Rachel R. Phillips

The safety and feasibility of extracorporeal high-intensity focused ultrasound (HIFU) for the treatment of liver and kidney tumours in a Western population

High-intensity focused ultrasound (HIFU) provides a potential noninvasive alternative to conventional therapies. We report our preliminary experience from clinical trials designed to evaluate the safety and feasibility of a novel, extracorporeal HIFU device for the treatment of liver and kidney tumours in a Western population. The extracorporeal, ultrasound-guided Model-JC Tumor Therapy System (HAIFU™ Technology Company, China) has been used to treat 30 patients according to four trial protocols. Patients with hepatic or renal tumours underwent a single therapeutic HIFU session under general anaesthesia. Magnetic resonance imaging 12 days after treatment provided assessment of response. The patients were subdivided into those followed up with further imaging alone or those undergoing surgical resection of their tumours, which enabled both radiological and histological assessment. HIFU exposure resulted in discrete zones of ablation in 25 of 27 evaluable patients (93%). Ablation of liver tumours was achieved more consistently than for kidney tumours (100 vs 67%, assessed radiologically). The adverse event profile was favourable when compared to more invasive techniques. HIFU treatment of liver and kidney tumours in a Western population is both safe and feasible. These findings have significant implications for future noninvasive image-guided tumour ablation.

Asymptomatic Children with Multiple Endocrine Neoplasia Type 1 Mutations May Harbor Nonfunctioning Pancreatic Neuroendocrine Tumors

CONTEXT Multiple endocrine neoplasia type 1 (MEN1) is characterized by the occurrence of parathyroid, pituitary, and pancreatic tumors. MEN1, an autosomal dominant disorder, has a high degree of penetrance, such that more than 95% of patients develop clinical manifestations by the fifth decade, although this is lower at approximately 50% by age 20 yr. However, the lower penetrance in the younger group, which is based on detecting hormone-secreting tumors, may be an underestimate because patients may have nonfunctioning tumors and be asymptomatic. OBJECTIVE The aim of the study was to evaluate the occurrence of nonfunctioning pancreatic neuroendocrine tumors in asymptomatic children with MEN1. PATIENTS Twelve asymptomatic Northern European children, aged 6 to 16 yr, who were known to have MEN1 mutations were studied. RESULTS Two asymptomatic children, who were aged 12 and 14 yr, had normal plasma fasting gastrointestinal hormones and were found to have nonfunctioning pancreatic neuroendocrine tumors that were more than 2 cm in size. Surgery and immunostaining revealed that the tumors did not have significant expression of gastrointestinal hormones but did contain chromogranin A and synaptophysin, features consistent with those of nonfunctioning pancreatic neuroendocrine tumors. The tumors had a loss of menin expression. The 14 yr old also had primary hyperparathyroidism and a microprolactinoma, and the 12 yr old had a nonfunctioning pituitary microadenoma. Three other children had primary hyperparathyroidism and a microprolactinoma. CONCLUSION Nonfunctioning pancreatic neuroendocrine tumors may occur in asymptomatic children with MEN1 mutations, and screening for such enteropancreatic tumors in MEN1 children should be considered earlier than the age of 20 yr, as is currently recommended by the international guidelines.

High-intensity focused ultrasound treatment of liver tumours: post-treatment MRI correlates well with intra-operative estimates of treatment volume

OBJECTIVES To assess the safety and feasibility of high-intensity focused ultrasound (HIFU) ablation of liver tumours and to determine whether post-operative MRI correlates with intra-operative imaging. METHODS 31 patients were recruited into two ethically approved clinical trials (median age 64; mean BMI 26 kg m(-2)). Patients with liver tumours (primary or metastatic) underwent a single HIFU treatment monitored using intra-operative B-mode ultrasound. Follow-up consisted of radiology and histology (surgical trial) or radiology alone (radiology trial). Radiological follow-up was digital subtraction contrast-enhanced MRI. RESULTS Treatment according to protocol was possible in 30 of 31 patients. One treatment was abandoned because of equipment failure. Transient pain and superficial skin burns were seen in 81% (25/31) and 39% (12/31) of patients, respectively. One moderate skin burn occurred. One patient died prior to radiological follow-up. Radiological evidence of ablation was seen in 93% (27/29) of patients. Ablation accuracy was good in 89% (24/27) of patients. In three patients the zone of ablation lay ≤2 mm outside the tumour. The median cross-sectional area (CSA) of the zone of ablation was 5.0 and 5.1 cm(2) using intra-operative and post-operative imaging, respectively. The mean MRI:B-mode CSA ratio was 1.57 [95% confidence interval (CI)=0.57-2.71]. There was positive correlation between MRI and B-mode CSA (Spearmans r=0.48; 95% CI 0.11-0.73; p=0.011) and the slope of linear regression was significantly non-zero (1.23; 95% CI=0.68-1.77; p<0.0001). CONCLUSIONS HIFU ablation of liver tumours is safe and feasible. HIFU treatment is accurate, and intra-operative assessment of treatment provides an accurate measure of the zone of ablation and correlates well with MRI follow-up.

