Background:CD70 is an ideal target for antibody-based therapies because of its aberrant high expression in renal carcinomas and non-Hodgkin lymphomas and its highly restricted expression in normal tissues. The expression profiling of CD70 in carcinomas has been limited because of the lack of a CD70-specific reagent that works in formalin-fixed paraffin-embedded (FFPE) tissues.Methods:We generated murine monoclonal antibodies (mAbs) specific for CD70 and validated their specificity by western blot analysis and developed a protocol for immunohistochemistry on FFPE tissues. CD70+ tumour cell lines were used for testing the anti-tumour activity of the anti-CD70 antibody–drug conjugate, SGN-75.Results:We report novel detection of CD70 expression in multiple cancers including pancreatic (25%), larynx/pharynx (22%), melanoma (16%), ovarian (15%), lung (10%), and colon (9%). Our results show that pancreatic and ovarian tumour cell lines, which express high levels of endogenous or transfected CD70, are sensitive to the anti-tumour activity of SGN-75 in vitro and in vivo.Conclusion:Development of murine mAbs for robust and extensive screening of FFPE samples coupled with the detection of anti-tumour activity in novel indications provide rationale for expanding the application of SGN-75 for the treatment of multiple CD70 expressing cancers.

Serum contains a variety of biomolecules, which play an important role in cell proliferation and survival. We sought to identify the serum factor responsible for mitigating tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis and to investigate its molecular mechanism. TRAIL induced effective apoptosis without serum, whereas bovine serum decreased apoptosis by suppressing cytochrome c release and caspase activation. Indeed, albumin-bound lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) inhibited TRAIL-induced apoptosis by suppressing caspase activation and cytochrome c release. LPA increased phosphatidylinositol 3-kinase (PI3K)-dependent Akt activation, cellular FLICE-inhibitory protein (cFLIP) expression, and Bad phosphorylation, resulting in inhibition of caspase-8 activation and Bad translocation to mitochondria. The antiapoptotic effect of LPA was abrogated by PI3K inhibitor, transfection with dominant-negative Akt, and specific downregulation of cFLIP expression using siRNA and further increased by siRNA-mediated suppression of Bad expression. Moreover, sera from ovarian cancer patients showed more protective effect against TRAIL-induced apoptosis than those from healthy donors, and this protection was suppressed by PI3K inhibitor. Our results indicate that albumin-bound LPA and S1P prevent TRAIL-induced apoptosis by upregulation of cFLIP expression and in part by Bad phosphorylation, through the activation of PI3K/Akt pathway.

Purpose To determine the imaging features at gadoxetic acid-enhanced magnetic resonance (MR) imaging of intrahepatic cholangiocarcinoma (IHCC) in a cirrhotic liver, with an emphasis on the distinction between IHCC and hepatocellular carcinoma (HCC) and on the comparison of nodule enhancement patterns between MR imaging and computed tomography (CT). Materials and Methods The institutional review board approved this study and waived the requirement for informed consent. Gadoxetic acid-enhanced MR and CT images in 72 consecutive patients (61 men; mean age, 56.6 years) with 78 IHCCs and one-to-one matched control patients (56 men; mean age, 56.6 years) with 77 HCCs were evaluated retrospectively by two independent readers. Findings that could differentiate IHCC from HCC were evaluated with univariate and multivariate analyses. Using the enhancement criteria and the Liver Imaging Reporting and Data System with modifications (mLI-RADS), the sensitivity and specificity for diagnosing HCC were calculated with conventional washout and portal venous phase (PVP) washout. Results At MR imaging with conventional washout, the specificities for diagnosing HCC were 94.9% (74 of 78) with the enhancement criteria and 96.2% (75 of 78) with mLI-RADS, while the use of PVP washout achieved 100% (78 of 78) specificity for diagnosing HCC with both diagnostic criteria at the expense of decreased sensitivity (from 76.6% [59 of 77] to 63.6% [49 of 77] with the enhancement criteria and from 64.9% [50 of 77] to 55.8% [43 of 77] with mLI-RADS, P ≤ .016). At CT, the sensitivities and specificities with conventional washout were 72.7% (56 of 77) and 97.4% (76 of 78), respectively, with the enhancement criteria and 67.5% (52 of 77) and 97.4% (76 of 78), respectively, with mLI-RADS. Conclusion The use of PVP washout instead of conventional washout at gadoxetic acid-enhanced MR imaging prevents the misclassification of IHCC as HCC in a cirrhotic liver but leads to a decreased sensitivity for HCC. RSNA, 2016 Online supplemental material is available for this article.

Background:Treatment options for patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP NETs) are still limited. We investigated the antitumour activity and safety profile of pazopanib – a multitarget drug with anti-angiogenic activity in patients with metastatic GEP NETs.Methods:This was a nonrandomised, open-labeled, single-center phase II study. Pazopanib was orally administered at a dose of 800 mg daily continuously with a 28-day cycle. The primary end point was an objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST). The secondary end points were progression-free survival (PFS), overall survival (OS) and safety. An independent review of objective response was planned. The trial is registered with ClinicalTrials.gov, NCT number 01099540. Correlative biomarker analyses were performed.Results:Between April 2010 and February 2012, a total of 37 patients were enrolled. Thirty-two percent of the enrolled patients had pancreatic primary and 22% of the patients had colorectal primary NETs. This phase II study demonstrated an objective response rate of 18.9% (7 of the 37, 95% CI 8.0–35.2) and a disease control rate (CR+confirmed PR+stable disease) of 75.7% (28 of the 37, 95% CI, 58.8–88.2) in metastatic GEP NETs. The independent review demonstrated a higher overall response rate of 24.3% (95% CI, 11.8–41.2%) with nine confirmed PRs.Conclusion:Pazopanib showed a comparable efficacy to other targeted agents not only in pancreatic NETs but also in NETs originating from gastrointestinal (GI) tract.