Esme J. Hill

Anatomical basis and histopathological changes resulting from selective internal radiotherapy for liver metastases

Background Knowledge that liver tumours preferentially take their blood supply from the arterial blood supply rather than the portal venous system can be used for local delivery of treatment or for embolisation to cut off the blood supply to tumours. Aims To present histological evaluation of malignant and non-malignant hepatic tissue of one such therapy, selective internal radiation therapy (SIRT) with yttrium-90 microspheres, to decipher its principal mechanism of action. Methods The H&E stained sections of hepatic resection specimens from three patients with liver metastases from colorectal (CRC) cancer, who underwent hepatic surgery 4–9 months following SIRT, were examined and the pathological changes documented. Results Resin microspheres were identified in the vascular tumour bed and vessels within the portal tracts of the background liver parenchyma. Microspheres were usually associated with giant cell reaction or histiocytes. In the tumour bed, tumour necrosis, mucinous alteration, collections of foamy histiocytes, ectatic vessels, calcification and fibrosis were observed. There was minimal cellular inflammatory response observed, suggestive of direct radiation injury as a non-immune mediated process. Conclusions We describe in detail the spectrum of histopathological changes in malignant tissue and liver parenchyma in patients with metastatic CRC treated with SIRT. Our findings are consistent with the hypothesis that the principal mechanism of action of SIRT appears to be via arterially directed delivery of highly radioactive microspheres in and around the vascular tumour bed rather than by micro-arterial embolisation.

Oxaliplatin as a radiosensitiser for upper and lower gastrointestinal tract malignancies: What have we learned from a decade of translational research?

Some of the greatest advances in the treatment of solid malignancies have resulted from the combination of chemotherapy and radiotherapy treatments. This article comprehensively reviews the current clinical evidence for oxaliplatin-based chemo-radiotherapy that may improve local control and survival. In order to understand how clinical studies should be designed, the pre-clinical evidence for the use of oxaliplatin chemotherapy as a radiosensitising agent is appraised. Particular focus is placed on oxaliplatins biological mechanisms of action, including cell cycle effects, the formation of DNA adducts and interstrand cross-links and the role of DNA repair proteins. At a clinical level, there is currently no evidence to suggest that oxaliplatin provides an additional benefit to concurrent chemo-radiation regimes that utilise fluoropyrimidines; we evaluate the reasons for this observation, the limitations of clinical trial design and the opportunities that currently exist to design clinical trials which are underpinned by an understanding of the basic biology.

Clinical Trial of Oral Nelfinavir before and during Radiation Therapy for Advanced Rectal Cancer.

Purpose: Nelfinavir, a PI3K pathway inhibitor, is a radiosensitizer that increases tumor blood flow in preclinical models. We conducted an early-phase study to demonstrate the safety of nelfinavir combined with hypofractionated radiotherapy (RT) and to develop biomarkers of tumor perfusion and radiosensitization for this combinatorial approach. Experimental Design: Ten patients with T3-4 N0-2 M1 rectal cancer received 7 days of oral nelfinavir (1,250 mg b.i.d.) and a further 7 days of nelfinavir during pelvic RT (25 Gy/5 fractions/7 days). Perfusion CT (p-CT) and DCE-MRI scans were performed pretreatment, after 7 days of nelfinavir and prior to the last fraction of RT. Biopsies taken pretreatment and 7 days after the last fraction of RT were analyzed for tumor cell density (TCD). Results: There were 3 drug-related grade 3 adverse events: diarrhea, rash, and lymphopenia. On DCE-MRI, there was a mean 42% increase in median Ktrans, and a corresponding median 30% increase in mean blood flow on p-CT during RT in combination with nelfinavir. Median TCD decreased from 24.3% at baseline to 9.2% in biopsies taken 7 days after RT (P = 0.01). Overall, 5 of 9 evaluable patients exhibited good tumor regression on MRI assessed by tumor regression grade (mrTRG). Conclusions: This is the first study to evaluate nelfinavir in combination with RT without concurrent chemotherapy. It has shown that nelfinavir-RT is well tolerated and is associated with increased blood flow to rectal tumors. The efficacy of nelfinavir-RT versus RT alone merits clinical evaluation, including measurement of tumor blood flow. Clin Cancer Res; 22(8); 1922–31. ©2016 AACR. See related commentary by Meyn et al., p. 1834