High-intensity focused ultrasound ablation of liver tumours: can radiological assessment predict the histological response?

Cancer therapies usually depend on cross-sectional imaging for the assessment of treatment response. This study was designed to evaluate the ability of MRI to predict zones of necrosis following the use of high-intensity focused ultrasound (HIFU) to treat liver metastases. Patients with liver metastases, who had been scheduled for elective surgical resection of their tumours, were recruited to this non-randomized Phase II study. In each case, a proportion of an index liver tumour target was ablated. The response to HIFU was assessed after 12 days using contrast-enhanced MRI and compared directly with histological analysis at the time of surgery. Eight patients were treated, of whom six were subsequently assessed with both MRI and histology. There were no major complications. MRI predicted complete ablation in three cases. In each case, histological analysis confirmed complete ablation. In one case, the region of ablation observed on MRI appeared smaller than predicted at the time of HIFU, but histology revealed complete ablation of the target region. The predominant characteristic of HIFU-ablated tissue was coagulative necrosis but heat fixation was evident in some areas. Heat-fixed cells appeared normal under haematoxylin and eosin staining, indicating that this is unreliable as an indicator of HIFU-induced cell death. This study demonstrates that HIFU is capable of achieving selective ablation of pre-defined regions of liver tumour targets, and that MRI evidence of complete ablation of the target region can be taken to infer histological success.

The use of time to maximum enhancement to indicate areas of ablation following the treatment of liver tumours with high-intensity focused ultrasound

The aim of this study was to investigate the use of time to maximum enhancement (t(max)) for each voxel in contrast-enhanced MRI (CE-MRI) as a non-invasive tool to determine areas of necrosis following treatment of liver tumours with high-intensity focused ultrasound (HIFU) and, having established the utility of t(max) maps, to develop a three-dimensional (3-D) representation to display this information concisely. 3-D T(1) weighted fast spoiled gradient echo images of the liver were acquired before and after administration of contrast agent. The CE-MR images were aligned to the pre-contrast volume and an estimate of t(max) was obtained for each voxel. Such pre- and post-contrast image sets were acquired before and after ablation. The t(max) maps before and after HIFU treatment were correlated with the procedure notes, radiological reports and gross histological specimen. Finally, 3-D t(max) maps of the whole liver were reconstructed to show all areas of abnormal tissue perfusion. Normal, healthy liver tissue uniformly enhances maximally after approximately 1 min. The computed t(max) maps accurately delineated areas of abnormal contrast agent uptake, corresponding to tumour deposits. Changes in t(max) and non-enhancing voxels after treatment correlate well with volumes targeted during ablation and the necrotic regions seen on gross histological specimens. Alignment of the contrast-enhanced images with the pre-contrast volume greatly improved the conspicuity of the t(max) maps. We conclude that t(max) maps and their 3-D views can be used as a non-invasive tool to assess and potentially to quantify the success of HIFU ablation, and concisely represent the large number of CE-MRI data.

Durable Response of Spinal Chordoma to Combined Inhibition of IGF-1R and EGFR.

Chordomas are rare primary malignant bone tumors arising from embryonal notochord remnants of the axial skeleton. Chordomas commonly recur following surgery and radiotherapy, and there is no effective systemic therapy. Previous studies implicated receptor tyrosine kinases, including epidermal growth factor receptor (EGFR) and type 1 insulin-like growth factor receptor (IGF-1R), in chordoma biology. We report an adult female patient who presented in 2003 with spinal chordoma, treated with surgery and radiotherapy. She underwent further surgery for recurrent chordoma in 2008, with subsequent progression in pelvic deposits. In June 2009, she was recruited onto the Phase I OSI-906-103 trial of EGFR inhibitor erlotinib with linsitinib, a novel inhibitor of IGF-1R/insulin receptor (INSR). Treatment with 100 mg QD erlotinib and 50 mg QD linsitinib was well-tolerated, and after 18 months a partial response was achieved by RECIST criteria. From 43 months, a protocol modification allowed intra-patient linsitinib dose escalation to 50 mg BID. The patient remained stable on trial treatment for a total of 5 years, discontinuing treatment in August 2014. She subsequently experienced further disease progression for which she underwent pelvic surgery in April 2015. Analysis of DNA extracted from 2008 (pre-trial) tissue showed that the tumor harbored wild-type EGFR, and a PIK3CA mutation was detected in plasma, but not tumor DNA. The 2015 (post-trial) tumor harbored a mutation of uncertain significance in ATM, with no detectable mutations in other components of a 50 gene panel, including EGFR, PIK3CA, and TP53. By immunohistochemistry, the tumor was positive for brachyury, the molecular hallmark of chordoma, and showed weak–moderate membrane and cytoplasmic EGFR. IGF-1R was detected in the plasma membrane and cytoplasm and was expressed more strongly in recurrent tumor than the primary. We also noted heterogeneous nuclear IGF-1R, which has been linked with sensitivity to IGF-1R inhibition. Similar variation in IGF-1R expression and subcellular localization was noted in 15 further cases of chordoma. In summary, this exceptionally durable response suggests that there may be merit in evaluating combined IGF-1R/INSR and EGFR inhibition in patients with chordomas that recur following failure of local treatment.

