Hyunseon C. Kang

Mutation Profiling in Cholangiocarcinoma: Prognostic and Therapeutic Implications

Background Cholangiocarcinoma (CCA) is clinically heterogeneous; intra and extrahepatic CCA have diverse clinical presentations. Next generation sequencing (NGS) technology may identify the genetic differences between these entities and identify molecular subgroups for targeted therapeutics. Methods We describe successful NGS-based testing of 75 CCA patients along with the prognostic and therapeutic implications of findings. Mutation profiling was performed using either a) NGS panel of hotspot regions in 46 cancer-related genes using a 318-chip on Ion PGM Sequencer or b) Illumina HiSeq 2000 sequencing platform for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X. Clinical data was abstracted and correlated with clinical outcome. Patients with targetable mutations were referred to appropriate clinical trials. Results There were significant differences between intrahepatic (n = 55) and extrahepatic CCA (n = 20) in regard to the nature and frequency of the genetic aberrations (GAs). IDH1 and DNA repair gene alterations occurred more frequently in intrahepatic CCA, while ERBB2 GAs occurred in the extrahepatic group. Commonly occurring GAs in intrahepatic CCA were TP53 (35%), KRAS (24%), ARID1A (20%), IDH1 (18%), MCL1 (16%) and PBRM1 (11%). Most frequent GAs in extrahepatic CCA (n = 20) were TP53 (45%), KRAS (40%), ERBB2 (25%), SMAD4 (25%), FBXW7 (15%) and CDKN2A (15%). In intrahepatic CCA, KRAS, TP53 or MAPK/mTOR GAs were significantly associated with a worse prognosis while FGFR GAs correlated with a relatively indolent disease course. IDH1 GAs did not have any prognostic significance. GAs in the chromatin modulating genes, BAP1 and PBRM1 were associated with bone metastases and worse survival in extrahepatic CCA. Radiologic responses and clinical benefit was noted with EGFR, FGFR, C-met, B-RAF and MEK inhibitors. Conclusion There are significant genetic differences between intra and extrahepatic CCA. NGS can potentially identify disease subsets with distinct prognostic and therapeutic implications.

HER2/neu-directed therapy for biliary tract cancer

BackgroundBiliary cancers are highly aggressive tumors that are often diagnosed an advanced disease stage and have a poor outcome with systemic therapy. Recent efforts towards molecular characterization have identified a subset of biliary patients that have HER2/neu amplification or mutation. HER2/neu amplification is associated with response to HER2/neu-directed therapy in breast and gastric cancers. However, the efficacy of HER2/neu-targeted therapy in biliary cancers is unknown.Patients and methodsWe retrospectively reviewed cases of advanced gallbladder cancer and cholangiocarcinoma with HER2/neu genetic aberrations or protein overexpression who received HER2/neu-directed therapy between 2007 and 2014. Clinical data were retrieved from medical records, and imaging studies were independently reviewed.ResultsNine patients with gallbladder cancer and five patients with cholangiocarcinoma had received HER2/neu-directed therapy (trastuzumab, lapatinib, or pertuzumab) during the study period. In the gallbladder cancer group, HER2/neu gene amplification or overexpression was detected in eight cases. These patients experienced disease stability (n = 3), partial response (n = 4), or complete response (n = 1) with HER2/neu-directed therapy. One patient had HER2/neu mutation and experienced a mixed response after lapatinib therapy. The duration of response varied from 8+ to 168 weeks (median 40 weeks), and three patients are still on therapy. One patient developed HER2/neu amplification as a secondary event after FGFR-directed therapy for FGF3-TACC3 gene fusion. The cholangiocarcinoma cases treated in this series had a higher proportion of HER2/neu mutations, and no radiological responses were seen in these patients despite HER2/neu-directed therapy.ConclusionsHER2/neu blockade is a promising treatment strategy for gallbladder cancer patients with gene amplification and deserves further exploration in a multi-center study.

