The landscape of targeted therapies for cholangiocarcinoma: current status and emerging targets

Cholangiocarcinoma (CCA) is a relatively rare malignancy that arises from the epithelial cells of the intrahepatic, perihilar and distal biliary tree. Intrahepatic CCA (ICC) represents the second most common primary liver cancer, after hepatocellular cancer. Two-thirds of the patients with ICC present with locally advanced or metastatic disease. Despite standard treatment with gemcitabine and cisplatin, prognosis remains dismal with a median survival of less than one year. Several biological plausibilities can account for its poor clinical outcomes. First, despite the advent of next generation and whole exome sequencing, no oncogenic addiction loops have been validated as clinically actionable targets. Second, the anatomical, pathological and molecular heterogeneity, and rarity of CCA confer an ongoing challenge of instituting adequately powered clinical trials. Last, most of the studies were not biomarker-driven, which may undermine the potential benefit of targeted therapy in distinct subpopulations carrying the unique molecular signature. Recent whole genome sequencing efforts have identified known mutations in genes such as epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog (BRAF) and tumor protein p53 (TP53), novel mutations in isocitrate dehydrogenase (IDH), BRCA1-Associated Protein 1 (BAP1) and AT-rich interactive domain-containing protein 1A (ARID1A), and novel fusions such as fibroblast growth factor receptor 2 (FGFR2) and ROS proto-oncogene 1 (ROS1). In this review, we will discuss the evolving genetic landscape of CCA, with an in depth focus on novel fusions (e.g. FGFR2 and ROS1) and somatic mutations (e.g. IDH1/2), which are promising actionable molecular targets

Biomarker analyses of clinical outcomes in patients with advanced hepatocellular carcinoma treated with Sorafenib with or without Erlotinib in the SEARCH Trial

Purpose: Sorafenib is the current standard therapy for advanced HCC, but validated biomarkers predicting clinical outcomes are lacking. This study aimed to identify biomarkers predicting prognosis and/or response to sorafenib, with or without erlotinib, in HCC patients from the phase 3 SEARCH trial. Experimental Design: 720 patients were randomized to receive oral sorafenib 400 mg BID plus erlotinib 150 mg QD or placebo. Fifteen growth factors relevant to the treatment regimen and/or to HCC were measured in baseline plasma samples. Results: Baseline plasma biomarkers were measured in 494 (69%) patients (sorafenib plus erlotinib, n=243; sorafenib plus placebo, n=251). Treatment arm–independent analyses showed that elevated HGF (HR, 1.687 [high vs low expression]; endpoint multiplicity adjusted [e-adj] P=0.0001) and elevated plasma VEGF-A (HR, 1.386; e-adj P=0..0377) were significantly associated with poor OS in multivariate analyses, and low plasma KIT (HR, 0.75 [high vs low]; P=0.0233; e-adj P=0.2793) tended to correlate with poorer OS. High plasma VEGF-C independently correlated with longer TTP (HR, 0.633; e-adj P=0.0010) and trended toward associating with improved disease control rate (univariate:OR, 2.047; P=0.030; e-adj P=0.420). In 67% of evaluable patients (339/494), a multimarker signature of HGF, VEGF-A, KIT, epigen, and VEGF-C correlated with improved median OS in multivariate analysis (HR, 0.150; P<0.00001). No biomarker predicted efficacy from erlotinib. Conclusions: Baseline plasma HGF, VEGF-A, KIT, and VEGF-C correlated with clinical outcomes in HCC patients treated with sorafenib with or without erlotinib. These biomarkers plus epigen constituted a multimarker signature for improved OS

Investigation of dose perturbations and the radiographic visibility of potential fiducials for proton radiation therapy of the prostate

Image guidance using implanted fiducial markers is commonly used to ensure accurate and reproducible target positioning in radiation therapy for prostate cancer. The ideal fiducial marker is clearly visible in kV imaging, does not perturb the therapeutic dose in the target volume and does not cause any artifacts on the CT images used for treatment planning. As yet, ideal markers that fully meet all three of these criteria have not been reported. In this study, 12 fiducial markers were evaluated for their potential clinical utility in proton radiation therapy for prostate cancer. In order to identify the good candidates, each fiducial was imaged using a CT scanner as well as a kV imaging system. Additionally, the dose perturbation caused by each fiducial was quantified using radiochromic film and a clinical proton beam. Based on the results, three fiducials were identified as good candidates for use in proton radiotherapy of prostate cancer. © 2011 Institute of Physics and Engineering in Medicine

Radiomics and circulating tumor cells: personalized care in hepatocellular carcinoma?

Personalized care in oncology is expected to significantly improve morbidity and mortality, facilitated by our increasing understanding of the molecular mechanisms driving tumors and the ability to target those drivers. Hepatocellular carcinoma has a very high mortality to incidence ratio despite localized disease being curable, emphasizing the importance of early diagnosis. Radiomics, the use of imaging technology to extrapolate molecular tumor data, and the detection of circulating tumor cells (CTCs) are two new technologies that could be incorporated into the clinical setting with relative ease. Here we discuss the molecular mechanisms leading to the development of hepatocellular carcinoma focusing on the latest developments in liver magnetic resonance imaging, CTC, and radiomic technology and their potential to improve diagnosis, staging, and therapy

Long term survivors with metastatic pancreatic adenocarcinoma treated with gemcitabine: a retrospective analysis

