[Show abstract][Hide abstract] ABSTRACT: Biomarkers and novel therapeutic targets are urgently needed in colorectal cancer (CRC). The pseudo tyrosine kinase receptor 7 (PTK7) is involved in planar cell polarity and it is deregulated in various malignancies, including CRC. Yet, little is known about its protein expression in human CRC, or about a possible correlation of its expression with clinical endpoints. Using a clinically annotated Tissue MicroArray (TMA) produced from from 192 consecutive CRC patients treated by initial surgery, we examined PTK7 expression by immunohistochemistry in tumoral tissue and matched normal mucosae, and correlated its expression with clinico-pathological features and patient outcome. PTK7 depletion by specific shRNA in HCT116 and HCT15 CRC cell lines was found to affect cell proliferation, resistance to drugs and cell migration. Tumor growth and metastatic phenotype were investigated in vivo using a xenograft mouse model of CRC cells with modulated expression of PTK7 levels. PTK7 was significantly up-regulated in CRC tissue as compared to matched healthy mucosae, and significant overexpression was found in 34% of patients. PTK7 overexpression was significantly associated with a reduced metastasis-free survival in non-metastatic patients. In HCT116 and HCT15 cells, shRNA PTK7 reduced migration but did not affect cell proliferation and resistance to drugs. In a xenograft mouse of HCT15 cells, downregulation of PTK7 led to reduced tumor growth, whereas its overexpression in PTK7-negative cancer cells led to increased metastatic events. PTK7 expression thus represents a potential prognostic biomarker and a novel therapeutic target in CRC.
PLoS ONE 05/2015; 10(5):e0123768. DOI:10.1371/journal.pone.0123768 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Yttrium-90 (Y90) radioembolization is an emerging strategy to treat liver malignancies, and clinical data supporting its use have accumulated in recent years. Y90-radioembolization has shown clinical effectiveness in intermediate and advanced hepatocellular carcinoma, with a favorable safety profile. Retrospective data show similar levels of effectiveness to transarterial chemoembolization in intermediate hepatocellular carcinoma, with some evidence of better tolerance. While phase 3 studies comparing Y90-radioembolization to chemoembolization in intermediate hepatocellular carcinoma would be difficult to conduct, studies comparing or combining Y90-radioembolization with sorafenib are under way. Questions also remain about the most suitable modalities for defining the dose to administer. Phase 3 studies are under way to clarify the place of Y90-radioembolization in the algorithm of HCC treatment.
[Show abstract][Hide abstract] ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of all pancreatic tumours, is a devastating malignancy. The prognosis is extremely poor because PDAC is usually a systemic disease at diagnosis. All stages, the survival does not exceed 5% at 5 years. However 15% of PDAC can be resected and today a margin-negative resection followed by adjuvant chemotherapy remains the only potential for a prolonged survival. Postoperative mortality had significantly decreased and the benefit of postoperative adjuvant chemotherapy has been clearly shown. Substantial progress has been made in the field of palliative chemotherapy by introducing new chemotherapy regimens (FOLFIRINOX [folinic acid, 5-fluorouracil, irinotecan and oxaliplatin] and gemcitabine/nab-paclitaxel), when the patient's performance status allows the use of these drugs. The role of radiation therapy remains controversial.
[Show abstract][Hide abstract] ABSTRACT: Pancreatic Ductal Adenocarcinoma (PDAC) is a disease with a great heterogeneity in the response to treatments. To improve the responsiveness to treatments there are two different approaches, the first one consist to develop new and more efficient drugs that intent to cure all patients and the second one is to use already-approved drugs, alone or in combination, but selecting beforehand the most sensitive patients. In this work we explored the efficiency of the second possibility. We developed a collection of 17 PDAC samples collected by Endoscopic Ultrasound-Guided Fine-Needle Aspiration (EUS-FNA) or surgery and preserved as xenografts and as primary cultures. This collection was characterized at molecular level by a transcriptomic analysis using an Affymetrix approach. In this paper we present data demonstrating that a subgroup of PDAC responds to low doses of 5-aza-dC. These tumors show a specific RNA expression profile that could serve as a marker, but there is no correlation with Dnmt1, Dnmt3A or Dnmt3B expression. Responder tumors corresponded to well-differentiated samples and longer survival patients. In conclusion, we present data obtained with the well-known drug 5-aza-dC as a proof of concept that a drug that seems to be inefficient in solid tumors in general could be applicable to a particular subgroup of patients with PDAC.
