Scott W. Young

Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma.

Advanced cholangiocarcinoma continues to harbor a difficult prognosis and therapeutic options have been limited. During the course of a clinical trial of whole genomic sequencing seeking druggable targets, we examined six patients with advanced cholangiocarcinoma. Integrated genome-wide and whole transcriptome sequence analyses were performed on tumors from six patients with advanced, sporadic intrahepatic cholangiocarcinoma (SIC) to identify potential therapeutically actionable events. Among the somatic events captured in our analysis, we uncovered two novel therapeutically relevant genomic contexts that when acted upon, resulted in preliminary evidence of anti-tumor activity. Genome-wide structural analysis of sequence data revealed recurrent translocation events involving the FGFR2 locus in three of six assessed patients. These observations and supporting evidence triggered the use of FGFR inhibitors in these patients. In one example, preliminary anti-tumor activity of pazopanib (in vitro FGFR2 IC50≈350 nM) was noted in a patient with an FGFR2-TACC3 fusion. After progression on pazopanib, the same patient also had stable disease on ponatinib, a pan-FGFR inhibitor (in vitro, FGFR2 IC50≈8 nM). In an independent non-FGFR2 translocation patient, exome and transcriptome analysis revealed an allele specific somatic nonsense mutation (E384X) in ERRFI1, a direct negative regulator of EGFR activation. Rapid and robust disease regression was noted in this ERRFI1 inactivated tumor when treated with erlotinib, an EGFR kinase inhibitor. FGFR2 fusions and ERRFI mutations may represent novel targets in sporadic intrahepatic cholangiocarcinoma and trials should be characterized in larger cohorts of patients with these aberrations.

US-guided Renal Transplant Biopsy: Efficacy of a Cortical Tangential Approach

PURPOSE To describe the cortical tangential approach to ultrasonographically (US) guided renal transplant biopsy and evaluate its efficacy in obtaining sufficient cortical tissue. MATERIALS AND METHODS This HIPAA-compliant retrospective study was exempted from review by the institutional review board. Informed consent was not required. The number of core biopsy samples, glomeruli, and small arteries obtained during 294 consecutive US-guided renal transplant biopsies in 254 patients (134 men, 120 women; age range, 19-79 years; mean age, 52.2 years) in one department between June 1 and December 31, 2008, were recorded, along with any ensuing complications. Procedural success was assessed according to Banff 97 criteria. RESULTS There were 1.2 +/- 0.4 (standard deviation) biopsy core samples taken per case by 11 radiologists using the cortical tangential approach. In 290 cases, biopsy results showed 21.7 +/- 10.1 glomeruli and 5.0 +/- 2.8 small arteries. Two hundred seventy-six (95%) cases were adequate or minimal according to Banff 97 assessment criteria. Of the 14 inadequate cases (5%), six were lacking only one glomerulus to achieve minimal status. Only one biopsy core sample was taken in all 14 inadequate cases and in 233 successful cases (success rate, 85%). None of the 43 cases with two or more biopsy core samples taken were inadequate (success rate, 100%). Two patients (0.7%) had a hemorrhagic complication requiring transfusion, and another four patients (1.4%) experienced a minor self-limiting complication. CONCLUSION The cortical tangential approach can be used by a cohort of radiologists to achieve 95% or higher collective success in obtaining cortical tissue during renal transplant biopsy, with few complications. The success rate is higher, without increased complications, when more than one core specimen is taken.

Diagnostic evaluation of t(4;14) in multiple myeloma and evidence for clonal evolution

The presence of a t(4;14) in multiple myeloma (MM) is associated with significantly inferior outcomes following both conventional chemotherapy and high-dose melphalan-based treatment regimens.1, 2 Detection of patients bearing the t(4;14) is therefore important in an MM molecular workup. Furthermore, since targeted inhibitors of the associated fibroblast growth factor receptor 3 (FGFR3) tyrosine kinase are now in clinical trials,3 detection of MM patients who express the FGFR3 protein is also of potential therapeutic relevance. With this in mind, we have employed the infrastructure of the Multiple Myeloma Research Consortium (MMRC) tissue bank to evaluate four different methodologies for the molecular diagnostic detection of this translocation. The methods employed are published previously4, 5, 6 or are provided as Supplementary Information.

Clinical Implementation of Integrated Genomic Profiling in Patients with Advanced Cancers

DNA focused panel sequencing has been rapidly adopted to assess therapeutic targets in advanced/refractory cancer. Integrated Genomic Profiling (IGP) utilising DNA/RNA with tumour/normal comparisons in a Clinical Laboratory Improvement Amendments (CLIA) compliant setting enables a single assay to provide: therapeutic target prioritisation, novel target discovery/application and comprehensive germline assessment. A prospective study in 35 advanced/refractory cancer patients was conducted using CLIA-compliant IGP. Feasibility was assessed by estimating time to results (TTR), prioritising/assigning putative therapeutic targets, assessing drug access, ascertaining germline alterations, and assessing patient preferences/perspectives on data use/reporting. Therapeutic targets were identified using biointelligence/pathway analyses and interpreted by a Genomic Tumour Board. Seventy-five percent of cases harboured 1–3 therapeutically targetable mutations/case (median 79 mutations of potential functional significance/case). Median time to CLIA-validated results was 116 days with CLIA-validation of targets achieved in 21/22 patients. IGP directed treatment was instituted in 13 patients utilising on/off label FDA approved drugs (n = 9), clinical trials (n = 3) and single patient IND (n = 1). Preliminary clinical efficacy was noted in five patients (two partial response, three stable disease). Although barriers to broader application exist, including the need for wider availability of therapies, IGP in a CLIA-framework is feasible and valuable in selection/prioritisation of anti-cancer therapeutic targets.