<p>Abstract</p> <p>Background</p> <p>Metastatic pancreatic adenocarcinoma has a short median overall survival (OS) of 5–6 months. However, a subgroup of patients survives more than 1 year. We analyzed the survival outcomes of this subgroup and evaluated clinical and pathological factors that might affect survival durations.</p> <p>Methods</p> <p>We identified 20 patients with metastatic or recurrent pancreatic adenocarcinoma who received single-agent gemcitabine and had an OS longer than 1 year. Baseline data available after the diagnosis of metastatic or recurrent disease was categorized as: 1) <it>clinical/demographic data </it>(age, gender, ECOG PS, number and location of metastatic sites); 2) <it>Laboratory data </it>(Hematocrit, hemoglobin, glucose, LDH, renal and liver function and CA19-9); 3) <it>Pathologic data </it>(margins, nodal status and grade); 4) <it>Outcomes data </it>(OS, Time to Treatment Failure (TTF), and 2 year-OS). The lowest CA19-9 levels during treatment with gemcitabine were also recorded. We performed a univariate analysis with OS as the outcome variable.</p> <p>Results</p> <p>Baseline logarithm of CA19-9 and total bilirubin had a significant impact on OS (HR = 1.32 and 1.31, respectively). Median OS and TTF on gemcitabine were 26.9 (95% CI = 18 to 32) and 11.5 (95% CI = 9.0 to 14.3) months, respectively. Two-year OS was 56.4%, with 7 patients alive at the time of analysis.</p> <p>Conclusion</p> <p>A subgroup of patients with metastatic pancreatic cancer has prolonged survival after treatment with gemcitabine. Only bilirubin and CA 19-9 levels were predictive of longer survival in this population. Further analysis of potential prognostic and predictive markers of response to treatment and survival are needed.</p

Magnetic resonance imaging biomarkers in hepatocellular carcinoma: association with response and circulating biomarkers after sunitinib therapy

Background: To investigate the hypothesis that MRI derived diffusion-weighted imaging (DWI) and perfusion (MRP) parameters are sensitive image biomarkers for monitoring early antiangiogenic effects and predicting progression free survival (PFS) in advanced hepatocellular carcinoma (HCC). Methods: In this phase II clinical trial, 23 of 34 patients were included in the imaging and circulating biomarker study. DWI and MRP were performed at the baseline and at 2-weeks after initiation of sunitinib. The imaging protocol included an axial DWI sequence using b values of 50, 400 and 800 sec/mm2, and MRP using a series of coronal 3D-VIBE following 20 ml of Gd-DTPA at 2 ml/sec. These parameters were compared with clinical outcome and PFS at 6-months. Correlation between changes in MRI parameters and plasma biomarkers was also evaluated. Results: After 2-week of sunitinib, substantial Ktrans changes in HCC were observed from median baseline value 2.15 min−1 to 0.94 min−1 (P = 0.0001) with increases in median apparent diffusion coefficient (ADC) from 0.88 × 10-3 mm2/s to 0.98 × 10-3 mm2/s (P = 0.0001). Tumor size remained unchanged by RECIST and mRECIST (both P > 0.05). Patients who showed larger drop in Ktrans and Kep at 2 weeks correlated with favorable clinical outcome, and higher baseline Ktrans and larger drop in EVF correlated with longer PFS (all P < 0.05). There was a significant association between a decrease in sVEGFR2 and the drop in Ktrans and Kep (P = 0.044, P = 0.030), and a significant and borderline association between decrease in TNF-α and the drop in Ktrans and Kep, respectively (P = 0.051, P = 0.035). Conclusion: In HCC, MRP may be a more sensitive biomarker in predicting early response and PFS following sunitinib than RECIST and mRECIST. Trial registration ClinicalTrials.gov: NCT0036130

Biofuels from crop residue can reduce soil carbon and increase CO\u3csub\u3e2\u3c/sub\u3e emissions

Removal of corn residue for biofuels can decrease soil organic carbon(SOC) and increase CO2 emissions because residue C in biofuels is oxidized to CO2 at a faster rate than when added to soil. Net CO2 emissions from residue removal are not adequately characterized in biofuel life cycle assessment (LCA). Here we used a model to estimate CO2 emissions from corn residue removal across the US Corn Belt at 580 million geospatial cells. To test the SOC model, we compared estimated daily CO2 emissions from corn residue and soil with CO2 emissions measured using eddy covariance, with 12% average error over nine years. The model estimated residue removal of 6 Mg per ha–1 yr–1 over five to ten years could decrease regional net SOC by an average of 0.47–0.66 Mg C ha–1 yr–1. These emissions add an average of 50–70 g CO2 per megajoule of biofuel (range 30–90) and are insensitive to the fraction of residue removed. Unless lost C is replaced, life cycle emissions will probably exceed the US legislative mandate of 60% reduction in greenhouse gas (GHG) emissions compared with gasoline. Supplementary information is attached below as an additional (pdf) file

Biofuels from crop residue can reduce soil carbon and increase CO\u3csub\u3e2\u3c/sub\u3e emissions

Removal of corn residue for biofuels can decrease soil organic carbon(SOC) and increase CO2 emissions because residue C in biofuels is oxidized to CO2 at a faster rate than when added to soil. Net CO2 emissions from residue removal are not adequately characterized in biofuel life cycle assessment (LCA). Here we used a model to estimate CO2 emissions from corn residue removal across the US Corn Belt at 580 million geospatial cells. To test the SOC model, we compared estimated daily CO2 emissions from corn residue and soil with CO2 emissions measured using eddy covariance, with 12% average error over nine years. The model estimated residue removal of 6 Mg per ha–1 yr–1 over five to ten years could decrease regional net SOC by an average of 0.47–0.66 Mg C ha–1 yr–1. These emissions add an average of 50–70 g CO2 per megajoule of biofuel (range 30–90) and are insensitive to the fraction of residue removed. Unless lost C is replaced, life cycle emissions will probably exceed the US legislative mandate of 60% reduction in greenhouse gas (GHG) emissions compared with gasoline. Supplementary information is attached below as an additional (pdf) file