[Show abstract][Hide abstract] ABSTRACT: Unlabelled:
This study aimed to evaluate the long-term prognostic usefulness of (18)F-FDG PET for patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEPNETs).
Thirty-eight patients with metastatic GEPNETs were prospectively enrolled. Initial check-up comprised CT scan, (111)In-pentetreotide scintigraphy (SRS), and (18)F-FDG PET. Only (18)F-FDG PET-positive lesions with a maximum standardized uptake value (SUVmax) greater than 4.5 or an SUV ratio (SUVmax tumor to SUVmax nontumoral liver tissue, or T/NT ratio) of 2.5 or greater were considered positive for prognosis-that is, indicating a poor prognosis. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Factors associated with survival were assessed with univariate and multivariate analyses, using the Cox regression model.
Median PFS and OS were significantly higher for patients with a negative (18)F-FDG PET finding, with an OS of 119.5 mo (95% confidence interval [CI], 72-∞), than for patients with a positive (18)F-FDG PET finding (only 15 mo [95% CI, 4-27]) (P < 10(-3)). Median PFS and OS were significantly higher for the patient group that had a positive SRS than the group with a negative SRS (P = 0.0002). For patients with a positive SRS, PFS and OS were significantly shorter when the (18)F-FDG PET finding was positive: 19.5 mo (95% CI, 4-37) for PFS and 119.5 mo (95% CI, 81-∞) for OS (P < 10(-3)). In the patient group with a low-grade GEPNET and a positive SRS, PFS and OS were also significantly lower for patients with a positive (18)F-FDG PET. At 48-mo follow-up, 100% of patients who had a positive (18)F-FDG PET for disease progression (of which 47% were also SRS-positive) were deceased, and 87% of patients with a negative (18)F-FDG PET were alive (P < 0.0001). The T/NT ratio was the only parameter associated with OS on multivariate analysis.
Overall, (18)F-FDG PET appears to be of major importance in the prognostic evaluation of metastatic GEPNET. A positive (18)F-FDG PET with an SUV ratio (T/NT) of 2.5 or greater was a poor prognostic factor, with a 4-y survival rate of 0%. A positive SRS does not eliminate the need for performing (18)F-FDG PET, which is of greater prognostic utility.
Journal of Nuclear Medicine 10/2014; 55(11). DOI:10.2967/jnumed.114.144386 · 6.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report a 57-year-old male who was treated with high-dose danazol for hereditary angioedema for more than 30 years; he developed hepatocellular carcinoma in the absence of cirrhosis. Despite surgical resection, he had a recurrence and received sorafenib, but had a poor skin tolerance. Such tumors arising after danazol are infrequent, and this case is highly unique due to the minor lesions found on the liver.
Case Reports in Oncology 09/2014; 7(3):825-7. DOI:10.1159/000370106
[Show abstract][Hide abstract] ABSTRACT: Hepatocellular carcinoma (HCC)-closely associated with liver cirrhosis and, in fact, the main cause of death in patients with such disease-is now recognized as one of the most-prevalent and lethal neoplasms worldwide. Prognosis and allocation of the multiple available treatment options for patients with HCC are influenced not only by tumour stage, but also by the degree of liver-function impairment. Therefore, accurate assessment and classification of disease is important for patient management. According to the Barcelona Clinic Liver Cancer (BCLC) algorithm, intermediate-stage HCC is defined as extensive multifocal disease without vascular invasion in patients with preserved liver function and absence of cancer-related symptoms; in this context, transarterial chemoembolization (TACE) is considered the standard treatment. The use of drug-eluting beads has enabled standardization of this procedure, resulting in higher reproducibility and tolerability of the treatment. Nevertheless, not all patients with intermediate-stage HCC are good candidates for TACE and, for such patients in whom TACE is not appropriate or has failed, other treatments can be considered, including sorafenib. Radioembolization is a promising alternative that deserves further prospective studies. Herein, we review the current approaches used to accurately stratify patients with intermediate-stage HCC and subsequently allocate the most-appropriate treatments. The key developments in therapeutic strategies are also discussed.
