bluuebunny/crossref_metadata_2025_split huggingface dataset:
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
Authors: Chan C. , Chen L. , Hsueh Y. , Chuang W. , Lee H. , Huang M. , Heieh R. , Weng W. 
Published: August 2020

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]
The predictive role of CA 19–9 kinetics for time-to-progression (TTP) and overall survival (OS) in patients receiving palliative first-line chemotherapy for advanced pancreatic cancer
Authors: Haas M. , Boeck S. , Stieber P. , Laubender R. P. , Buchner H. , Klose C. , Kullmann F. , Bruns C. J. , Mansmann U. , Heinemann V. 
Published: August 2020

e15637 Background: Previous studies showed contradictory results for a predictive role of CA 19–9 kinetics during chemotherapy in patients (pts) with pancreatic cancer (PC). Methods: We performed a retrospective, multicenter study in order to evaluate the role of CA 19–9 as a biomarker for TTP and OS in PC. Main inclusion criteria: histological confirmed diagnosis of PC, treatment with first-line chemotherapy for advanced disease, pre-treatment CA 19–9 level of > 5.2 U/ml. As CA 19–9 measurements were conducted in different laboratories using different commercial assays, we defined a subgroup of pts where CA 19–9 was assessed exclusively by the Elecsys assay (Roche Diagnostics). For the analysis of CA 19–9 kinetics, at least one follow-up measurement between day 20 and 64 during first-line chemotherapy had to be available. Pts were divided into two subgroups of CA 19–9 responders and non-responders by cut-offs of a 25% and 50% decline, respectively. OS and TTP were estimated with the Kaplan-Meier-Method, differences between the subgroups were analyzed by using the log-rank test. Results: One hundred and eighty-six pts were included, 83 of them were tested with the Elecsys method. Median age was 63 years, 90 % of the pts were treated within prospective clinical trials. Median pre-treatment CA 19–9 was 1076 U/ml (range 5.7–100,000 U/ml), the median bilirubin was 0.6 mg/dl. Median OS and TTP were 9.8 months (mo) and 5.4 mo, respectively. In univariate analysis, pts with a CA 19–9 decline of at least 25% during chemotherapy lived significantly longer (11.9 mo vs. 8.2 mo, p=0.003) and had a significantly prolonged TTP (5.8 mo vs. 4.4 mo, p=0.018) than those with a lower decline or even CA 19–9 increase. Data for the Elecsys-measurements were comparable (OS: 13.4 mo vs. 8.6 mo, p=0.004; TTP: 7.0 mo vs. 2.6 mo, p=0.003). None of the analyses demanding a CA 19–9 drop of at least 50% reached the level of statistical significance. Conclusion: An early CA 19–9 decline of 25% during first-line chemotherapy may predict OS and TTP in pts with advanced PC. Innovative statistical methods are required to improve our understanding of the utility of CA 19–9 as a predictive biomarker in PC. [Table: see text]
PhaseI/II clinical trial of dose escalation using daily on-line cone beam CT guided radiotherapy combined with active breath control after transcatheter arterial chemoembolization for hepatocellular carcinoma
Authors: Yue J. , Yu J. , LI S. , Yin Y. , Liu T. , Zhu J. , Lu J. 
Published: August 2020

e15654 Background: The radiation dose is the key factor to improve survival of patients with hepatocellular carcinoma (HCC). The optimal way to increase radiation dose is to reduce uncertainties of target mainly due to respiratory motion and setup error in radiotherapy. Our previous study demonstrated that lipiodol can be a reliable surrogate of direct tumor targeting in Kv- cone beam CT(CBCT) for patients with good lipiodol embolization. Relying on lipiodol,the daily on-line CBCT guidance with ABC is feasible. By reducing geometric position uncertainty, as well as liver movement, the technique of ABC combined with on-line CBCT guidance can permit CTV(clinical target volume)-PTV(planning target volume) margin reduction and dose escalation. The purpose of the study is to apply the new technique for clinical application and investigate the dose escalation, toxicities and response of liver tumors with the technique combined with chemoembolization(TACE). Methods: 20 HCC patients with Child-Pugh A liver function score were treated by daily on-line CBCT guided radiotherapy relying on lipiodol combined with ABC after TACE. After current doses of 45Gy/ 9 fractions,3 fractions/weeks were delivered,the scheduled dose escalation ranged from 5 to 20Gy. Each mean liver dose not reached 23G y, V30 ( the percentage of normal liver volume with radiation dose≥30 Gy) less than 28%. Results: The planned dose escalation was finished in all subgroups. None of these patients developed Grade 2 or greater liver toxicity except two patients developed Grade 2 gastrointestinal complications and one had grade 1 acute liver toxicity.The overall immediate tumor response rate was 76.3%. 1-year overall survival rate was 80.5%. Conclusions: The technique of daily on-line CBCT guided radiotherapy combined with ABC after TACE is a safe and effective treatment which can reduce CTV-PTV margin significantly and increase target precision greatly. With the technique combined with TACE, the total irradiation dose above 65Gy is feasible in daily fraction of 5Gy. No significant financial relationships to disclose.
Leptomeningeal carcinomatosis of gastric cancer: Multicenter retrospective analysis of 54 cases
Authors: Oh S. , Kim S. , Kwon H. , Kim H. , Hwang I. , Kang J. , Lee S. , Lee J. , Kang W. 
Published: August 2020