XPF protein levels determine sensitivity of malignant melanoma cells to oxaliplatin chemotherapy: Suitability as a biomarker for patient selection

As the options for systemic treatment of malignant melanoma (MM) increase, the need to develop biomarkers to identify patients who might benefit from cytotoxic chemotherapy becomes more apparent. In preclinical models, oxaliplatin has activity in cisplatin‐resistant cells. In this study, we have shown that oxaliplatin forms interstrand crosslinks (ICLs) in cellular DNA and that loss of the heterodimeric structure‐specific endonuclease XPF‐ERCC1 causes hypersensitivity to oxaliplatin in mammalian cells. XPF deficiency resulted in late S‐phase arrest and persistence of double‐strand breaks following oxaliplatin treatment. In a panel of 12 MM cell lines, oxaliplatin sensitivity correlated with XPF and ERCC1 protein levels. The knockdown of ERCC1 and XPF protein levels by RNA interference increased sensitivity of cancer cells to oxaliplatin; overexpression of exogenous ERCC1 significantly decreased drug sensitivity. Following immunohistochemical optimization, XPF protein levels were quantified in MM tissue samples from 183 patients, showing variation in expression and no correlation with prognosis. In 57 patients with MM treated with cisplatin or carboplatin, XPF protein levels did not predict the likelihood of clinical response. We propose that oxaliplatin should not be discarded as a potential treatment for MM on the basis of the limited activity of cisplatin in unselected patients. Moreover, we show that XPF‐ERCC1 protein levels are a key determinant of the sensitivity of melanoma cells to oxaliplatin in vitro. Immunohistochemical detection of XPF appears suitable for development as a tissue biomarker for potentially selecting patients for oxaliplatin treatment in a prospective clinical trial.

Multi-modality Therapy of Hepatic Metastases from Colorectal Carcinoma: Optimal Combination of Systemic Chemotherapy with Radio-embolization

The commonest cause of death from advanced colorectal cancer is disease progression of hepatic metastases. A number of technologies are in clinical development to improve local control of liver metastases and potentially improve overall survival. Radio-embolization (RE) is a technique for administering resin or glass microspheres that contain yttrium-90 to unresectable primary or secondary hepatic malignancies internally via the livers arterial supply in a single procedure. Clinical trials of RE used with concomitant radiosensitizing chemotherapy have shown promising results in patients with metastatic colorectal cancer. In this article, the evidence base for combining RE with systemic chemotherapy in the first line therapy of metastatic colorectal cancer is appraised and the scientific rationale for combining RE with chemotherapy in first and subsequent lines of therapy is outlined. Clinical trials of RE and chemotherapy currently recruiting patients with metastatic colorectal cancer are discussed in detail and practical recommendations offered on how best to combine RE and systemic chemotherapy.

Personalised Estimation of the Arterial Input Function for Improved Pharmacokinetic Modelling of Colorectal Cancer Using dceMRI

dceMRI is becoming a key modality for tumour characterisation and monitoring of response to therapy, because of the ability to identify the underlying tumour physiology. Pharmacokinetic PK models relate the contrast enhancement seen in dceMRI to physiological parameters but require accurate measurement of the AIF, the time-dependant contrast concentration in blood plasma. In this study, a novel method is introduced that overcomes the challenges of direct AIF measurement, by automatically estimating the AIF from the tumour tissue. This approach was evaluated on synthetic data 10% noise and achieved a relative error in K trans and k ep of 11.8 ±3.5% and 25.7 ±4.7 %, respectively, compared to 41 ±15 % and 60 ±32 % using a population model. The method improved the fit of the PK model to clinical colorectal cancer cases, was stable for independent regions in the tumour, and showed improved localisation of the PK parameters. This demonstrates that personalised AIF estimation can lead to more accurate PK modelling.