[Show abstract][Hide abstract] ABSTRACT: Assessing treatment responses in hepatocellular carcinoma (HCC) is challenging, and alternative radiologic methods of measuring treatment response are required. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for HCC and alpha-fetoprotein (AFP) levels were assessed in a post hoc analysis of a phase II study of brivanib, a selective dual inhibitor of fibroblast growth factor and vascular endothelial growth factor signaling.
HCC patients were treated with first-line (cohort A; n = 55) or second-line (cohort B; n = 46) brivanib alaninate 800 mg once daily. Outcomes were compared between World Health Organization (WHO) criteria and (retrospectively by) mRECIST by independent review. The relationship between on-study AFP changes and outcome was analyzed in patients with elevated AFP at baseline.
Response rates were higher with mRECIST versus WHO criteria in cohorts A (25.5% vs. 7.3%) and B (10.9% vs. 4.3%). Progressive disease (PD) as assessed by mRECIST was associated with a very short median overall survival (OS; cohort A, 2.8 months; cohort B, 5.3 months); PD as assessed by WHO criteria reflected a mixed population of patients with better outcomes. mRECIST responders tended to have a>50% AFP decrease during therapy. In cohorts A and B pooled, an early AFP response (>20%or >50% decline from baseline within the first 4 weeks) was not associated with longer median OS.
Tumor response as assessed by mRECIST differed from that by WHO criteria, with mRECIST possibly identifying true nonresponders with a poor prognosis. Many patients had AFP decreases correlating with tumor shrinkage, yet an association with long-term benefit was unclear. mRECIST and on-treatment AFP levels are being explored further with brivanib in HCC.
[Show abstract][Hide abstract] ABSTRACT: The treatment of hepatocellular carcinoma (HCC) is difficult due to the underlying cirrhosis which has its own influence on therapeutic issues. An inquiry was performed in centres with specialized multidisciplinary team meetings dedicated to HCC (HCC-MTM) or in centres with non-specialized (digestive oncology or general oncology) multidisciplinary team meetings (NS-MTM). The number of cases of HCCs taken in charge yearly was significantly higher in HCC-MTM than in NS-MTM (p=0,0014). Interventional radiologists and transplant surgeons were more frequently implied in HCC-MTM than in NS-MTM (respectively p=0,009 and p=0,02). On site availability of every treatment of HCC was higher in RCP-MTM than in NS-MTM (p=0,015). There were no inclusion in clinical trials in 40.5 % of NS-MTM versus only 17.6 % of HCC-MTM (p=0,0086). In three clinical cases out of seven there were discrepancies between the therapeutic options of HCC-MTM and NS-MTM. In all three cases, the treatment offered to the patient by HCC-MTM was more consistent with clinical standards. These results prompt to perform more studies on the quality of management of patients with HCCs by MTMs.
Bulletin du cancer 06/2014; 101(6). DOI:10.1684/bdc.2014.1918 · 0.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Although the prevalence of esophageal cancer increases in elderly patients, its clinical history and outcome after treatment remain poorly described.
Methods: Between January 2001 and December 2011, 58 patients (pts) older than 75 years received 3D-conformal radiotherapy (mean dose 51 Gy) in two French cancer centers. 47/58 (82%) patients received concomitant chemotherapy (with CDDP and/or FU regimens) and 8 patients underwent surgery after primary radiochemotherapy (RCT).
