Chaan S. Ng

Phase II Trial of Curcumin in Patients with Advanced Pancreatic Cancer

Purpose: Pancreatic cancer is almost always lethal, and the only U.S. Food and Drug Administration–approved therapies for it, gemcitabine and erlotinib, produce objective responses in <10% of patients. We evaluated the clinical biological effects of curcumin (diferuloylmethane), a plant-derived dietary ingredient with potent nuclear factor-κB (NF-κB) and tumor inhibitory properties, against advanced pancreatic cancer. Experimental Design: Patients received 8 g curcumin by mouth daily until disease progression, with restaging every 2 months. Serum cytokine levels for interleukin (IL)-6, IL-8, IL-10, and IL-1 receptor antagonists and peripheral blood mononuclear cell expression of NF-κB and cyclooxygenase-2 were monitored. Results: Twenty-five patients were enrolled, with 21 evaluable for response. Circulating curcumin was detectable as drug in glucuronide and sulfate conjugate forms, albeit at low steady-state levels, suggesting poor oral bioavailability. Two patients showed clinical biological activity. One had ongoing stable disease for >18 months; interestingly, one additional patient had a brief, but marked, tumor regression (73%) accompanied by significant increases (4- to 35-fold) in serum cytokine levels (IL-6, IL-8, IL-10, and IL-1 receptor antagonists). No toxicities were observed. Curcumin down-regulated expression of NF-κB, cyclooxygenase-2, and phosphorylated signal transducer and activator of transcription 3 in peripheral blood mononuclear cells from patients (most of whom had baseline levels considerably higher than those found in healthy volunteers). Whereas there was considerable interpatient variation in plasma curcumin levels, drug levels peaked at 22 to 41 ng/mL and remained relatively constant over the first 4 weeks. Conclusions: Oral curcumin is well tolerated and, despite its limited absorption, has biological activity in some patients with pancreatic cancer.

NRAS mutation status is an independent prognostic factor in metastatic melanoma

There is a need for improved prognostic markers in melanoma. In this study, the authors tested the prognostic significance and clinicopathologic correlations of v‐raf murine sarcoma viral oncogene homolog B1 (BRAF) and neuroblastoma RAS viral (v‐ras) oncogene homolog (NRAS) mutations in patients with metastatic melanoma.

Activity of XL184 (Cabozantinib), an Oral Tyrosine Kinase Inhibitor, in Patients With Medullary Thyroid Cancer

PURPOSE XL184 (cabozantinib) is a potent inhibitor of MET, vascular endothelial growth factor receptor 2 (VEGFR2), and RET, with robust antiangiogenic, antitumor, and anti-invasive effects in preclinical models. Early observations of clinical benefit in a phase I study of cabozantinib, which included patients with medullary thyroid cancer (MTC), led to expansion of an MTC-enriched cohort, which is the focus of this article. PATIENTS AND METHODS A phase I dose-escalation study of oral cabozantinib was conducted in patients with advanced solid tumors. Primary end points included evaluation of safety, pharmacokinetics, and maximum-tolerated dose (MTD) determination. Additional end points included RECIST (Response Evaluation Criteria in Solid Tumors) response, pharmacodynamics, RET mutational status, and biomarker analyses. RESULTS Eighty-five patients were enrolled, including 37 with MTC. The MTD was 175 mg daily. Dose-limiting toxicities were grade 3 palmar plantar erythrodysesthesia (PPE), mucositis, and AST, ALT, and lipase elevations and grade 2 mucositis that resulted in dose interruption and reduction. Ten (29%) of 35 patients with MTC with measurable disease had a confirmed partial response. Overall, 18 patients experienced tumor shrinkage of 30% or more, including 17 (49%) of 35 patients with MTC with measurable disease. Additionally, 15 (41%) of 37 patients with MTC had stable disease (SD) for at least 6 months, resulting in SD for 6 months or longer or confirmed partial response in 68% of patients with MTC. CONCLUSION Cabozantinib has an acceptable safety profile and is active in MTC. Cabozantinib may provide clinical benefit by simultaneously targeting multiple pathways of importance in MTC, including MET, VEGFR2, and RET. A global phase III pivotal study in MTC is ongoing (ClinicalTrials.gov number NCT00215605).

Comparison of CT methods for determining the fat content of the liver.