An MRF-Based Discrete Optimization Framework for Combined DCE-MRI Motion Correction and Pharmacokinetic Parameter Estimation

Dynamic contrast-enhanced MRI (DCE-MRI) images are increasingly used for assessing cancer treatment outcome. These time sequences are typically affected by motion, which causes significant errors in tracer kinetic model analysis. Current intra-sequence registration methods for contrast enhanced data either assume restricted transformations (e.g. translation) or employ continuous optimization, which is prone to local optima. In this work, we propose a new approach to DCE-MRI intra-sequence registration and pharmacokinetic modelling, which is formulated in an MRF optimization framework. The complete 4D graph corresponding to a DCE-MRI sequence is reduced to a concatenation of minimum spanning trees, which can be optimized more efficiently. To address the changes due to contrast, a data cost function which incorporates pharmacokinetic modelling information is formulated. The advantages of this method are demonstrated on 8 DCE-MRI image sequences of patients with advanced rectal tumours, presenting mild to severe motion.

pCT derived arterial input function for improved pharmacokinetic analysis of longitudinal dceMRI for colorectal cancer

Dynamic contrast-enhanced MRI is a dynamic imaging technique that is now widely used for cancer imaging. Changes in tumour microvasculature are typically quantified by pharmacokinetic modelling of the contrast uptake curves. Reliable pharmacokinetic parameter estimation depends on the measurement of the arterial input function, which can be obtained from arterial blood sampling, or extracted from the image data directly. However, arterial blood sampling poses additional risks to the patient, and extracting the input function from MR intensities is not reliable. In this work, we propose to compute a perfusion CT based arterial input function, which is then employed for dynamic contrast enhanced MRI pharmacokinetic parameter estimation. Here, parameter estimation is performed simultaneously with intra-sequence motion correction by using nonlinear image registration. Ktrans maps obtained with this approach were compared with those obtained using a population averaged arterial input function, i.e. Orton. The dataset comprised 5 rectal cancer patients, who had been imaged with both perfusion CT and dynamic contrast enhanced MRI, before and after the administration of a radiosensitising drug. Ktrans distributions pre and post therapy were computed using both the perfusion CT and the Orton arterial input function. Perfusion CT derived arterial input functions can be used for pharmacokinetic modelling of dynamic contrast enhanced MRI data, when perfusion CT images of the same patients are available. Compared to the Orton model, perfusion CT functions have the potential to give a more accurate separation between responders and non-responders.

Management of a thyroid "incidentaloma" in a patient with cancer: a case report.

The routine use of 18F-fluorodeoxyglucose-positron emission tomography (PET)/computed tomography scans for staging and assessment of treatment response for cancer has resulted in a large number of thyroid abnormalities being detected as incidental findings (“incidentalomas”). Since most PET/CT scans are performed in the setting of a known nonthyroid malignancy, the need for “incidentalomas” to be further investigated and managed depends on the stage, prognosis, and current treatment plan for the known malignancy. We present a case describing the management of an incidental F-fluorodeoxyglucose-avid thyroid nodule detected in a patient with known metastatic colorectal cancer. On the basis of this case, we discuss the management of incidental PET-detected thyroid nodules in patients with metastatic cancer. Thyroid “incidentalomas” must be seen in the context of the prognosis and treatment plan for the known malignancy.

A Semi-automated Toolkit for Analysis of Liver Cancer Treatment Response Using Perfusion CT

Delineation of hepatic tumours is challenging in CT due to limited inherent tissue contrast, leading to significant intra-/inter-observer variability. Perfusion CT (pCT) allows quantitative assessment of enhancement patterns in normal and abnormal liver. This study aims to develop a semi-automated perfusion analysis toolkit that classifies hepatic tissue based on perfusion-derived parameters. pCT data from patients with hepatic metastases were used in this study. Tumour motion was minimized through image registration; perfusion parameters were derived and then employed in the training of a machine learning algorithm used to classify hepatic tissue. This method was found to deliver promising results for 10 data sets, with recorded sensitivity and specificity of the tissue classification in the ranges of 0.92–0.99 and 0.98–0.99 respectively. This semi-automated method could be used to analyze response over the treatment course, as it is not based on intensity values.