e15658 Background: Leptomeningeal carcinomatosis occurs in approximately 5% of patients with cancer. The most common cancers involving the leptomeninges are breast and lung cancer. However, gastric adenocarcinoma has been rarely reported with leptomeningeal carcinomatosis (LMC). Methods: We analyzed 54 cases of cytological confirmed gastric LMC at 4 institutions from 1994 to 2007. Results: Male to female ratio was 1.5:1. Median age of these patients was 49 years. The majority of patients had advanced disease at the initial diagnosis of gastric cancer. The clinical or pathologic TNM stages of the primary gastric cancer were IV in 38 patients (70%). The median interval from the diagnosis of the primary malignancy to the diagnosis of LMC was 6.3 months (range, 0 - 73.1 months). Of the initial endoscopic finding available 45 patients, Bormann type III and IV were 23 (51%) and 15 (33%) patients, respectively. Headache (85%) and nausea/vomiting (58%) were most common presenting symptoms of LMC. The intrathecal (IT) chemotherapy was administered to 36 patients - mainly with methotraxate alone (59%) or combination with ara- C/hydrocortisone (41%). Median IT treatment number was 7 (range, 1–18). Concomitant radiotherapy or chemotherapy was done in 25 patients and 10 patients, respectively. 17 patients (46%) were achieved cytological negative conversion. Median OS duration from diagnosis of LMC was 6.7 weeks (95% CI; 4.3–9.1 weeks). Clinically, initial advanced stage was predictive value of poor prognosis (P=0.009). But, Cytology negative conversion was predictive value of relatively longer survival duration (P=0.005). And, not only IT chemotherapy but also intravenous chemotherapy had been shown improvement of survival duration (P=0.010, P=0.005, respectively). Conclusions: Although gastric LMC has dismal prognosis, IT and IV chemotherapy could be help to extend survival duration of gastric LMC. No significant financial relationships to disclose.
The optimal threshold of 18F-FLT PET and 18F-FDG PET to estimate the length of gross tumor volume in patients with squamous cell carcinoma of the thoracic esophagus verified by pathological examination
Authors: Yu J. , Han D. , Zhong Xiaojun , Mu Dianbin , Fu Zheng , Zhan g Baijiang , Zhang Limin , Zhang Weidi 
Published: August 2020

