Over-expression of TNNI3K is associated with early-stage carcinogenesis of cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a devastating disease with very poor prognosis due to late diagnosis and resistance to traditional chemotherapies and radiotherapies. Herein, thioacetamide (TAA)-induced rat CCA model and CGCCA cell line were used; we aim to study the cytogenetic features during tumoral development of CCA and uncover the mystery regarding carcinogenesis of CCA. The Array comparative genomic hybridization analysis, in silico method, gene knockdown, Western blot, cell count proliferation assay, clonogenecity assay, and IHC staining were applied in this study. Array comparative genomic hybridization analysis was performed on all different TAA-induced phases of rat tissues to reveal the certain pattern, +2q45, +Xq22, -12p12, have been identified for the tumor early stage, where involve the gene TNNI3K. In addition, 16 genes and 3 loci were associated with rapid tumor progression; JAK-STAT signaling pathway was highly correlated to late stage of CCA. In silico database was used to observe TNNI3K was highly express at tumor part compared with normal adjacent tissue in CCA patients from TCGA dataset. Furthermore, the growth of TNNI3K-knockdown SNU308 and HuCCT1 cells decreased when compared with cells transfected with an empty vector cell demonstrated by proliferation and colonogenecity assay. Besides, over expression of TNNI3K was especially confirmed on human CCA tumors and compared with the intrahepatic duct stone bile duct tissues and normal bile duct tissues (P < 0.001). Our findings might uncover the mystery regarding carcinogenesis of CCA, and provide the potential genetic mechanism to the clinicians some ideas for the patients' treatment.

A web-based audiometry database system.

To establish a real-time, web-based, customized audiometry database system, we worked in cooperation with the departments of medical records, information technology, and otorhinolaryngology at our hospital. This system includes an audiometry data entry system, retrieval and display system, patient information incorporation system, audiometry data transmission program, and audiometry data integration. Compared with commercial audiometry systems and traditional hand-drawn audiometry data, this web-based system saves time and money and is convenient for statistics research.

Gene expression-based chemical genomics identifies heat-shock protein 90 inhibitors as potential therapeutic drugs in cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is an aggressive tumor with a poor prognosis. There is no standard therapy for CCA, and novel drugs for treating refractory CCA need to be identified. METHODS: The authors hypothesized that, if a drug could reverse the gene expression signature of CCA, then it may inhibit the carcinogenesis of CCA and, hence, would be a potential therapeutic agent. Thus, the gene expression signatures from patients with CCA were queried using the bioinformatic method Connectivity Map, resulting in the enrichment of heat-shock protein 90 (HSP90) inhibitors with therapeutic potentials. RESULTS: Two HSP90 inhibitors, 17-AAG (tanespimycin) and the synthetic diarylisoxazole amide resorcinol NVP-AUY922, demonstrated potent antiproliferative activity in in vitro studies. In a thioacetamide-induced animal model, NVP-AUY922 also had antitumor activity and resulted in objective tumor regression. In addition, NVP-AUY922 reduced the expression of client oncoproteins involved in CCA oncogenesis and inhibited downstream proteins of both the phosphatidylinositol 3-kinase catalytic subunit α/v-akt murine thymoma viral oncogene homolog 1 protein kinase (PIK3/AKT) pathway and the v-Ki-ras2 Kirsten rat sarcoma viral oncogene/mitogen-activated protein kinase (KRAS/MAPK) pathway. CONCLUSIONS: Preclinical data from the current study suggest that NVP-AUY922 may be an effective treatment option for patients with CCA.

Cytoplasmic overexpression with membrane accentuation of stratifin in intrahepatic mass-forming cholangiocarcinoma after hepatectomy: correlation with clinicopathologic features and patient survival.

