plasma concentration is significant throughout the whole process of management of GIST patients receiving IM treatment. In particular, regular monitoring IM plasma concentration and developing appropriate treatment strategies can bring better therapeutic benefits for patients with low doses, diarrhea, advanced condition and older age.

[Analysis of imatinib trough concentration at steady state in adjuvant therapy of patients with high risk gastrointestinal stromal tumor].

Objective: To explore the features of imatinib mesylate (IM) plasma concentration during adjuvant therapy and clinical factors associated with IM plasma concentration in patients with high risk gastrointestinal stromal tumors (GIST), and to determine whether IM plasma concentration <1100 µg/L influences the efficacy of adjuvant therapy. Methods: A retrospective case control study method was used. Case inclusion criteria: (1) complete resection of lesion and GIST confirmed by pathology; (2) high risk classified according to modified National Institutes of Health classification system (2008); (3) administration of IM 400 mg/d for at least 1 month; (4) not taking the medication likely affecting IM pharmacokinetic, such as rifampicin, dilantin, and carbamazepine, within 1 month before blood collection. Data of GIST patients who visited GIST Disease - Oriented Outpatient, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology between January 2015 to December 2018 were retrospectively analyzed. After taking IM for 22-26 hours, 5 ml of peripheral venous blood was collected into EDTA anticoagulant tube. IM plasma concentration was detected by using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Patients were divided into <1100 µg/L group and ≥1100 µg/L group according to plasma concentration. Linear regression was used to analyze the relevance between clinical features and IM plasma concentration. Parameters with normal distribution were analyzed by Pearson correlation coefficient, and parameters with non-normal distribution were analyzed by Spearman correlation. Kaplan-Meier survival curves and COX regression model were used for survival analysis. Results: Among the 85 patients enrolled in the study, 49 patients (57.6%) were male and 36 (42.4%) were female, with mean age of (51.9±11.0) years. The body mass index was (22.5±2.9) kg/m(2) and body surface area was (1.6±0.2) m(2). Thirty patients received gene test, including 23 patients with c-Kit exon 11 mutation, 4 with c-Kit exon 9 mutation, 1 with c-Kit exon 11 and 17 mutation and 2 without c-Kit or PDGFRA gene mutation. The mean IM plasma concentration was (1391.4±631.3) µg/L, and there were 32 patients with plasma concentration <1100 µg/L and 53 patients with plasma concentration ≥1100 µg/L. There were no statistically significant differences between the two groups in gender, age, body mass index, body surface area, hematological examination (white blood cells, albumin, alanine aminotransferase, aspartate aminotransferase and serum creatinine), tumor location, tumor size, mitotic counts, duration of adjuvant therapy and methods of operation (all P>0.05). Positive correlation between IM plasma concentration and serum creatinine was observed in linear regression analysis (r=0.297, P=0.007), but there were no correlations between IM plasma concentration and age (r=0.044, P=0.686), body mass index (r=0.066, P=0.547), body surface area (r=-0.010, P=0.924), white blood cells (r=-0.080, P=0.478), albumin (r=-0.065, P=0.563), alanine aminotransferase (r=0.114, P=0.308), aspartate aminotransferase (r=0.170, P=0.127) and duration of adjuvant therapy (ρ=0.060, P=0.586). There was no statistically significant difference in IM plasma concentration between patients with different genders (t=0.336, P=0.738) and patients with different surgical methods (F=0.888, P=0.451). Up to March 1, 2019. the median follow-up time was 30 (range 4-49) months. Tumor recurrence was detected in two patients with plasma concentration <1100 µg/L and two with plasma concentration ≥1100 µg/L. One recurrent patient with plasma concentration <1100 µg/L was detected to harbor c-Kit exon 11 and exon 17 mutations, and the other did not receive gene detection. Two recurrent patients with plasma concentration ≥1100 µg/L were both detected to harbor c-Kit exon 9 mutation. The 3-year relapse-free survival rate was 96.4% in the cohort, 96.2% in patients with plasma concentration <1100 µg/L, and 96.6% in patients with plasma concentration ≥1100 µg/L. No significant difference in relapse-free survival was observed between the two groups (P=0.204). Univariate Cox analysis showed that IM plasma concentration <1100 µg/L was not a risk factor for patients with high risk GIST (HR=0.238, 95% CI: 0.022-2.637, P=0.242). Conclusions: IM plasma concentration of adjuvant therapy in patients with high risk GIST varies with individual. Patients with higher level of serum creatinine are more likely to have a higher plasma concentration. A blood drug concentration standard of less than 1100 µg/L for advanced GIST patients may not influence the prognosis of patients with high risk GIST.

Optimizing the dose in patients treated with imatinib as first line treatment for gastrointestinal stromal tumours: A cost-effectiveness study.