e15665 Background: To determine the optimal method of using 3-deoxy-3-18F-fluorothymidine (FLT) positron emission tomography (PET) to estimate gross tumor length in esophageal carcinoma, and compared with that of 18F- fluorodeoxyglucose(FDG) PET. Methods: Twenty patients with esophageal squamous cell carcinoma treated with radical surgery were enrolled and detected by FLT PET, eighteen of them underwent FDG PET scan. Gross tumor volumes (GTVs) were delineated using seven different methods with FLT PET: visual interpretation, standardized uptake value (SUV) 1.3, SUV 1.4, SUV 1.5, and 20% of maximum standard uptake value (SUVmax), 25% SUVmax,30% SUVmax, on FLT PET imaging, and three different methods with FDG PET: visual interpretation, SUV 2.5, and 40%SUVmax on FDG PET imaging. The length of tumors on FLT PET scan were measured and recorded as LFLTvis, LFLT1.3, LFLT1.4, LFLT1.5, LFLT20%, LFLT25%, and LFLT30%, and FDG PET scan were measured and recorded as LFDGvis, LFDG2.5, and LFDG40%, respectively, and compared with the length of gross tumor in the resected specimen measured by pathological examination (LPath). Results: The mean (±SD) LPath was 5.16±2.19cm. The mean LFLTvis, LFLT1.3, LFLT1.4, LFLT1.5, LFLT20%, LFLT25%, and LFLT30%were 5.17±2.40cm, 5.55±2.43cm, 5.17±2.41cm, 4.95±2.44cm, 5.82±2.23cm, 5.32±2.31cm, and 5.04±2.28cm, respectively. Compared with the LPath, the P value were 0.971, 0.045, 0.972, 0.255, 0.066, 0.644, and 0.714, respectively. The correlation coefficients were 0.952, 0.944, 0.959, 0.948, 0.763, 0.783, and 0.800, respectively. The mean LFDGvis, LFDG2.5, and LFDG40% were 5.41±2.27cm, 5.38±2.25cm, and 4.02±1.57cm, respectively. Compared with the LPath, the P value were 0.098, 0.085 and 0.000, respectively. The correlation coefficients were 0.984, 0.990 and 0.932, respectively. On FLT PET, LFLT1.4, and on FDG PET, L FDG2.5 seem more approximate to LPath. The difference between LFLT1.4 and LFDG2.5 was not significantly (P=0.442), the correlation coefficients was 0.960. Conclusions: An SUV cutoff of 1.4 on FLT PET, and an SUV cutoff of 2.5 on FDG PET, provided the closest estimation of GTV length in this study No significant financial relationships to disclose.
Recurrence patterns of Chinese patients with gastric cancer after complete resection
Authors: Lu M. , Shen L. 
Published: August 2020

e15667 Background: Recurrence after radical resection was the most important factor that influence the prognosis of patients with gastric adenocarcinoma. Focusing on the clinicopathologic features and recurrence patterns, this study aims to find the characteristics of recurrence pattern and the predictive factors of gastric cancer patients in China. Methods: This is a retrospective analysis of the gastric adenocarcinoma patients who accepted adjuvant treatment and follow up in our medical department after R0 resection. From June 1995 through June 2007, among 845 patients with R0 resection, 773 cases with detailed information of follow-up enrolled in this study. The location of first recurrence were reviewed. Recurrences location were categorized as locoregional, peritoneal, or distant. Locoregional recurrence was defined as dominant masses in the gastric bed, regional nodes or anastomotic recurrence. Peritoneal recurrence was documented by positive cytology in ascitic fluid, peritoneal nodules or ovaries with tumors involved. Distant metastases were defined as the specific organ or distant lymph nodes involved. Univariate and multivariate analyses were performed to identify predictive factors of recurrence patterns. Results: Till the last follow-up date in November 2008, 426 patients (55.1%) recurred, and 303(71.1%) recurred within 2 years after resection. The pattern of recurrence was locoregional in 240 patients (31%), distant in 261 patients (33.8%) and peritoneal in 88 patients (11.4%). On multivariate analysis, proximal location, the rate of positive lymph node > 0.33, number of lymph node dissetion<15 and operated in general hospital increase the risk of locoregional recurrence. Distant recurrence was significant associated with male gender, advanced T-stage, positive lymph nodes and number of lymph node dissection<15; female gender, poor differentiation and advanced T-stage were high risk factors of peritoneal recurrence. Conclusions: Different recurrence pattern has remarkable relationship with various clinicopathologic factors. It is noteworthy that both locoregional recurrence and distant recurrence are associated with the number of lymph node dissection, confirming the importantace of lymph node dissection. No significant financial relationships to disclose.
Pharmacokinetics of intraperitoneal docetaxel and S-1 in patients with gastric cancer with peritoneal carcinomatosis
Authors: Hayashi K. , Kamikozuru H. 
Published: August 2020