OBJECTIVE The purpose of this study was to assess which of a number of methods of measuring attenuation on CT scans is best for prediction of hepatic fat content. MATERIALS AND METHODS This retrospective study was approved by our institutional review board. Consecutively registered patients who underwent liver resection for metastatic disease formed the study group. Attenuation measurements were obtained from 12 regions of interest in the liver and three in the spleen on both unenhanced and portal phase contrast-enhanced preoperative hepatic CT images. Hepatic attenuation measurements were analyzed both with and without normalization with the spleen. Normalization included both differences and ratios between hepatic and splenic attenuation values. Pathologic fat content was graded semiquantitatively as a percentage of the nonneoplastic liver parenchyma of the resected specimen. Average attenuation values of the liver were compared with pathologic fat content, as were the differences and ratios between hepatic and splenic attenuation values. Linear regression analysis was conducted on a log-log scale. RESULTS Data on 88 patients were analyzed. On unenhanced and contrast-enhanced CT images, all associations between pathologic fat content and attenuation measurements were significant (p < 0.0001). All series of R2 values for unenhanced CT scans were much higher than those for contrast-enhanced CT scans. The R2 values of liver-only measurement were higher than those of hepatic values normalized with splenic values on both unenhanced (0.646-0.649 > 0.523, 0.565) and contrast-enhanced (0.516 > 0.242, 0.344) CT. CONCLUSION Measurement of attenuation of liver only on unenhanced CT scans is best for prediction of pathologic fat content.

Phase II trial of imatinib mesylate in patients with metastatic melanoma

Metastatic melanoma cells express a number of protein tyrosine kinases (PTKs) that are considered to be targets for imatinib. We conducted a phase II trial of imatinib in patients with metastatic melanoma expressing at least one of these PTKs. Twenty-one patients whose tumours expressed at least one PTK (c-kit, platelet-derived growth factor receptors, c-abl, or abl-related gene) were treated with 400 mg of imatinib twice daily. One patient with metastatic acral lentiginous melanoma, containing the highest c-kit expression among all patients, had dramatic improvement on positron emission tomographic scan at 6 weeks and had a partial response lasting 12.8 months. The responder had a substantial increase in tumour and endothelial cell apoptosis at 2 weeks of treatment. Imatinib was fairly well tolerated: no patient required treatment discontinuation because of toxicity. Fatigue and oedema were the only grade 3 or 4 toxicities that occurred in more than 10% of the patients. Imatinib at the studied dose had minimal clinical efficacy as a single-agent therapy for metastatic melanoma. However, based on the characteristics of the responding tumour in our study, clinical activity of imatinib, specifically in patients with melanoma with certain c-kit aberrations, should be examined.

Imaging and Staging of Transitional Cell Carcinoma: Part 2, Upper Urinary Tract

OBJECTIVE Transitional cell carcinoma (TCC) of the upper urinary tract is a common malignancy affecting the genitourinary tract. It is commonly multifocal with a high incidence of recurrence requiring rigorous urothelial surveillance. In this article, we discuss the epidemiology, pathologic characteristics, and patterns of tumor spread. We illustrate and discuss the role of imaging in the diagnosis, staging, and surveillance of TCC of the renal pelvis and the ureter. CONCLUSION The hallmark of TCC is multiplicity and recurrence. Nearly 2-4% of patients with bladder cancer develop upper tract TCC, but 40% of patients with upper tract TCC develop bladder cancer. Diagnosis of upper tract TCC is heavily dependent on imaging. Understanding the appearances of upper tract TCC on the different imaging techniques used is important in the accurate interpretation of imaging studies. Newer techniques such as CT urography are now increasingly used instead of conventional excretory urography in the surveillance of the upper tract in patients with bladder cancer.

Renal Cell Carcinoma: Diagnosis, Staging, and Surveillance

OBJECTIVE This educational review focuses on the staging and radiologic evaluation of renal cell carcinoma. It includes discussion of the epidemiology, pathology, and therapeutic options of renal cell carcinoma and the implications for radiologic follow-up. CONCLUSION The incidence of renal cell carcinoma has been increasing. Imaging plays a central role in its detection, staging, and treatment evaluation and follow-up.

