Kathryn J. Fowler

Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial

BACKGROUND In pancreatic ductal adenocarcinoma, the CCL2-CCR2 chemokine axis is used to recruit tumour-associated macrophages for construction of an immunosuppressive tumour microenvironment. This pathway has prognostic implications in pancreatic cancer, and blockade of CCR2 restores anti-tumour immunity in preclinical models. We aimed to establish the safety, tolerability, and recommended phase 2 oral dose of the CCR2 inhibitor PF-04136309 in combination with FOLFIRINOX chemotherapy (oxaliplatin and irinotecan plus leucovorin and fluorouracil). METHODS We did this open-label, dose-finding, non-randomised, phase 1b study at one centre in the USA. We enrolled treatment-naive patients aged 18 years or older with borderline resectable or locally advanced biopsy-proven pancreatic ductal adenocarcinoma, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1, and normal end-organ function. Patients were allocated to receive either FOLFIRINOX alone (oxaliplatin 85 mg/m(2), irinotecan 180 mg/m(2), leucovorin 400 mg/m(2), and bolus fluorouracil 400 mg/m(2), followed by 2400 mg/m(2) 46-h continuous infusion), administered every 2 weeks for a total of six treatment cycles, or in combination with oral PF-04136309, administered at a starting dose of 500 mg twice daily in a standard 3 + 3 dose de-escalation design. Both FOLFIRINOX and PF-04136309 were simultaneously initiated with a total treatment duration of 12 weeks. The primary endpoints were the safety, tolerability, and recommended phase 2 dose of PF-04136309 plus FOLFIRINOX, with an expansion phase planned at the recommended dose. We analysed the primary outcome by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01413022. RESULTS Between April 19, 2012, and Nov 12, 2014, we treated 47 patients with FOLFIRINOX alone (n=8) or with FOLFIRINOX plus PF-04136309 (n=39). One patient had a dose-limiting toxic effect in the dose de-escalation group receiving FOLFIRINOX plus PF-04136309 at 500 mg twice daily (n=6); this dose was established as the recommended phase 2 dose. We pooled patients in the expansion-phase group (n=33) with those in the dose de-escalation group that received PF-04136309 at the recommended phase 2 dose for assessment of treatment-related toxicity. Six (75%) of the eight patients receiving FOLFIRINOX alone were assessed for treatment toxicity, after exclusion of two (25%) patients due to insurance coverage issues. The median duration of follow-up for treatment toxicity was 72·0 days (IQR 49·5-89·0) in the FOLFIRINOX alone group and 77·0 days (70·0-90·5) in the FOLFIRINOX plus PF-04136309 group. No treatment-related deaths occurred. Two (5%) patients in the FOLFIRINOX plus PF-04136309 group stopped treatment earlier than planned due to treatment-related toxic effects. Grade 3 or higher adverse events reported in at least 10% of the patients receiving PF-04136309 included neutropenia (n=27), febrile neutropenia (n=7), lymphopenia (n=4), diarrhoea (n=6), and hypokalaemia (n=7). Grade 3 or higher adverse events reported in at least 10% of patients receiving FOLFIRINOX alone were neutropenia (n=6), febrile neutropenia (n=1), anaemia (n=2), lymphopenia (n=1), diarrhoea (n=2), hypoalbuminaemia (n=1), and hypokalaemia (n=3). Therapy was terminated because of treatment-related toxicity in one (17%) of the six patients receiving FOLFIRINOX alone. 16 (49%) of 33 patients receiving FOLFIRINOX plus PF-04136309 who had undergone repeat imaging achieved an objective tumour response, with local tumour control achieved in 32 (97%) patients. In the FOLFIRINOX alone group, none of the five patients with repeat imaging achieved an objective response, although four (80%) of those patients achieved stable disease. INTERPRETATION CCR2-targeted therapy with PF-04136309 in combination with FOLFIRINOX is safe and tolerable. FUNDING Washington University-Pfizer Biomedical Collaborative.

Combined Hepatocellular and Cholangiocarcinoma (Biphenotypic) Tumors: Imaging Features and Diagnostic Accuracy of Contrast- Enhanced CT and MRI

OBJECTIVE The purpose of this study was to evaluate the diagnostic accuracy of preoperative imaging for diagnosis of combined hepatocellular cholangiocarcinoma tumors and to evaluate the clinical and imaging features and demographics of patients presenting to our institution with such tumors. MATERIALS AND METHODS From January 2001 to January 2011, 29 patients presented with pathologically proven combined hepatocellular cholangiocarcinoma tumors to our institution. A retrospective review of the imaging studies, clinical data, and demographic information in these patients was conducted. Two radiologists with 6 and 18 years of experience reviewed the imaging studies of patients with combined hepatocellular cholangiocarcinoma tumors and matched control cases of hepatocellular carcinoma (HCC) (n = 15) and cholangiocarcinoma (n = 18). The reviewers were blinded to the pathologic diagnosis. Imaging features on contrast-enhanced MRI and CT with the suggested final diagnosis were recorded. RESULTS The demographics of our patient population were similar to other reported U.S. populations, with cirrhosis and hepatitis present in a minority of patients. The imaging features of combined hepatocellular cholangiocarcinoma tumors overlapped with those of HCC and cholangiocarcinoma. The correct diagnosis of combined hepatocellular cholangiocarcinoma tumors was made in a minority of cases by either radiologist, with misdiagnosis more often leading to suggestion of cholangiocarcinoma than HCC. Sensitivities and specificities for diagnosis of combined hepatocellular cholangiocarcinoma tumors ranged from 33% to 34% and 81% to 100%, respectively. CONCLUSION Preoperative diagnosis of combined hepatocellular cholangiocarcinoma tumors on the basis of imaging features is accurate in the minority of cases. Tumor markers and risk factors may help improve accuracy; however, in the absence of classic imaging features and supportive information for HCC or cholangiocarcinoma, biopsy should be considered for confirmation of diagnosis.