Biliary cancer: Utility of next‐generation sequencing for clinical management

Biliary tract cancers (BTCs) typically present at an advanced stage, and systemic chemotherapy is often of limited benefit.

Phase 1 and pharmacodynamic trial of everolimus in combination with cetuximab in patients with advanced cancer

Preclinical and clinical studies suggest mTOR (mammalian target of rapamycin) inhibitors may have metabolic and antiangiogenic effects, and synergize with epidermal growth factor pathway inhibitors. Therefore, a phase 1/pharmacodynamic trial of everolimus with cetuximab was performed.

MRI Assessment of Early Tumor Response in Metastatic Renal Cell Carcinoma Patients Treated With Sorafenib

OBJECTIVE The purpose of this study was to examine early MRI changes in renal cell carcinoma (RCC) treated with the antiangiogenic agent sorafenib and to identify MRI biomarkers of RCC response to sorafenib. MATERIALS AND METHODS Sixteen patients with RCC were evaluated by MRI before and 3-12 weeks after commencing treatment with sorafenib. Two experienced MR radiologists, blinded to treatment status, independently graded tumor appearance on T1-weighted, T2-weighted, and gadolinium-enhanced images. The proportional odds mixed model was used to compare qualitative appearance of tumors before and after therapy. Time-to-progression was correlated with Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 and MR-modified Choi criteria, incorporating changes in both tumor enhancement and size. RESULTS After sorafenib therapy, there was a significant increase in T1 signal intensity of tumors (p < 0.0001) and a significant decrease in degree of tumor enhancement (p < 0.0001). The sum of unidimensional tumor diameters decreased significantly after therapy (p = 0.005). However, the average decrease in size at early follow-up was 13%, and all patients except one had stable disease by RECIST 1.0. Early responders defined by MR-modified Choi criteria had increased time-to-progression compared with nonresponders, whereas early RECIST evaluation did not predict clinical outcome. CONCLUSION Decreased enhancement and T1 shortening of tumors on MRI may be useful biomarkers of RCC response to angiogenesis inhibitors. Response criteria combining early changes in size and enhancement lead to better correlation with clinical outcome compared with size decrease alone.

Using Focused Missed-Case Conferences to Reduce Discrepancies in Musculoskeletal Studies Interpreted by Residents On Call

OBJECTIVE The purpose of this study is to determine whether focused missed-case conferences can significantly reduce the number of major discrepancies in musculoskeletal imaging studies interpreted by residents on call. MATERIALS AND METHODS A review of major discrepancies in musculoskeletal conventional radiography imaging studies interpreted by radiology residents and fellows on call from July 2008 to July 2009 revealed 31 common and important musculoskeletal injuries missed or misinterpreted at our institution. These missed cases were presented during focused missed-case conferences from July through October 2009. Only residents attended missed-case conferences. RESULTS Over the 12 months before the missed-case conferences, there were 55 resident major discrepancies and 25 fellow major discrepancies, representing 31 common and important missed musculoskeletal injuries. Over the 12 months after the missed-case conferences, there were 18 resident major discrepancies and 21 fellow major discrepancies involving these injuries. This corresponds to a 67% reduction in the number of resident major discrepancies involving the 31 musculoskeletal injuries covered during the missed-case conferences (chi-square p < 0.001). The overall major discrepancy rate for all musculoskeletal conventional radiography studies was 1.19% for residents and 1.55% for fellows (not significant) before the missed-case conferences and 0.87% for residents and 1.46% for fellows (p < 0.05) after the missed-case conferences. During this time, fellows missed more musculoskeletal injuries related to the topics discussed during missed-case conferences (16) compared with residents (8) although fellows read significantly fewer studies overall. This accounted for 0.49% of the 0.59% difference between residents and fellows. CONCLUSION Focused missed-case conferences are an effective educational intervention to significantly reduce the number of major discrepancies in radiology resident interpretation of musculoskeletal imaging studies on call.