PURPOSE: Cholangiocarcinoma (CCA) is a lethal malignancy that afflicts thousands of patients worldwide. Stratifin has been shown to participate in mediating G2 arrest in several cancers, and cells that express stratifin could contribute to the chemo- and radioresistance of cancers and poor prognosis. However, the clinical impact of stratifin on clinicopathological features of mass forming (MF)-CCA is still unclear. METHODS: Seventy-eight patients with MF-CCA who had undergone hepatectomy were selected for an immunohistochemical study of stratifin. Sixteen clinicopathological variables were used for the survival analyses. RESULTS: Seventy-eight MF-CCA patients (36 men and 42 women) were studied. Cytoplasmic immunostaining with membrane prominence was found in 52.6% (41/78) of patients with MF-CCA after hepatectomy; this was significantly associated with elevated carcinoembryonic antigen (CEA) levels. During the median follow-up duration of 13.6 months, the 5-year overall survival (OS) rate was 14.9%. Univariate analysis showed that an absence of clinical symptoms, better nutritional status, lower alkaline phosphatase, smaller tumor, negative lymph node metastasis, negative stratifin staining, and curative hepatic resection were associated with favorable OS rate for MF-CCA patients after hepatectomy. Multivariate Cox proportional hazard analysis showed that the absence of clinical symptoms, negative lymph node metastasis, and curative hepatectomy independently predicted MF-CCA patients with favorable OS rate after hepatectomy. CONCLUSIONS: Overexpression of stratifin was significantly associated with elevated CEA levels in patients with MF-CCA. The favorable OS for MF-CCA patients depends on the absence of clinical symptoms, negative lymph node metastasis, and curative hepatectomy.

Surgical management in metastatic gastrointestinal stromal tumor (GIST) patients after imatinib mesylate treatment.

PURPOSE: Imatinib mesylate (IM) demonstrates substantial efficacy in most patients with metastatic gastrointestinal stromal tumors (GISTs). However, progression of GIST eventually develops and emerges as a challenge. To assess the role of surgery in the multidisciplinary management of GISTs, we studied the surgical outcomes in GIST patients receiving IM. MATERIALS AND METHODS: Between 2001 and May 2009, 161 metastatic GIST patients received IM. Among them, 35 patients undergoing 38 surgeries were investigated. Patients were categorized based on extent of disease before surgery (responsive or stable disease (PR, SD), local progression (LP), and generalized progression (GP)). Each tumor was investigated for genetic alteration before and after surgery. RESULTS: Disease status before surgery was significantly associated with surgical result. Gross tumor clearance was achieved in 42.9% of patients with responsive disease, but only 4.8% of those with focal resistance and 0% of those with disease progression (P = 0.022). GIST patients with PR, SD, and LP had significant better 2-year progression-free survival and overall survival than those with GP. Secondary mutations tended to be found more frequently in GIST patients with LP after surgery than those with response (10/21 (47.6%) vs. 2/14 (14.3%); P = 0.07), indicating that surgery may prevent potential development of secondary mutation in GIST patients with response. Secondary kit mutations were also found more frequently with primary exon 11 mutation than those with exon 9 mutation (38.7% vs. 16.7%; P = 0.394). CONCLUSIONS: Surgery may benefit selected GIST patients with PR, SD, and LP, especially for patients with LP because patients with LP had comparable survival to that of patients with responsive lesion. Surgery may prevent potential development of secondary mutations in selected patients with response after IM treatment. Secondary kit mutation was found more frequently in GIST patients with a primary kit exon 11 mutation than those with a primary kit exon 9 mutation.

Expression of thymidylate synthase determines the response of gastric cancer patients undergoing gastrectomy to 5-fluorouracil-based adjuvant chemotherapy.

