S. Mouli

Yttrium-90 radioembolization for intrahepatic cholangiocarcinoma: safety, response, and survival analysis.

PURPOSE To present data on safety, antitumoral response, and survival following yttrium-90 ((90)Y) radioembolization for patients with unresectable intrahepatic cholangiocarcinoma (ICC). MATERIALS AND METHODS The present study expands on the cohort of 24 patients with ICC described in a pilot study, and includes 46 patients treated with (90)Y radioembolization at a single institution during an 8-year period. Via retrospective review of a prospectively collected database, patients were stratified by performance status, tumor distribution (solitary or multifocal), tumor morphology (infiltrative or peripheral), and presence/absence of portal vein thrombosis. Primary endpoints included biochemical and clinical toxicities, and secondary endpoints included imaging response (World Health Organization [WHO] and European Association for the Study of Liver Disease [EASL] criteria) and survival. Uni-/multivariate analyses were performed. RESULTS Ninety-two treatments were performed, with a mean of two per patient. Fatigue and transient abdominal pain occurred in 25 patients (54%) and 13 patients (28%), respectively. Treatment-related gastroduodenal ulcer developed in one patient (2%). WHO imaging findings included partial response (n = 11; 25%), stable disease (n = 33; 73%), and progressive disease (n = 1; 2%). EASL imaging findings included partial/complete response (n = 33; 73%) and stable disease (n = 12; 27%). Survival varied based on presence of multifocal (5.7 mo vs 14.6 mo), infiltrative (6.1 mo vs 15.6 mo), and bilobar disease (10.9 mo vs 11.7 mo). Disease was converted to resectable status in five patients, who successfully underwent curative (ie, R0) resection. CONCLUSIONS Radioembolization with (90)Y is safe and demonstrates antitumoral response and survival benefit in select patients with ICC. Results are most pronounced in patients with solitary tumors, for whom conversion to curative resection is possible.

Image-guided local delivery strategies enhance therapeutic nanoparticle uptake in solid tumors.

Nanoparticles (NP) have emerged as a novel class of therapeutic agents that overcome many of the limitations of current cancer chemotherapeutics. However, a major challenge to many current NP platforms is unfavorable biodistribution, and limited tumor uptake, upon systemic delivery. Delivery, therefore, remains a critical barrier to widespread clinical adoption of NP therapeutics. To overcome these limitations, we have adapted the techniques of image-guided local drug delivery to develop nanoablation and nanoembolization. Nanoablation is a tumor ablative strategy that employs image-guided placement of electrodes into tumor tissue to electroporate tumor cells, resulting in a rapid influx of NPs that is not dependent on cellular uptake machinery or stage of the cell cycle. Nanoembolization involves the image-guided delivery of NPs and embolic agents directly into the blood supply of tumors. We describe the design and testing of our innovative local delivery strategies using doxorubicin-functionalized superparamagnetic iron oxide nanoparticles (DOX-SPIOs) in cell culture, and the N1S1 hepatoma and VX2 tumor models, imaged by high resolution 7T MRI. We demonstrate that local delivery techniques result in significantly increased intratumoral DOX-SPIO uptake, with limited off-target delivery in tumor-bearing animal models. The techniques described are versatile enough to be extended to any NP platform, targeting any solid organ malignancy that can be accessed via imaging guidance.

Lymphotropic nanoparticle enhanced MRI for the staging of genitourinary tumors

Nanotechnology is poised to have a substantial influence on biomedicine. A unique example of a nanotechnology that has progressed from proof-of-concept to human clinical trials is the use of ultrasmall superparamagnetic iron oxide nanoparticles as a cell-specific contrast agent for MRI. When injected systemically, these particles are taken up by macrophages of the reticuloendothelial system and accumulate in lymph nodes. This passive, cell-specific targeting of the iron oxide nanoparticles to lymph nodes, and the differential cellular content of benign versus malignantly infiltrated nodes make this method suitable for cancer staging. By using lymphotropic nanoparticle enhanced MRI, differences in benign versus malignant infiltration of lymph nodes can be visualized, which adds accuracy to standard MRI beyond criteria based solely upon the size and shape of lymph nodes. This technology has been used to assess lymph node metastases in a large number of human cancer types. In this Review, we focus on lymphotropic nanoparticle enhanced MRI and its application for the staging of genitourinary malignancies.

90Y radiation lobectomy: Outcomes following surgical resection in patients with hepatic tumors and small future liver remnant volumes

The purpose of this study is to assess operative, post‐operative, and long‐term outcomes in patients who underwent radiation lobectomy (RL) for tumor control and/or hypertrophy of small future liver remnant (FLR) prior to resection.