AIMS: Patients with metastatic gastrointestinal stromal tumours (GIST) are treated in first line with the oral tyrosine kinase inhibitor, imatinib, until progressive disease. With this fixed dosing regimen, only approximately 40% of patients reach adequate plasma levels within the therapeutic index. Therapeutic drug monitoring (TDM) is a solution to reach plasma levels within the therapeutic index. However, introducing TDM will also increase costs, due to prolonged imatinib use and laboratory costs. The aim of this study was to evaluate the cost-effectiveness of TDM in patients with metastatic/unresectable GIST treated with imatinib as a first line treatment, compared with fixed dosing. METHODS: A survival model was created to simulate progression, mortality and treatment costs over a 5-year time horizon, comparing fixed dosing vs TDM-guided dosing. The outcomes measured were treatments costs, life-years and quality-adjusted life-years. RESULTS: Total costs over the 5-year time horizon were estimated to be €106 994.85 and €150 477.08 for fixed dosing vs TDM-guided dosing, respectively. A quality-adjusted life year gain of 0.74 (95% confidence interval 0.66-0.90) was estimated with TDM-guided dosing compared to fixed dosing. An average incremental cost-effectiveness ratio of €58 785.70 per quality-adjusted life year gained was found, mainly caused by longer use and higher dosages of imatinib. CONCLUSION: Based on the currently available data, this analysis suggests that TDM-guided dosing may be a cost-effective intervention for patients with metastatic/unresectable GIST treated with imatinib which will be improved when imatinib losses its patency.

Prognostic impact of preoperative neutrophil-lymphocyte ratio for surgically resected gastrointestinal stromal tumors.

Neutrophil-lymphocyte ratio (NLR) was shown to be prognostic value in various malignancies. There are limited data about predictive or prognostic role of NLR during gastrointestinal stromal tumors (GISTs) patients. This study evaluated the prognostic significance of preoperative NLR in patients with GIST.We retrospectively enrolled 72 primary GIST patients who received initial curative surgical resection with or without adjuvant imatinib therapy. The preoperative NLR in the peripheral blood was calculated. Univariate and multivariate Cox proportional hazard regression models were used to identify potential predictors of tumor outcomes.The NLR cut-off value of 4.18 was selected. Multivariate analysis revealed that high NLR was associated with a unfavorable prognosis of GISTs (P < .05). Tumor size, tumor location, and age were significantly correlated with the NLR (P < .05).High NLR was an unfavorable prognostic factor of overall survival in GISTs and may be a useful preoperative biomarker of the prognosis of GISTs.

Diagnosis and Treatment Monitoring of a Patient with Gastrointestinal Stromal Tumor by Next-Generation Sequencing and Droplet Digital Polymerase Chain Reaction Assay of a PDGFRA Mutation in Plasma-Derived Cell-Free Tumor DNA.

In patients with a suspected malignancy, standard-of care management currently includes histopathologic examination and analysis of tumor-specific molecular abnormalities. Herein, we present a 77-year-old patient with an abdominal mass suspected to be a gastrointestinal stromal tumor (GIST) but without the possibility to collect a tumor biopsy. Cell-free DNA extracted from a blood sample was analyzed for the presence of mutations in GIST-specific genes using next generation sequencing. Furthermore, liquid biopsies were used to monitor the levels of mutant DNA copies during treatment with a tumor-specific mutation droplet digital PCR assay that correlated with the clinical and radiological response. Blood-based testing is a good alternative for biopsy-based testing. However, it should only be applied when biopsies are not available or possible to obtain because overall, in only 50%-85% of the cell-free plasma samples is the known tumor mutation detected.

Prognostic value of fibrinogen and D-dimer-fibrinogen ratio in resectable gastrointestinal stromal tumors.

AIM: To investigate the prognostic value of preoperative fibrinogen concentration (FIB) and D-dimer-fibrinogen ratio (DFR) in gastrointestinal stromal tumors (GISTs). METHODS: The purpose of this study was to retrospectively analyze 170 patients with GISTs who were admitted to our hospital from January 2010 to December 2015. The optimal cutoff values of related parameters were estimated by receiver operating characteristic (ROC) curve analysis. The recurrence free survival (RFS) rate was evaluated using Kaplan-Meier curves. Univariate analysis and multivariate Cox regression models were used to analyze the prognostic factors of GISTs. The relationship between the FIB, D-dimer, DFR, platelet count (PLT), and the clinicopathological features of GISTs was described by the chi-square test or nonparametric rank sum test (Mann-Whitney test). RESULTS: In ROC analysis, the optimal cutoff values of FIB, D-dimer, DFR, and PLT were 3.24 g/L, 1.24 mg/L, 0.354, and 197.5 (× 109/L), respectively. Univariate analysis and the Kaplan-Meier survival curve showed that FIB, D-dimer, DFR, PLT, National Institutes of Health (NIH) risk category, tumor size, tumor location, and mitotic index were significantly relevant to the 3-year and 5-year survival rate of patients (P < 0.05). Cox multivariate regression analysis illustrated that FIB (RR: 0.108, 95%CI: 0.031-0.373), DFR (RR: 0.319, 95%CI: 0.131-0.777), and NIH risk category (RR: 0.166, 95%CI: 0.047-0.589) were independent prognostic factors of the RFS rate (P < 0. 05). Moreover, FIB, D-dimer, DFR, and PLT were correlated with the clinical features of GISTs. CONCLUSION: FIB, D-dimer, DFR, and PLT are all related to the prognosis of GISTs. Moreover, FIB and DFR may be independent risk factors for predicting the prognosis of resectable GISTs.