PURPOSE: We investigated whether the intensity of thymidylate synthase (TS) staining in tissue samples obtained from gastric cancer (GC) patients undergoing gastrectomy could predict response to 5-FU-based adjuvant chemotherapy after gastrectomy. METHOD AND MATERIALS: Clinicopathological features of 124 patients with histologically proven GC who underwent radical gastrectomy were retrospectively reviewed. Tissue samples obtained from these patients were immunohistochemically stained for assessing TS expression. We arbitrarily classified the TS staining results as low (<20% cytoplasmic immunostaining) and high (> or =20% cytoplasmic immunostaining) TS expression. RESULTS: The clinicopathological features of the low TS expression group patients were typically similar to those of the high TS expression group patients. However, multivariate forward stepwise logistic regression analysis revealed that low TS expression was independently associated with females and responders to 5-FU-based adjuvant chemotherapy. The median follow-up duration for the 124 GC patients who had undergone curative resection was 41.3 months. The GC patients who showed poor tumor differentiation and high TS expression had short disease-free survival (DFS) and overall survival (OS). CONCLUSIONS: Low TS expression is significantly associated with female GC patients and responders to 5-FU-based adjuvant chemotherapy. It predicts longer DFS and OS in selected GC patients treated with 5-FU-based adjuvant chemotherapy after curative resection. The results suggest that prospective assessment of TS staining intensity in tissue samples obtained from GC patients undergoing gastrectomy would be useful to predict the patients who would be benefited from 5-FU-based adjuvant chemotherapy after gastrectomy.

Expression of ezrin is associated with invasion and dedifferentiation of hepatitis B related hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the fifth most common malignancy in the world and constitutes the leading cause of cancer-related death among men, and second among women in Taiwan. Liver cirrhosis and HCC are relatively prevalent, and 80% to 85% of the patients with these conditions have positive results for hepatitis B surface antigen in Taiwan. Only 5% of the general population is seronegative for all hepatititis B virus (HBV) markers. This is the first study to determine the role of ezrin upon HBV HCC cell and patients with HBV HCC undergoing hepatectomy METHODS: Immunohistochemical study with ezrin in 104 human HBV-HCC cases were carried out to investigate its association with the clinicopathological features and the outcomes of 104 HBV-HCC patients undergoing hepatetomy. In addition, DNA constructs including the wild type ezrin (wt-ezrin) and mutant ezrin Tyr353 (Y353) were transfected into Hep3B cell to study its role in tumor invasion and differentiation. RESULTS: HBV HCC patients with ezrin over-expression independently have smaller tumor size, cirrhotic liver background, poor tumor differentiation, and more vascular invasion. Ezrin expression status has no impact on survival for HBV-HCC patients undergoing hepatectomy. The in vitro assay showed that wt-ezrin Hep3B cells have a significant higher level of AFP secretion and higher invasion ability as compared with the control and Y353- ezrin Hep3B cells. CONCLUSION: Ezrin over-expression contributed to de-differentiation and invasion of HBV-HCC cell. HBV-HCC patients with ezrin over-expression were independently associated with tumor with smaller size, cirrhotic liver background, poor differentiation, and vascular invasion.

Prognostic value of MUC4 for mass-forming intrahepatic cholangiocarcinoma after hepatectomy.

Cholangiocarcinoma (CCA), a lethal malignancy afflicting many thousands of patients throughout the world, develops through a multi-step progression. We have established an oral thioacetamide-induced model of rat CCA recapitulating the histologic progression of human CCA, especially for mass-forming CCA (MF-CCA). Our previous DNA microarray study showed MUC4 is overexpressed in rat CCA. Herein, we investigated the prognostic value of MUC4 for predicting overall survival rate (OS) for MF-CCA patients undergoing hepatectomy. Overexpression of MUC4 in rat CCA is demonstrated by RT-PCR. From the archives of Chang Gung Memorial Hospital, 53 MF-CCA patients undergoing hepatectomy were selected for an immunohistochemical study of MUC4. Fifteen clinicopathological variables (including MUC4 staining status) were used for survival analysis. MUC 4 is overexpressed in rat CCA. Fifty-three MF-CCA patients, 26 men and 27 women, with a median age of 60 years (range: 29-89) were studied. During the median follow-up duration of 14.7 months, the OS rates at 1, 3, and 5 years were 58.8, 25.5, and 16.5%, respectively. Univariate analysis showed that an absence of physical findings, better nutritional status, small tumor size, negative lymph node metastasis, an absence of MUC4 staining, and curative hepatic resection were associated with favorable OS rate for MF-CCA patients after hepatectomy. However, multivariate Cox proportional hazard analysis showed that an absence of MUC4 staining, small tumor size, and curative hepatectomy independently predicted MF-CCA patients with favorable OS rate after hepatectomy. In conclusion, an absence of MUC4 staining, small tumor size, and curative hepatectomy could independently predict MF-CCA patients with favorable OS rate after hepatectomy.