Magnetic resonance imaging of focal liver lesions: Approach to imaging diagnosis

This article is a review of magnetic resonance imaging (MRI) of incidental focal liver lesions. This review provides an overview of liver MRI protocol, diffusion‐weighted imaging, and contrast agents. Additionally, the most commonly encountered benign and malignant lesions are discussed with emphasis on imaging appearance and the diagnostic performance of MRI based on a review of the literature. (HEPATOLOGY 2011)

Hepatobiliary agents and their role in LI-RADS

The Liver Imaging Reporting and Data System (LI-RADS) was introduced with the goal of standardizing the diagnosis of hepatocellular carcinoma. The 2014 version of LI-RADS incorporates the use of hepatobiliary contrast agents (HBAs) into the diagnostic algorithm, including gadoxetate disodium and gadobenate dimeglumine. Three new ancillary features are introduced: hepatobiliary phase (HBP) hypointensity and HBP hypointense rim favor malignancy, while HBP isointensity favors benignity. HBP hyperintensity favors neither malignancy nor benignity. In this review, we describe how to use these new features as well as numerous pitfalls associated with the use ofHBAs, including hemangiomas, cholangiocarcinomas, and focal confluent fibrosis. Importantly, findings on the HBP are not included as major criteria and therefore the criteria for the diagnosis of LI-RADS 5 observations remain unchanged, and so congruence with the Organ Procurement Transplant Network system remains intact. Additionally, we review how the major features in LI-RADS, arterial phase hyperenhancement, threshold growth, and washout and capsule appearance, may be affected with HBAs. Notably with HBAs, hypointensity on the delayed phase, termed the transitional phase, does not qualify as washout appearance due to the possibility of early parenchymal enhancement. It is hoped that the incorporation of HBAs into LI-RADS will help create consistency when interpreting HBA enhanced MRIs.

Gadolinium-based contrast agents: A comprehensive risk assessment

Gadolinium‐based contrast agents (GBCAs) have been used in magnetic resonance imaging (MRI) since the 1980s and are now administered in up to 35% of all MRI examinations. While GBCAs were initially felt to carry minimal risk, the subsequent identification of GBCAs as the key etiologic factor in the development of nephrogenic systemic fibrosis (NSF) has raised concerns about the broader health impacts of gadolinium exposure. Clinicians, radiologists, and patients should be aware of the most up‐to‐date data pertaining to the risks of GBCA administration. Specific issues covered in this review article include immediate adverse reactions; pregnancy and lactation; and gadolinium deposition and toxicity, with a special focus on NSF. Practice recommendations based on the presented data, as well as current professional society guidelines, are provided for each section.

Combined hepatocellular-cholangiocarcinoma: what the radiologist needs to know about biphenotypic liver carcinoma.

Combined hepatocellular-cholangiocarcinoma (CHC), also referred to as primary liver carcinoma (PLC) with biphenotypic differentiation, is an increasingly recognized subtype of malignant PLC encompassing varying morphologic forms thought to arise either from progenitor cell lineage or dedifferentiation of mature liver cells. Tumor cells express both biliary and hepatocellular markers by immunohistochemistry, and may also express progenitor cell and stem cell markers. Due to the relative rarity of this tumor type, little is known about the risk factors, imaging appearance, or prognosis. Few studies have demonstrated risk factors that overlap with hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC), though not all appear to arise in the background of cirrhosis. The imaging appearances of these tumors may overlap with those of HCC and CC and discriminating features such as classic enhancement patterns and biliary ductal dilation are not universally present. Serum tumor markers, such as alpha-fetoprotein and carbohydrate antigen 19-9, may be helpful when they are discordant with imaging or if both are elevated to a significant degree. In regards to management and prognosis, most studies demonstrate worse outcomes compared with HCC or CC. In the United States, the diagnosis of HCC is frequently made with imaging alone, and subsequent management decisions, including organ allocation for transplantation, rely upon the radiological diagnosis. Given the importance of radiological diagnosis, awareness of this tumor type is essential for appropriate management.