Preliminary Experience Using Extracorporeal High‐Intensity Focused Ultrasound For The Treatment Of Kidney And Liver Tumours

High‐intensity focused ultrasound (HIFU) provides a potentially non‐invasive alternative to conventional therapies. We have been using the extracorporeal ultrasound‐guided Model‐JC Tumor Therapy System (HAIFU™ Technology Co, China) in clinical trials to evaluate the safety and feasibility of treating renal and liver tumours. 30 patients have been treated (22 liver and 8 kidney tumours), all of whom were available for adverse event reporting. Of the 22 liver tumours, 20 are evaluable for response to treatment; 14 were followed up with magnetic resonance imaging (MRI) alone, and 6 with both MRI and histological resection. Evidence of ablation was seen in 20/20 (100%) cases radiologically, and 6/6 (100%) cases histologically. Of the 8 kidney tumours treated, 7 are evaluable; 2 were followed up with MRI alone, and 5 with both MRI and histological resection. Evidence of ablation was seen in 4/7 (57%) radiologically and 1/5 (20%) histologically. Mild, moderate or severe transient pain was reported by 16 (53%), ...

HIGH INTENSITY FOCUSED ULTRASOUND ABLATION OF SMALL RENAL TUMOURS WITH AN EXTRA-CORPOREAL DEVICE: 3 YEAR OUTCOME DATA

INTRODUCTION AND OBJECTIVES: Surgery currently remains the gold standard treatment for localized renal cell carcinoma. Partial nephrectomy is indicated for T1a (<4cm) renal cancer. However, morbidity with partial nephrectomy approaches 20-25%. A variety of minimally invasive treatments have been proposed for small renal tumours; these include radiofrequency ablation, cryotherapy and high-intensity focused ultrasound (HIFU). HIFU results in ‘trackless’ homogenous tissue ablation and when administered via an extracorporeal device, is entirely non-invasive. METHODS: 17 patients (mean age 76 years; mean BMI 26 kgm2) with localised radiologically suspicious renal lesions <4cm maximum diameter were treated with extracorporeal HIFU using the Model-JC System (HAIFUTM). Mean tumour dimension was 3.5cm; 12/17 tumours were right sided. Real-time diagnostic ultrasound was used for targeting and monitoring; mean insonication time 21 minutes. Patients were followed with subtraction gandalinium-enhanced MRI at day 12 and six monthly. RESULTS: There were no major complications related to HIFU treatment. All patients were discharged within 24 hours. 14 patients completed six months radiological follow-up; two treatments were abandoned due to intervening bowel in the target field and were advised to undergo surgery. One patient underwent partial nephrectomy prior to six month follow-up as a result of a small area of residual enhancement. Radiological evidence of ablation was seen in seven out of 15 patients (47%) at day 12 imaging. Eight (53%) showed no clear radiological ablation at 12 days four underwent surgery at a mean of 11 months post HIFU and one underwent radiofrequency ablation 16 months after HIFU. Ten patients remain under surveillance at a mean of 36 months post treatment (range 24-51). The targeted lesion shows central loss of enhancement in all ten patients; a rim of peripheral enhancement was seen in all patients. Notably, there has been no increase in tumour dimension over the mean 3 year follow-up. CONCLUSIONS: This is the first medium term follow-up study of extracorporeal HIFU for renal cancer. 10 out of 15 (67%) patients have stable renal lesions at a mean of 3 years following treatment. However, half of patients showed no radiological evidence of ablation at 12 days and one third of all patients underwent alternative treatment modalities. Extracorporeal HIFU may yet have a role in the primary management of small renal cancers but the technique and treatment parameters need further refinement.