Animal PET for thioacetamide-induced rat cholangiocarcinoma: a novel and reliable platform.

PURPOSE: Cholangiocarcinoma (CCA) is a lethal disease afflicting many thousands of patients worldwide. We have previously developed an oral thioacetamide (TAA)-induced model of rat CCA that recapitulates the histologic progression of human CCA. Our objective was to evaluate the feasibility of animal PET in detecting CCA in the setting of the TAA rat model. PROCEDURES: Male Sprague-Dawley rats (n = 30) were used in this study. Drinking water with TAA 300 mg/l was administered orally in 26 rats, and animal PET was performed at 20 weeks after initiation of TAA. A total of four rats served as controls. Animal PET images were acquired sequentially using both C-11 acetate and 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) to determine the optimal tracer. Dynamic animal PET images were collected to assess the optimal scan time based on the highest tumor-to-liver (T/L) ratio using time-activity curves. Animal PET findings were compared lesion by lesion with the results of autoradiography and the histological data. RESULTS: FDG animal PET images had a higher T/L ratio compared to images obtained with C-11 acetate as a marker. The optimal scan time for FDG animal PET was determined as 90 min postinjection of the tracer. This was when the T/L ratio reached its peak. Necropsy and histology confirmed the presence of TAA-induced CCA in 22 rats (84.6 %). Static animal PET images showed intense FDG uptake in 17 of the 22 tumor-bearing animals (77.3%). The average T/L ratio was 1.60 +/- 0.09. The sensitivity and specificity of animal PET in the detection of CCA were 77% (17/22) and 100% (4/4), respectively. CONCLUSIONS: We conclude that animal PET in the setting of the TAA rat model seems to be feasible for the detection of CCA. Future translational studies are needed to confirm and expand our findings.

Synthesis and evaluation of ortho-[18F] fluorocelecoxib for COX-2 cholangiocarcinoma imaging.

BACKGROUND: An 18F-tagged NSAID analog was prepared for use as a probe for COX-2 expression, which is associated with tumor development. METHODS: The in vivo uptake of celecoxib was monitored with ortho-[18F]fluorocelecoxib using positron emission tomography (PET). The binding affinity of ortho-[18F]fluorocelecoxib to COX-1 and COX-2 enzymes were assessed using the competitor celecoxib. RESULTS: The IC50 values were 0.039 µM and 0.024 µM, respectively. A selectivity index of 1.63 was obtained (COX-2 vs COX-1). COX-2 overexpressed cholangiocarcinoma (CCA) murine cells took up more ortho-[18F]fluorocelecoxib than that by usual CCA cells from 10 to 60 minutes post incubation. Competitive inhibition (blocking) of the tracer uptake of ortho-[18F]fluorocelecoxib in the presence of celecoxib by the COX-2 overexpressed CCA cells and the usual CCA cells gave the IC50 values of 0.5 µM and 46.5 µM, respectively. Based on the in vitro accumulation data and in vivo metabolism half-life (30 min), PET scanning was performed 30-60 min after the administration of ortho-[18F]fluorocelecoxib through the tail vein. Study of ortho-[18F]F-celecoxib in the CCA rats showed a tumor to normal ratio (T/N) of 1.38±0.23 and uptake dose of 1.14±0.25 (%ID/g). CONCLUSION: The inferior in vivo blocking results of 1.48±0.20 (T/N) and 1.18±0.22 (%ID/g) suggests that the nonspecificity is associated with the complex role of peroxidase or the binding to carbonic anhydrase.