Radiologic Manifestations of Immune-Related Adverse Events in Patients With Metastatic Melanoma Undergoing Anti- CTLA-4 Antibody Therapy

OBJECTIVE Monoclonal antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4) used for treatment of metastatic melanoma produce inflammatory immune-related adverse events. The purpose of the current study was to retrospectively identify and characterize the radiologic manifestations of immune-related adverse events and to evaluate the possible association between these events and clinical responses to anti-CTLA-4 therapy. MATERIALS AND METHODS We retrospectively reviewed the images and medical records of 119 patients with metastatic melanoma treated with anti-CTLA-4 at our institution and assessed the presence of radiologic manifestations of immune-related adverse events and the clinical responses to therapy. The responses were categorized as progressive or controlled disease. The controlled disease category included stable disease, partial response, and complete response according to the Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS Radiologic manifestations of immune-related adverse events were found in 20 patients (16.8%). Clinically evident manifestations included colitis, hypophysitis, thyroiditis, and arthritis. Clinically silent manifestations were benign lymphadenopathy and inflammatory changes in the soft tissues, such as myositis, fasciitis, and retroperitoneal fat haziness. There was a significant association between the incidence of radiologic manifestations of immune-related adverse events and clinical responses to anti-CTLA-4 therapy. The disease control rates were 18% for the entire group, 55% for the group with, and 10% for the group without radiologic manifestations of immune-related adverse events. In three patients (2.5%), lymphadenopathy related to radiologic manifestations of immune-related adverse events was interpreted as suspected metastasis but was proved benign at biopsy. CONCLUSION Radiologic manifestations of immune-related adverse events are associated with significant clinical benefit of anti-CTLA-4 therapy. In the era of developing immune checkpoint-targeted therapy for metastatic melanoma, radiologists should be alert to the possibility of these manifestations, which can mimic radiologic disease progression.

Phase I trial of cixutumumab combined with temsirolimus in patients with advanced cancer

Purpose: Mammalian target of rapamycin (mTOR) inhibitors mediate AKT activation through a type 1 insulin-like growth factor receptor (IGF-1R)–dependent mechanism. Combining the mTOR inhibitor temsirolimus with cixutumumab, a fully human immunoglobulin G1 monoclonal antibody directed against IGF-1R, was expected to enhance mTOR-targeted anticancer activity by modulating resistance to mTOR inhibition. The objectives of this phase I study were to evaluate the tolerability and activity of temsirolimus and cixutumumab. Experimental Design: Patients in sequential cohorts (“3 + 3” design) received escalating doses of temsirolimus with cixutumumab weekly for 28 days. At the maximum tolerated dose (MTD), 21 patients were randomized into three separate drug sequence treatment groups for serial blood draws and 2[18F]fluoro-2-deoxy-d-glucose positron emission tomography combined with X-ray computed tomography (FDG-PET/CT) scans for pharmacodynamic analyses (PD). Results: Forty-two patients with advanced cancer (19 male/23 female, median age = 53, median number of prior therapies = 4) were enrolled. MTD was reached at cixutumumab, 6 mg/kg IV and temsirolimus, 25 mg IV. Dose-limiting toxicities included grade 3 mucositis, febrile neutropenia, and grade 4 thrombocytopenia. The most frequent toxicities were hypercholesterolemia, hypertriglyceridemia, hyperglycemia, thrombocytopenia, and mucositis. Tumor reduction was observed in 2 of 3 patients with Ewings sarcoma and in 4 of 10 patients with adrenocortical carcinoma. PD data suggest that cixutumumab alone or combined with temsirolimus increased plasma IGF-1 and IGF binding protein 3. FDG-PET/CT showed the odds of achieving stable disease decreased by 58% (P = 0.1213) with a one-unit increase in absolute change of standard uptake value from baseline to day 3. Conclusions: Temsirolimus combined with cixutumumab was well tolerated. We are currently enrolling expansion cohorts at the MTD for Ewings sarcoma and adrenocortical carcinoma. Clin Cancer Res; 17(18); 6052–60. ©2011 AACR.

Papillary Renal Cell Carcinoma: Radiologic-Pathologic Correlation and Spectrum of Disease

Papillary renal cell carcinoma (pRCC) is the second most common type of renal cell carcinoma (RCC). pRCC has unique imaging and clinical features that may allow differentiation from clear cell RCC (cRCC). There have been significant advances in our knowledge of the natural history and treatment of pRCC, with data suggesting that it may be best to manage pRCC differently from the other subtypes of RCC. At contrast material-enhanced computed tomography, pRCC enhances less than does cRCC in all phases of contrast-enhanced imaging. The difference in the degree of enhancement between pRCC and cRCC is due to differences in their intratumoral vascularity. In general, if a heterogeneous mass enhances to a degree similar to that manifested by the renal cortex, it is likely to be a cRCC. A mass that enhances to a lesser degree is likely to be a non-clear cell RCC. It is common for metastatic lesions from pRCC to show enhancement characteristics similar to those of the primary tumor and be hypovascular.