e15672 Background: One of the most causes of death from gastric cancer is peritoneal cartinomatosis. Intraperitoneal docetaxel infusion is expected to be a new strategy for a treatment of peritoneal carcinomatosis. The purpose of this study is to evaluate the plasma and peritoneal pharmacokinetic of intraperitoneal docetaxel infusion in combination with oral administration of S-1. Methods: Eight patients with peritoneal carcinomatosis of advanced gastric cancer were enrolled. Docetaxel was dissolved in an isotonic saline to a final 1 liter solution and administered in 2 hour via an implanted intraperitoneal catheter at dosage of 40mg/m2. Five of eight patients were administered S-1 orally at dosage of 80mg/m2. Blood and peritoneal fluid were collected before administration, on completion of the docetaxel infusion(hour 0) and at hours 1,2,4,6,12,24,48,and 72 after completion of the infusion of the docetaxel. Plasma and peritoneal fluid concentrations of docetaxel and 5FU were evaluated. Results: The mean peak peritoneal and plasma concentrations of docetaxel were 18.6×103 ng/ml (at hour 0) and 45 ng/ml (at hour 0 to 2), respectively. The peritoneal concentrations of docetaxel were remained even after 24 and 72 hours (24 hours: 1150ng/ml, 72 hours: 74ng/ml). In seven out of eight patients, plasma concentrations of docetaxel were disappeared after 24 hours, but in only one patient with severe ascites, concentration of plasma docetaxel at hour 24 could be obtained (20 ng/ml). The mean peritoneal and plasma areas under the curves (AUC) of doceta×el were 141x103 ng/ml×hr and 480 ng/ml×hr, respectively. The mean peritoneal concentrations of 5FU kept over 60% of plasma concentrations (plasma: 164.3ng/ml, peritoneal: 105ng/ml). Conclusions: Intaperitoneal docetaxel kept relatively high concentrations even after 72hours. 5FU concentrations were well transfered in peritoneal fluid from plasma via oral S-1 administration. Intraperitoneal docetaxel in combination with S-1 orally may be a useful regimen to the patients with carcinomatosis of advanced gastric cancer. No significant financial relationships to disclose.
Assessment of serum concentrations of Dkk1 as potential biomarker for esophageal squamous cell carcinoma
Authors: Zer C. , Dong X. , Kernstine K. , Zhong L. 
Published: August 2020

e15675 Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common fatal cancers worldwide due to the lack of an early disease screening strategy. Identification of diagnostic markers will greatly improve the morbid outcome. Dickkopf 1 (Dkk1) is a secreted antagonist of Wnt signaling pathway, an important pathway in tumorigenesis. The expressions of Dkk1 seem to be tumor-specific: reduced expressions have been seen in colorectal cancer, but elevated levels were reported for hepatoblastomas. In ESCC, the situation is less clear, for both elevation and reduction of Dkk1 were reported. The serum concentrations of Dkk1 have also been shown to be higher in ESCC patients’ sera in one study. In view of the varied outcome from Dkk1 tissue expressions and the scarce reports on Dkk1 serum concentration from ESCC patients, we therefore sought to determine the tissue expression and serum concentrations of Dkk1 as our first step to evaluate the potential of Dkk1 as a diagnostic marker for ESCC. Methods: The expression levels of Dkk1 in ten ESCC tumor and adjacent non-tumor tissues were examined by Western blot. Serum Dkk1 level of 168 samples were quantified in a double-blind fashion by ELISA (Dkk1 Duoset ELISA development kit from R & D Systems, Minneapolis, MN). To ensure that the serum Dkk1 detection was not affected by autoantibodies against Dkk1 present in sera, we also measured serum Dkk1 autoantibody levels by ELISA with modifications to the ELISA kit. Results: Seven out of ten of the tumors showed elevated Dkk1 level, while only two out of ten of the control normal tissue showed elevation. Surprisingly, after decoding of our serum samples into 80 patients and 88 normal controls, we found that Dkk1 level was significantly lower in patient sera (2.99ng/ml) than the normal samples (5.32ng/ml) (p=0.0001; t-test). The measurements were not obscured by the presence of Dkk1 autoantibodies, as they were not different between patient and control samples. Conclusions: Contrary to previous published results, we found Dkk1 is suppressed in patient sera, and thus our result undermines the potential of serum Dkk1 level as a predictive marker for ESCC. Further investigations will be needed to explain the discrepancies between the studies. No significant financial relationships to disclose.
Diagnostic yield of nonfunctional pancreatic neuroendocrine tumor using endoscopic ultrasound-guided fine needle aspiration biopsy
Authors: Matsumoto K. , Sawaki A. , Kobayashi Y. , Mizuno N. , Hara K. , Takagi T. , Sawai Y. , Shimizu Y. , Yatabe Y. , Yamao K. 
Published: August 2020