Surgical management of patients with progressing metastatic gastrointestinal stromal tumors receiving sunitinib treatment: A prospective cohort study.

BACKGROUND: For selected patients with metastatic gastrointestinal stromal tumor (GIST) who have received first-line imatinib (IM) and are undergoing cytoreductive surgery, response to IM at time of surgery correlates with resection completeness as well as favorable progression-free survival (PFS) and overall survival (OS). However, surgical impact in GIST patients receiving second-line sunitinib (SU) is still not well clarified. MATERIALS AND METHODS: Between 2001 and 2014, 86 of 311 metastatic GIST patients received SU. Among them, 69 patients eventually experienced progression. Twenty-six patients who experienced local progression (LP) and underwent surgeries were investigated. Each tumor was assessed for genetic alterations before and after surgery. RESULTS: Twenty-six GIST patients receiving SU who experienced LP underwent surgery after a median of 6.2 months of SU use. Nineteen patients (73.1%) had undergone prior surgery on IM. The complication rate was 15.3%, and no additional operation was required for GIST patients receiving SU and experiencing LP who underwent surgery. The median PFS and OS times after surgery and start of SU were 5.2 and 18.9 months, respectively, and 16.4 and 26.0 months, respectively (median follow-up of 15.2 months). GIST patients receiving SU with LP (N = 26) may gain a significant PFS and OS benefit with surgery when compared with those not undergoing surgery (N = 43) (p = 0.003 and p = 0.02, respectively). Secondary exon 17 mutation occurred commonly and might explain SU resistance (8/23; 34.8%). CONCLUSION: Surgery is feasible in highly selected patients with metastatic GIST who are receiving SU and experiencing LP. Those patients may also have significantly prolonged PFS and OS after surgery. Secondary exon 17 mutation might explain SU resistance.

Dataset on the synthesis and characterization of boron fenbufen and its F-18 labeled homolog.

The data presented in this article are related to the research article entitled "Synthesis and Characterization of Boron Fenbufen and its F-18 Labeled Homolog for Boron Neutron Capture Therapy of COX-2 Overexpressed Cholangiocarcinoma". The contents of the data article include 1) the set up for performing in vitro binding assay, 2) 1H-, 13C- and 19F-NMR of compounds described in main text, 3) HPLC chromatogram of the fluorination mixtures, 4) data of in vitro stability test, cell survival assay, western blot and PCR analysis, 5) the modules for fixing the two CCA rats for BNCT, and 6) bar diagram for tumor reduction using [18F]FDG-PET 24 h post treatment with BNCT.

Synthesis and characterization of boron fenbufen and its F-18 labeled homolog for boron neutron capture therapy of COX-2 overexpressed cholangiocarcinoma.

Boron neutron capture therapy (BNCT) is a binary therapy that employs neutron irradiation on the boron agents to release high-energy helium and alpha particles to kill cancer cells. An optimal response to BNCT depends critically on the time point of maximal 10B accumulation and highest tumor to normal ratio (T/N) for performing the neutron irradiation. The aggressive cholangiocarcinoma (CCA) representing a liver cancer that overexpresses COX-2 enzyme is aimed to be targeted by COX-2 selective boron carrier, fenbufen boronopinacol (FBPin). Two main works were performed including: 1) chemical synthesis of FBPin as the boron carrier and 2) radiochemical labeling with F-18 to provide the radiofluoro congener, m-[18F]fluorofenbufen ester boronopinacol (m-[18F]FFBPin), to assess the binding affinity, cellular accumulation level and distribution profile in CCA rats. FBPin was prepared from bromofenbufen via 3 steps with 82% yield. The binding assay employed [18F]FFBPin to compete FBPin for binding to COX-1 (IC50=0.91±0.68µM) and COX-2 (IC50=0.33±0.24µM). [18F]FFBPin-derived 60-min dynamic PET scans predict the 10B-accumulation of 0.8-1.2ppm in liver and 1.2-1.8ppm in tumor and tumor to normal ratio=1.38±0.12. BNCT was performed 40-55min post intravenous administration of FBPin (20-30mg) in the CCA rats. CCA rats treated with BNCT display more tumor reduction than that by NCT with respect of 2-[18F]fluoro-2-deoxy glucose uptake in the tumor region of interest, 20.83±3.00% (n=12) vs. 12.83±3.79% (n=10), P=0.05. The visualizing agent [18F]FFBPin resembles FBPin to generate the time-dependent boron concentration profile. Optimal neutron irradiation period is thus determinable for BNCT. A boron-substituted agent based on COX-2-binding features has been prepared. The moderate COX-2/COX-1 selectivity index of 2.78 allows a fair tumor selectivity index of 1.38 with a mild cardiovascular effect. The therapeutic effect from FBPin with BNCT warrants a proper COX-2 targeting of boron NSAIDs.