Diagnostic Approach to Hereditary Renal Cell Carcinoma

OBJECTIVE The purpose of this article is to discuss the histopathologic features, genetics, clinical presentation, and imaging of hereditary renal cancer syndromes. CONCLUSION Hereditary renal cell carcinoma syndromes can be diagnosed with a pattern-based approach focused on the predominant histologic renal cell carcinoma subtype and associated renal and extrarenal features of each syndrome.

The ABCs of BHD: An In-Depth Review of Birt-Hogg-Dubé Syndrome

OBJECTIVE Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant inherited syndrome involving multiple organs. In young patients, renal neoplasms that are multiple, bilateral, or both, such as oncocytomas, chromophobe renal cell carcinoma (RCC), hybrid chromophobe RCC-oncocytomas, clear cell RCC, and papillary RCC, can suggest BHD syndrome. Extrarenal findings, including dermal lesions, pulmonary cysts, and spontaneous pneumothoraces, also aid in diagnosis. CONCLUSION Radiologists may be one of the first medical specialists to suggest the diagnosis of BHD syndrome. Knowledge of pathogenesis and management, including the importance of the types of renal neoplasms in a given patient, is needed to properly recognize this rare condition.

Staging, surveillance, and evaluation of response to therapy in renal cell carcinoma: role of MDCT

Renal cell carcinoma is the most common malignant renal tumor in the adults. Significant advances have been made in the management of localized and advanced renal cell carcinoma. Surgery is the standard of care and accurate pre-operative staging based on imaging is critical in guiding appropriate patient management. Besides staging, imaging plays a key role in the post-operative surveillance and evaluation of response to systemic therapies. Both CT and MR are useful in the staging and follow up of renal cell carcinoma, but CT is more commonly used due to its lower costs and wider availability. In this article, we discuss and illustrate the role of multi-detector CT in pre-operative staging, post-operative surveillance, and evaluation of response to systemic therapy in renal cell carcinoma.

Free-breathing radial volumetric interpolated breath-hold examination vs breath-hold cartesian volumetric interpolated breath-hold examination magnetic resonance imaging of the liver at 1.5T.

AIM To compare breath-hold cartesian volumetric interpolated breath-hold examination (cVIBE) and free-breathing radial VIBE (rVIBE) and determine whether rVIBE could replace cVIBE in routine liver magnetic resonance imaging (MRI). METHODS In this prospective study, 15 consecutive patients scheduled for routine MRI of the abdomen underwent pre- and post-contrast breath-hold cVIBE imaging (19 s acquisition time) and free-breathing rVIBE imaging (111 s acquisition time) on a 1.5T Siemens scanner. Three radiologists with 2, 4, and 8 years post-fellowship experience in abdominal imaging evaluated all images. The radiologists were blinded to the sequence types, which were presented in a random order for each patient. For each sequence, the radiologists scored the cVIBE and rVIBE images for liver edge sharpness, hepatic vessel clarity, presence of artifacts, lesion conspicuity, fat saturation, and overall image quality using a five-point scale. RESULTS Compared to rVIBE, cVIBE yielded significantly (P < 0.001) higher scores for liver edge sharpness (mean score, 3.87 vs 3.37), hepatic-vessel clarity (3.71 vs 3.18), artifacts (3.74 vs 3.06), lesion conspicuity (3.81 vs 3.2), and overall image quality (3.91 vs 3.24). cVIBE and rVIBE did not significantly differ in quality of fat saturation (4.12 vs 4.03, P = 0.17). The inter-observer variability with respect to differences between rVIBE and cVIBE scores was close to zero compared to random error and inter-patient variation. Quality of rVIBE images was rated as acceptable for all parameters. CONCLUSION rVIBE cannot replace cVIBE in routine liver MRI. At 1.5T, free-breathing rVIBE yields acceptable, although slightly inferior image quality compared to breath-hold cVIBE.