Results: Median age was 77.9 years and the performance status (PS) was 0 or 1 in 89%. Tumors were mainly adenocarcinoma of lower esophagus or gastroesophageal junction (n = 51, 89%), T3T4 (n = 54, 95%), and N1 (n = 44, 77%). The mean follow-up was 21.9 months. In the overall population, the median progression-free survival was 9.6 months and median overall survival (OS) was 14.5 months. Using univariate analysis, OS was significantly associated with age (p = 0.048), PS (p < 0.001), and surgery (p = 0.035). 35 (60.3%) and 18 patients (31%) experienced grade 1–2 or 3–4 toxicity, respectively (CTCAE v4.0).
Conclusion: Radiochemotherapy in elderly patients is a feasible treatment and its outcome is close to younger patient’s outcome published in the literature. Surgical resection, after comprehensive geriatric assessment, should be recommended as the standard treatment for adenocarcinoma of lower esophagus or gastroesophageal junction in elderly patients with good PS and low co-morbidity profile, as it is in younger patients.
Frontiers in Oncology 05/2014; 4:100. DOI:10.3389/fonc.2014.00100
[Show abstract][Hide abstract] ABSTRACT: We report the case of a 57-year-old man who was diagnosed with a large unresectable cholangiocarcinoma associated with 2 satellite nodules and without clear margins with the right hepatic vein. Despite 4 cycles of GEMOX (stopped due to a hypertransaminasemia believed to be due to gemcitabine) and 4 cycles of FOLFIRINOX, the tumor remained stable and continued to be considered unresectable. Radioembolization (resin microspheres, SIRS-spheres(®)) targeting the left liver (474 MBq) and segment IV (440 MBq) was performed. This injection was very well tolerated, and 4 more cycles of FOLFIRINOX were given while waiting for radioembolization efficacy. On computed tomography scan, a partial response was observed; the tumor was far less hypervascularized, and a margin was observed between the tumor and the right hepatic vein. A left hepatectomy enlarged to segment VIII was performed. On pathological exam, most of the tumor was acellular, with dense fibrosis around visible microspheres. Viable cells were observed only at a distance from beads. Radioembolization can be useful in the treatment of cholangiocarcinoma, allowing in some cases a secondary resection.
World Journal of Gastroenterology 05/2014; 20(17):5131-4. DOI:10.3748/wjg.v20.i17.5131 · 2.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In Europe, trans-arterial chemoembolization (TACE) is usually given to patients with Barcelona Clinic Liver Cancer (BCLC) "intermediate stage" hepatocellular carcinoma (HCC), and is associated with a modest improvement in median overall survival. In the two positive randomized trials that have been reported, TACE was stopped in cases of severe toxicity, worsening of liver cirrhosis or performance status and tumor progression, including local progression, extrahepatic spread and portal vein thrombosis. The necessity to stop TACE leads to the concept of untreatable progression, which is characterized by massive liver involvement, extrahepatic spread, vascular invasion, impaired liver function or performance status. More recently, the assessment for re-treatment with TACE (ART) score has been developed to determine which patients will not benefit from a second or a third TACE therapy. Herein, we propose an algorithm that summarizes our experience with TACE.
[Show abstract][Hide abstract] ABSTRACT: We herein report the case of a 73-year-old woman who developed skin and nail disorders 2 months before her digestive symptoms started, which lead to the diagnosis of gastric adenocarcinoma. The lesions were diagnosed as Bazex syndrome, usually seen in squamous cell carcinoma. Under systemic chemotherapy, the cutaneous signs improved for some months before worsening when the disease progressed.
Case Reports in Oncology 04/2014; 7(1):285-7. DOI:10.1159/000362787
[Show abstract][Hide abstract] ABSTRACT: We report a series of three cases of oxaliplatin-related hematological immune reactions. Two patients developed acute immune hemolytic anemia and the third patient had severe thrombocytopenia. One patient had minor undiagnosed hemolysis after the previous chemotherapy cycle and two of our three patients had minor allergic signs just before the hemolysis. Fifteen cases of immune hemolytic anemia have been reported in the literature, of which only the first was fatal. One case of hemolytic uremic syndrome has been described. Anemia in cancer patients is not always related to myelosuppression and hemolytic anemia can be a severe side effect of oxaliplatin administration.