Sporadic somatic mutation of c-kit gene in a family with gastrointestinal stromal tumors without cutaneous hyperpigmentation.

We described two members in a family with gastrointestinal stromal tumors (GISTs) without cutaneous hyperpigmentation. The patients were father and son who did not have cutaneous hyperpigmentation. Histological examination showed that these tumors were GISTs expressing CD34 and CD117. Tumor DNA extracted from paraffin-embedded specimens revealed somatic mutation with a deletion mutation at different codons in exon 11 of c-kit gene after direct sequencing analysis. No germline mutation was detected in DNA extracted from peripheral leukocytes obtained from the father and son. We propose that GISTs could be caused by sporadic somatic mutation in a family without germline mutation and hyperpigmentation.

Treatment of patients with advanced gastrointestinal stromal tumor of small bowel: implications of imatinib mesylate.

AIM: To examine the impact of imatinib mesylate (Glivec) on patient survival and response and its safety, and the correlation of the response rate with the kit gene mutation status. METHODS: Thirty-three of 74 (44.6%) small bowel gastrointestinal stromal tumor (GIST) patients who developed recurrence after curative resection and not treated with Glivec were classified as group A patients. Twenty-two advanced small bowel GIST patients treated with Glivec were classified as group B patients. Clinicopathological features, post-recurrence and overall survival rates were compared. Each tumor in group B patients was investigated for mutations of kit or platelet-derived growth factor alpha (PDGFRA). The mutation type was correlated with clinical outcomes. The anti-tumor effect and safety of Glivec in group B patients were also assessed. RESULTS: Advanced small bowel GIST patients treated with Glivec had substatntially longer post-recurrence survival and higher overall survival rates than those not treated with Glivec. A total of 15 patients had a partial response (PR) (67.8%). Activated mutations of c-kit were found in 16 of 19 tested patients and no PDGFRA mutant was identified. In 13 patients with GISTs harboring exon 11 kit mutations, the partial response rate (PR) was 69.3%, whereas two of three patients with tumors containing an exon 9 kit mutation had an overall response rate (ORR) of 66.7% (not significant). CONCLUSION: Glivec significantly prolongs the post-recurrence and overall survival of Asian patients with advanced GISTs. Glivec induces a sustained objective response in more than half of Asian patients with advanced small bowel GISTs. Activated mutations of kit exon 11 are detectable in the vast majority of GISTs. There is no difference in the PR rate for patients whose GISTs have kit exon 9 and exon 11 mutations.

Advanced gastrointestinal stromal tumor patients with complete response after treatment with imatinib mesylate.