Independent Analysis of Albumin-Bilirubin Grade in a 765-Patient Cohort Treated with Transarterial Locoregional Therapy for Hepatocellular Carcinoma.

PURPOSE To assess validity of albumin-bilirubin (ALBI) grade as a predictor of survival in patients undergoing transarterial embolization for hepatocellular carcinoma. MATERIALS AND METHODS Baseline albumin and bilirubin values of 765 consecutive patients treated with conventional transarterial chemoembolization or yttrium-90 ((90)Y) radioembolization at a single institution were used to determine liver function according to ALBI grade. Survival outcomes were stratified by ALBI grade using Kaplan-Meier and stratified by Child-Pugh (C-P) class and Barcelona Clinic Liver Cancer (BCLC) stage. Discriminatory ability was assessed by C-index. RESULTS For 428 patients receiving (90)Y radioembolization, ALBI grade yielded distinct survival curves (P < .001). When stratified by C-P class and BCLC stage, ALBI grade revealed different survival outcomes for C-P B (P = .001), BCLC A (P < .001), BCLC B (P = .001), and BCLC C (P < .001). When substratified by BCLC stage, ALBI grade was a better discriminator of survival than C-P class (C-index 0.792, 0.763, respectively). For 337 patients receiving transarterial chemoembolization, ALBI grade yielded distinct survival curves (P < .001). When stratified by C-P class and BCLC stage, ALBI grade provided distinct survival curves for C-P B (P = .02), BCLC B (P = .001), and BCLC C (P = .02). When substratified by BCLC stage, ALBI grade was a better discriminator of survival than C-P class (C-index 0.739, 0.735, respectively). CONCLUSIONS ALBI grade outperforms C-P class at discriminating survival in patients receiving transarterial chemoembolization or (90)Y radioembolization. ALBI grade is also valuable in patients with moderate liver dysfunction and BCLC B disease.

PDE5 inhibitors for LUTS

To review the current literature regarding the relationship between lower urinary tract symptoms (LUTS) and erectile dysfunction (ED), and the role of phosphodiesterase-5 (PDE5) inhibitors for the treatment of LUTS. Review of recently published (1990–2009) data regarding epidemiologic and pathophysiologic mechanisms are involved in LUTS–ED, focusing on PDE5 inhibitors particularly evidenced from level 1 clinical trials. Search terms included phosphodiesterase inhibitors, nitric oxide, autonomic hyperactivity, Rho-kinase, atherosclerosis, LUTS, benign prostatic hypertrophy, and ED. Results of several epidemiologic studies show a possible causal relationship between LUTS and ED. Four possible mechanisms have been proposed to explain this association. Multiple large clinical trials have shown a benefit in LUTS after PDE5-inhibitors treatment. PDE5 inhibitors show promise as a future treatment for LUTS, either in conjunction with existing therapies or as a primary treatment.

Genomic sequencing in clinical trials

Human genome sequencing is the process by which the exact order of nucleic acid base pairs in the 24 human chromosomes is determined. Since the completion of the Human Genome Project in 2003, genomic sequencing is rapidly becoming a major part of our translational research efforts to understand and improve human health and disease. This article reviews the current and future directions of clinical research with respect to genomic sequencing, a technology that is just beginning to find its way into clinical trials both nationally and worldwide. We highlight the currently available types of genomic sequencing platforms, outline the advantages and disadvantages of each, and compare first- and next-generation techniques with respect to capabilities, quality, and cost. We describe the current geographical distributions and types of disease conditions in which these technologies are used, and how next-generation sequencing is strategically being incorporated into new and existing studies. Lastly, recent major breakthroughs and the ongoing challenges of using genomic sequencing in clinical research are discussed.