Impact of a Quality Assessment Program on Radiologist Performance in Ultrasound-Guided Renal Transplant Biopsy

PURPOSE The purpose of this study was to analyze the impact of a quality assessment (QA) program on radiologist performance in ultrasound-guided renal transplant biopsy. METHODS The numbers of glomeruli and small arteries obtained during ultrasound-guided renal transplant biopsy of all consecutive patients performed by any of 8 radiologists in an ultrasound section between September 1, 2007, and May 31, 2010, were recorded. Procedural success was assessed using Banff 97 criteria. Two subgroups were defined on the basis of each radiologists approximate fractional full-time equivalent effort in the section, with 2 radiologists who were engaged 100% of their clinical noncall time in the ultrasound section constituting the primary ultrasound subgroup and 6 radiologists who were engaged <25% of their clinical noncall time in the ultrasound section constituting the secondary ultrasound subgroup. The biopsy success rate for individuals, subgroups, and the entire section for 9 months before (pre-QA) and 24 months after (post-QA) the onset of quarterly dissemination of the QA data was analyzed. RESULTS Of 339 biopsies in the pre-QA period, 90.5% were successful. Of 1,063 biopsies in the post-QA period, 96.0% were successful (P < .001). The pre-QA individual radiologist success rates ranged between 71.4% and 96.7% (mean, 86.2 ± 10.3%). The post-QA individual radiologist success rates ranged between 80.0% and 97.9% (mean, 92.5 ± 6.6%). The primary ultrasound subgroup success rate increased from 93.4% to 97.5% (P = .005). The secondary ultrasound subgroup success rate increased from 85.7% to 93.8% (P = .004). CONCLUSIONS A renal transplant biopsy QA program improves operator performance.

Inherited renal carcinomas

Hereditary forms of kidney carcinoma account for 5–8% of all malignant kidney neoplasms. The renal tumors are often multiple and bilateral and occur at an earlier age. Each of the hereditary kidney carcinoma syndromes is associated with specific gene mutations as well as a specific histologic type of kidney carcinoma. The presence of associated extrarenal manifestations may suggest a hereditary kidney cancer syndrome. Radiology is most commonly used to screen and manage patients with hereditary kidney cancer syndromes. This manuscript reviews the clinical and imaging findings of well-defined inherited kidney cancer syndromes including von Hippel–Lindau disease, Birt–Hogg–Dubé syndrome, hereditary papillary renal carcinoma syndrome, hereditary leiomyomatosis and RCC syndrome, tuberous sclerosis complex, and Lynch syndrome.

Sonographic evaluation of deep endometriosis: protocol for a US radiology practice

Endometriosis is a common condition with significant morbidity, including pain and subfertility, which is often subject to a delay in diagnosis. Ultrasound has been successfully utilized, mostly outside North America, to preoperatively stage deep endometriosis, but in these international settings, imaging is typically performed solely by expert radiologists and gynecologists. We outline a method for detailed sonographic survey of the lower abdomen and pelvis to ensure optimum detection and communication of disease extent that is geared to radiologists practicing ultrasound in the United States, with the use of diagnostic medical sonographers.

Factors Contributing to the Success of Ultrasound-Guided Native Renal Biopsy

The purpose of this study was to evaluate factors contributing to the success of ultrasound‐guided native renal biopsy.

Granular Cell Tumor of the Anterior Abdominal Wall

We report a case of granular-cell tumor (GCT) arising in the subcutaneous tissue of the abdominal wall and describe its radiologic and histologic characteristics. The differential diagnosis of a mass in this site may include multiple benign and malignant stromal lesions. In this case, the presentation, location, and radiological features suggested a desmoid tumor (aggressive fibromatosis). Treatment of the mass involved surgical excision with negative margins, and histological analysis confirmed the presence of a benign GCT. We report a case of this rare, benign tumor to allow the radiologist and pathologist to consider this disease in the differential diagnosis when presented with similar cases.

Ultrasound-guided renal transplant biopsy: practical and pragmatic considerations

Sonographically guided percutaneous core biopsy of renal allografts has been performed for decades, providing valuable information in monitoring the status of normally functioning renal transplants as well as investigating the cause of renal transplant dysfunction. This article reviews practical aspects of biopsy technique using the cortical tangential approach, with consideration of factors that may influence biopsy success, including selection of biopsy device. Clinically important complications from renal transplant biopsy are uncommon; the most recent experience for one institution is analyzed in the context of existing evidence regarding the frequency and timing of these major complications, to understand pragmatic implications for peri-procedural care.