AIM: Most gastrointestinal stromal tumors (GISTs) express constitutively activated mutant isoforms of kit kinase or platelet-derived growth factor receptor alpha (PDGFRA), which are potential therapeutic targets for imatinib mesylate (Glivec). Partial response occurred in almost two thirds of GIST patients treated with Glivec. However, complete response (CR) after Glivec therapy was sporadically reported. Here we illustrated advanced GIST patients with CR after Glivec treatment. METHODS: Between January 2001 and June 2005, 42 advanced GIST patients were treated with Glivec. Patients were administered 400 mg of Glivec in 100-mg capsules, taken orally daily with food. The response of the tumor to Glivec was evaluated after one month, three months, and every three months thereafter or whenever medical need was indicated. Each tumor of patients was investigated for mutations of kit or PDGFRA. RESULTS: The median follow-up time of the 42 advanced GIST patients treated with Glivec was 16.9 months (range, 1.0-47.0 months). Overall, 3 patients had complete response CR (7.1%), 26 partial response (67.8%), 5 stationary disease (11.9%), and 3 progressive disease (11.9%). The median duration of Glivec administration for the three patients was 36 months (range, 23-36 months). The median time to CR after Glivec treatment was 20 months (range, 9-26 months). Deletion and insertion mutations of c-kit exon 11 and insertion mutation of c-kit exon 9 were found in two cases and one case, respectively. CONCLUSION: Complete response (CR) can be achi-eved in selected advanced GIST patients treated with Glivec. The median time to CR after Glivec treatment was 20 months. Deletion and insertion mutations of kit exon 11 and insertion mutation of kit exon 9 contribute to the genetic features in these selected cases.

Peritumoral SPARC expression and patient outcome with resectable intrahepatic cholangiocarcinoma.

BACKGROUND AND OBJECTIVES: Cholangiocarcinoma (CCA) affects thousands worldwide with increasing incidence. SPARC (secreted protein acidic and rich in cysteine) plays an important role in cellular matrix interactions, wound repair, and cellular migration, and has been reported to prevent malignancy from growth. SPARC undergoes epigenetic silencing in pancreatic malignancy, but is frequently expressed by stromal fibroblasts adjacent to infiltrating pancreatic adenocarcinomas. CCA is also a desmoplastic tumor, similar to pancreatic adenocarcinoma. SPARC's clinical influence on clinicopathological characteristics of mass-forming (MF)-CCA still remains unclear. In this study, we evaluate the expression of SPARC in tumor and stromal tissue to clarity its relation with prognosis. METHODS: Seventy-eight MF-CCA patients who underwent hepatectomy with curative intent were enrolled for an immunohistochemical study of SPARC. The expression of immunostaining of SPARC was characterized for both tumor and stromal tissues. We conducted survival analysis with 16 clinicopathological variables. The overall survival (OS) was analyzed by Kaplan-Meier analysis and Cox proportional hazards regression modeling. RESULTS: Thirty-three men and 45 women with MF-CCA were studied. Within total 78 subjects, 12 (15.4%) were classified as tumor negative/stroma negative, 37 (47.4%) as tumor positive/stroma negative, four (5.1%) as tumor negative/stroma positive, and 25 (32.1%) as tumor positive/stroma positive. With a median follow-up of 13.6 months, the 5-year OS was 14.9%. Cox proportional hazard analysis revealed that SPARC tumor positive and stromal negative immunostaining and curative hepatectomy predicted favorable OS in patients with MF-CCA after hepatectomy. CONCLUSION: MF-CCA patients with SPARC tumor positive and stromal negative expression may have favorable OS rates after curative hepatectomy.

Fractioned dose regimen of sunitinib for patients with gastrointestinal stromal tumor: a pharmacokinetic and treatment efficacy study.

AIM: Sunitinib has shown benefit in patients with imatinib (IM)-resistant gastrointestinal stromal tumor (GIST). However, its advantages are somewhat diminished because of associated toxicities. Herein, we clarify the efficacy and safety of fractioned dose regimen of sunitinib by a pharmacokinetic and efficacy study. MATERIALS AND METHODS: Between 2001 and March 2013, a total of 214 patients with metastatic GIST was treated at Chang Gung Memorial Hospital. Among them, 55 (11.6%) patients who received sunitinib were investigated. One group of patients was administered with standard dose of once-daily sunitinib (standard dose group) and the other group was administered with standard total daily dose of sunitinib in fractioned doses (fractioned dose group). RESULTS: Thirty-two male and 23 female patients with a median age of 55 years received sunitinib. The median duration of sunitinib administration was 9.2 months. The clinical benefit was 65.2%. The mean peak blood level of sunitinib in patients with fractioned doses was significantly lower than that in those with once-daily dose (83.4 vs 50.1 ng/ml, P = .01). The rates of adverse effects of hand-foot syndrome, mucositis, and yellow skin were significantly decreased by fractioned doses of sunitinib. However, the progression-free and overall survival did not differ between patients with different treatment regimens. CONCLUSION: The fractioned dose regimen of sunitinib appears to be a safe and effective treatment for patients with IM-resistant/intolerant GISTs. Significantly decreased toxicity of this regimen could be explained by significantly lower peak sunitinib blood level. However, the treatment efficacy is not reduced by this regimen.