Institutional decision to adopt Y90 as primary treatment for hepatocellular carcinoma informed by a 1,000-patient 15-year experience

Yttrium‐90 transarterial radioembolization (TARE) is a locoregional therapy (LRT) for hepatocellular carcinoma (HCC). In this study, we present overall survival (OS) outcomes in a 1,000‐patient cohort acquired over a 15‐year period. Between December 1, 2003 and March 31, 2017, 1,000 patients with HCC were treated with TARE as part of a prospective cohort study. A comprehensive review of toxicity and survival outcomes was performed. Outcomes were stratified by baseline Child‐Pugh (CP) class, United Network for Organ Sharing (UNOS), and Barcelona Clinic Liver Cancer (BCLC) staging systems. Albumin and bilirubin laboratory toxicities were compared to baseline. OS outcomes were reported using censoring and intention‐to‐treat methodologies. All treatments were outpatient, with a median one treatment per patient. Five hundred six (51%) were CP A, 450 (45%) CP B, and 44 (4%) CP C. Two hundred sixty‐three (26%) patients were BCLC A, 152 (15%) B, 541 (54%) C, and 44 (4%) D. Three hundred sixty‐eight (37%) were UNOS T1/T2, 169 (17%) T3, 147 (15%) T4a, 223 (22%) T4b, and 93 (9%) N/M. In CP A patients, censored OS for BCLC A was 47.3 (confidence interval [CI], 39.5‐80.3) months, BCLC B 25.0 (CI, 17.3‐30.5) months, and BCLC C 15.0 (CI, 13.8‐17.7) months. In CP B patients, censored OS for BCLC A was 27 (CI, 21‐30.2) months, BCLC B 15.0 (CI, 12.3‐19.0) months, and BCLC C 8.0 (CI, 6.8‐9.5) months. Forty‐nine (5%) and 110 (11%) patients developed grade 3/4 albumin and bilirubin toxicities, respectively. Conclusion: Based on our experience with 1,000 patients over 15 years, we have made a decision to adopt TARE as the first‐line transarterial LRT for patients with HCC. Our decision was informed by prospective data and incrementally reported demonstrating outcomes stratified by BCLC, applied as either neoadjuvant or definitive treatment. (Hepatology 2017).

Radioembolization for hepatocellular carcinoma: Statistical confirmation of improved survival in responders by landmark analyses

Does imaging response predict survival in hepatocellular carcinoma (HCC)? We studied the ability of posttherapeutic imaging response to predict overall survival. Over 14 years, 948 patients with HCC were treated with radioembolization. Patients with baseline metastases, vascular invasion, multifocal disease, Child‐Pugh > B7, and transplanted/resected were excluded. This created our homogeneous study cohort of 134 patients with Child‐Pugh ≤ B7 and solitary HCC. Response (using European Association for Study of the Liver [EASL] and Response Evaluation Criteria in Solid Tumors 1.1 [RECIST 1.1] criteria) was associated with survival using Landmark and risk‐of‐death methodologies after reviewing 960 scans. In a subanalysis, survival times of responders were compared to those of patients with stable disease (SD) and progressive disease (PD). Uni/multivariate survival analyses were performed at each Landmark. At the 3‐month Landmark, responders survived longer than nonresponders by EASL (hazard ratio [HR], 0.46; confidence interval [CI], 0.26‐0.82; P = 0.002) but not RECIST 1.1 criteria (HR, 0.70; CI, 0.37‐1.32; P = 0.32). At the 6‐month Landmark, responders survived longer than nonresponders by EASL (HR, 0.32; CI, 0.15‐0.77; P < 0.001) and RECIST 1.1 criteria (HR, 0.50; CI, 0.29‐0.87; P = 0.021). At the 12‐month Landmark, responders survived longer than nonresponders by EASL (HR, 0.34; CI, 0.15‐0.77; P <  0.001) and RECIST 1.1 criteria (HR, 0.52; CI 0.27‐0.98; P = 0.049). At 6 months, risk of death was lower for responders by EASL (P <  0.001) and RECIST 1.1 (P = 0.0445). In subanalyses, responders lived longer than patients with SD or PD. EASL response was a significant predictor of survival at 3‐, 6‐, and 12‐month Landmarks on uni/multivariate analyses. Conclusion: Response to radioembolization in patients with solitary HCC can prognosticate improved survival. EASL necrosis criteria outperformed RECIST 1.1 size criteria in predicting survival. The therapeutic objective of radioembolization should be radiologic response and not solely to prevent progression. (Hepatology 2018;67:873–883)

Imaging Features of Common and Uncommon Bladder Neoplasms

In this article, the authors discuss imaging features of common and less-common epithelial and nonepithelial bladder neoplasms. Epithelial tumors include entities, such as urothelial cell carcinoma, squamous cell carcinoma, and adenocarcinoma, along with less-common entities, such as small cell and carcinoid tumors. Nonepithelial or mesenchymal tumors are also less commonly encountered and include benign entities, such as leiomyoma and neurofibroma, and malignant entities, including leiomyosarcoma and lymphoma. Their imaging features with an emphasis on computed tomography and magnetic resonance imaging are described.