e15680 Background: Radiological examinations including computed tomography (CT) and endoscopic ultrasound sonography (EUS) are important for the diagnosis of pancreatic neuroendocrine tumors (PNETs). Pathological diagnosis is not needed with functional PNETs because the diagnosis is made by biochemical testing. Therefore, pathological diagnosis is essential for the non-functional PNETs (nf-PNETs). In this study, we examined the diagnostic yield of radiological examinations and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for nf-PNETs. Methods: From January 1997 to December 2007, consecutive 38 cases were pathologically diagnosed from as nf-PNETs at Aichi Cancer Center Hospital. Of these 33 patients was diagnosed with surgical specimen, 5 patients with EUS-FNA specimen. Of 33 patients, 16 patients underwent EUS-FNA preoperatively, and were examined further: their EUS-FNA specimens were submitted for additional immunohistochemical examination for CD 56, chromogranin A, synaptophysin, somatostatin receptor 2A (SSTR2A) and Ki-67 using cell block method. Staging of PNETs was performed according to WHO classification. Results: 16 patients (10 men and 6 women) who ranged in age from 23 to 81 years. The mean of tumor size was 2.2 cm and ranged from 0.7 to 4.4 cm. Diagnosis by CT and EUS was 12 (75.0%) PNETs, two pancreatic cancer, one solid papillary tumors and one malignant lymphoma. Accurate diagnosis by cytology and immunohistochemistry was 75.0% and 93.8%, respectively. The Ki-67 in specimens of malignancy tended to be higher than those of benign or uncertain behavior. If we assumed that a tumor with Ki-67 of more than 2% was malignancy, the diagnostic accuracy was 75.0%. Positive reaction to SSTR2A was up to 14 out of 16 nf-PNETs. Conclusions: The EUS-FNA is a useful tool for diagnosing nf-PNETs with immunohistochemical staining compared to cytology and radiological examinations. Ki-67 may be also effective to predict the degree of malignancy. No significant financial relationships to disclose.
Modulation of regulatory T cells and myeloid-derived suppressor cells by sorafenib and sunitinib in renal cell carcinoma patients
Authors: Floercken A. , Takvorian A. , Singh A. , Hopfenmüller W. , Pezzutto A. , Dörken B. , Westermann J. 
Published: August 2020

e16002 Background: Induction of regulatory T (Treg) and myeloid-derived suppressor cells (MDSC) is a major mechanism for the escape of tumors from immunological control. Increased levels of Treg cells have been described in renal cell cancer (RCC) patients and seem to correlate with an adverse outcome. Furthermore, reduction of Treg has been reported for RCC patients under sunitinib therapy. The aim of our study was to analyse the influence of sorafenib and sunitinib on the frequency of Treg and MDSC in patients with metastatic RCC (mRCC). Methods: The number of T reg, MDSC and lymphocyte subpopulations was analysed by flowcytometry in peripheral blood (pb) of patients (n=19) with histologically confirmed mRCC under treatment with either sunitinib (50 mg/d, n=11) or sorafenib (800 mg/d, n=8). After informed consent blood samples were taken before and during the 1st, 2nd, and 3rd month of therapy. Flowcytometric analysis was performed using fluorochrome labeled antibodies against CD3, CD4, CD8, CD25, CD127, FOXp3, CD33, C14, CD11b and HLA-DR. Results: The baseline level of Treg did not differ from healthy controls. However, there was a significant increase of CD3+CD4+CD25+FOXp3+Treg (13,5% vs. 36,3% of gated cells, p= 0.02) and the ratio FOXp3+/FOXp3- CD3+CD4+ T cells (0,16% vs. 0,56% of gated cells, p= 0.02) in the group of sorafenib-treated patients compared to sunitinib-treated patients during the 1st month of therapy and thereafter. This effect was confirmed in an intragroup analysis. There was no influence of Sunitinib on the frequency of Treg. Analysis of CD33+/HLA-DR-/11b+ MDSC did not reveal any change under treatment with sorafenib or sunitinib. Conclusions: Sorafenib, but not sunitinib, leads to an early and sustained increase of Treg in pb of mRCC patients. A negative influence of sorafenib on primary immune responses has been described and has mainly been attributed to functional impairment of dendritic cells (DC). Whether altered DC function under sorafenib is responsible for the induction of Treg in RCC patients will have to be addressed in future studies. In immunoresponsive tumors such as RCC, immunological effects of kinase inhibitors are particularly relevant for the design of combination trials with immunotherapeutic agents. No significant financial relationships to disclose.