Clinical significance of pathological complete response in patients with metastatic gastrointestinal stromal tumors after imatinib mesylate treatment--lessons learned.

AIM: Imatinib mesylate (IM) has substantial efficacy in patients with metastatic gastrointestinal stromal tumors (GISTs), and pathological complete response (pCR) following IM treatment has been sporadically reported; however, its clinical significance for GIST needs to be clarified. PATIENTS AND METHODS: From 2001 to 2010, 26 out of 171 patients with metastatic GIST who received IM with response or stable disease underwent operation. Among them, 12 operations with pCR were compared to 14 operations without pCR regarding clinicopathological features, mutation status, progression-free survival (PFS), and overall survival (OS). Following the operation, each tumor was assessed immunohistologically, and genetic analysis was performed on the tumor tissue. RESULTS: Twelve out of 26 (46.2%) patients with metastatic GIST who received IM with response or stable disease had pCR. After a median follow-up of 40.8 months, patients with pCR had significantly better PFS and OS than those without pCR [2-year PFS and OS: 82.5% and 100% versus 35.6% and 49.4%, (p=0.014 and p=0.004) respectively]. Predictive factors for pCR were: origin of GIST, response after IM therapy, and duration of IM use before operation. Patients without pCR had a significantly higher frequency of secondary mutation when compared to those with pCR (47.4% versus 0%; p=0.004). CONCLUSION: Patients with colorectal GIST receiving IM who responded more quickly to IM treatment prior to surgery had a higher chance of pCR. pCR results in significantly favorable PFS and OS, however, IM cannot be withdrawn. Patients without pCR had a significantly higher frequency of secondary mutation when compared to those with pCR.

Imatinib escalation or sunitinib treatment after first-line imatinib in metastatic gastrointestinal stromal tumor patients.

AIM: Imatinib mesylate (IM) is effective in metastatic gastrointestinal stromal tumor (GIST) patients; however, disease progression eventually occurs due to IM resistance or intolerance. Treatment options include IM escalation or a direct shift to sunitinib, but comparison of these strategies is required. PATIENTS AND METHODS: This study included 91 out of 214 metastatic GIST patients treated with IM, who experienced progression or intolerance between August 2001 and December 2012 at the Chang Gung Memorial Hospital. Treatment efficacy and safety profiles were retrospectively compared between groups of patients who either received escalated IM or were directly switched to sunitinib. RESULTS: There were no significant differences in age, gender, second-line treatment causes or gene mutations in the IM escalation group (N=63) versus the sunitinib group (N=28). The 2 groups had similar progression-free survival (PFS, p=0.316) and overall survival (OS, p=0.599). Patients without primary KIT exon 9 mutations and who treated with sunitinib had significantly better PFS (14.3 vs. 6.2 months, p=0.037) and a trend toward better OS (not reached vs. 16.4 months, p=0.161) compared to the IM-escalation group. Patients in both groups with responses and stable disease (SD), and IM escalation patients who underwent surgery and who had KIT exon 9 mutations, had favorable PFS. The most common non-hematological adverse events were edema in the IM escalation group and hand-foot syndrome and hypertension in the sunitinib group. CONCLUSION: Comparable results were achieved by IM escalation and sunitinib treatment. Physicians should consider kinase mutations and specific adverse effects when choosing between these treatments.