New Approaches to Molecular Imaging of Multiple Myeloma

Molecular imaging plays an important role in detection and staging of hematologic malignancies. Multiple myeloma (MM) is an age-related hematologic malignancy of clonal bone marrow plasma cells characterized by destructive bone lesions and is fatal in most patients. Traditional skeletal survey and bone scans have sensitivity limitations for osteolytic lesions manifested in MM. Progressive biomedical imaging technologies such as low-dose CT, molecularly targeted PET, MRI, and the functional–anatomic hybrid versions (PET/CT and PET/MRI) provide incremental advancements in imaging MM. Imaging with PET and MRI using molecularly targeted probes is a promising precision medicine platform that might successfully address the clinical ambiguities of myeloma spectrum diseases. The intent of this focus article is to provide a concise review of the present status and promising developments on the horizon, such as the new molecular imaging biomarkers under investigation that can either complement or potentially supersede existing standards.

Cervical Gross Tumor Volume Dose Predicts Local Control Using Magnetic Resonance Imaging/Diffusion-Weighted Imaging—Guided High-Dose-Rate and Positron Emission Tomography/Computed Tomography—Guided Intensity Modulated Radiation Therapy

PURPOSE Magnetic resonance imaging/diffusion weighted-imaging (MRI/DWI)-guided high-dose-rate (HDR) brachytherapy and (18)F-fluorodeoxyglucose (FDG) - positron emission tomography/computed tomography (PET/CT)-guided intensity modulated radiation therapy (IMRT) for the definitive treatment of cervical cancer is a novel treatment technique. The purpose of this study was to report our analysis of dose-volume parameters predicting gross tumor volume (GTV) control. METHODS AND MATERIALS We analyzed the records of 134 patients with International Federation of Gynecology and Obstetrics stages IB1-IVB cervical cancer treated with combined MRI-guided HDR and IMRT from July 2009 to July 2011. IMRT was targeted to the metabolic tumor volume and lymph nodes by use of FDG-PET/CT simulation. The GTV for each HDR fraction was delineated by use of T2-weighted or apparent diffusion coefficient maps from diffusion-weighted sequences. The D100, D90, and Dmean delivered to the GTV from HDR and IMRT were summed to EQD2. RESULTS One hundred twenty-five patients received all irradiation treatment as planned, and 9 did not complete treatment. All 134 patients are included in this analysis. Treatment failure in the cervix occurred in 24 patients (18.0%). Patients with cervix failures had a lower D100, D90, and Dmean than those who did not experience failure in the cervix. The respective doses to the GTV were 41, 58, and 136 Gy for failures compared with 67, 99, and 236 Gy for those who did not experience failure (P<.001). Probit analysis estimated the minimum D100, D90, and Dmean doses required for ≥90% local control to be 69, 98, and 260 Gy (P<.001). CONCLUSIONS Total dose delivered to the GTV from combined MRI-guided HDR and PET/CT-guided IMRT is highly correlated with local tumor control. The findings can be directly applied in the clinic for dose adaptation to maximize local control.

Imaging Features of Biphenotypic Primary Liver Carcinoma (Hepatocholangiocarcinoma) and the Potential to Mimic Hepatocellular Carcinoma: LI-RADS Analysis of CT and MRI Features in 61 Cases

OBJECTIVE The purpose of this study was to determine the frequency with which biphenotypic primary liver carcinoma (also called hepatocholangiocarcinoma) may be misclassified as hepatocellular carcinoma (HCC) when only Liver Imaging Reporting and Data System (LI-RADS) major features are used and after consideration of ancillary features. MATERIALS AND METHODS A review of all pathologically proven biphenotypic primary liver carcinomas diagnosed at one institution from 2006 to 2014 was performed. Two subspecialized abdominal imagers independently reviewed cases using LI-RADS version 2014 and assigned major features, ancillary features, and additional findings. The number of lesions meeting imaging criteria for HCC was determined after assessment of major features alone and after the addition of ancillary features. RESULTS Sixty-one patients (30 men, 31 women; mean age, 62 years; range, 22-89 years) with biphenotypic primary liver carcinomas who underwent pretreatment multiphasic contrast-enhanced MRI (48 patients) or CT (13 patients) were included. According to LI-RADS major features alone, 33 (54.1%) lesions met criteria for HCC and therefore might have been misclassified. Thirteen had arterial phase hyperenhancement, washout, and a capsule. Twenty had arterial phase hyperenhancement with either washout (15 lesions) or a capsule (five lesions). After evaluation of ancillary features, 29 of these potential mimics exhibited at least one ancillary feature favoring non-HCC malignancy, possibly leading to appropriate reclassification. Of the four carcinomas that met criteria for HCC by major features and did not have ancillary features favoring non-HCC malignancy, two (3.3% of all tumors) fell within the Milan criteria. CONCLUSION Most biphenotypic primary liver carcinomas have features of non-HCC malignancy and can be correctly categorized as such. Addition of ancillary features to major features may improve diagnostic accuracy over systems in which only major features are used.

Colorectal Liver Metastases: State of the Art Imaging

Colorectal cancer is a leading cause of death with mortality determined predominately by metastatic involvement of the liver. Treatment of liver metastases continues to evolve and imaging plays an essential role in initial staging, preoperative planning, and treatment monitoring. This review article discusses the current role of imaging in the management of patients with colorectal liver metastases. Particular challenges such as hepatic steatosis, disappearing metastases, and following treated lesions are addressed.