Peter M. Evans

Investigation of the Safety of Irreversible Electroporation in Humans

PURPOSE A single-center prospective nonrandomized cohort study was performed to investigate the safety of irreversible electroporation (IRE) for tumor ablation in humans. MATERIALS AND METHODS Thirty-eight volunteers with advanced malignancy of the liver, kidney, or lung (69 separate tumors) unresponsive to alternative treatment were subjected to IRE under general anesthesia. Clinical examination, biochemistry, and computed tomography (CT) scans of the treated organ were performed before, immediately after, and at 1 month and 3 months after the procedure. RESULTS No mortalities occurred at 30 days. Transient ventricular arrhythmia occurred in four patients, and electrocardiographically (ECG) synchronized delivery was used subsequently in the remaining 30 patients, with two further arrhythmias (supraventricular tachycardia and atrial fibrillation). One patient developed obstruction of the upper ureter after IRE. One adrenal gland was unintentionally directly electroporated, which produced transient severe hypertension. There was no other evidence of adjacent organ damage related to the electroporation. Other adverse events were not directly related to IRE, but two patients developed temporary neurapraxia as a result of arm extension during a prolonged period of anesthesia. Although not a primary aim of this preliminary study, complete target tumor ablation verified by CT was achieved in 46 of the 69 tumors treated with IRE (66%). Most treatment failures occurred in renal and lung tumors. Biopsy in three patients showed coagulative necrosis in the regions treated by IRE. CONCLUSIONS IRE appears to be safe for human clinical use provided ECG-synchronized delivery is used. Comparative evaluation with alternative ablative technologies is warranted.

KRAS Mutation Is Associated with Lung Metastasis in Patients with Curatively Resected Colorectal Cancer

Purpose: Oncogene mutations contribute to colorectal cancer development. We searched for differences in oncogene mutation profiles between colorectal cancer metastases from different sites and evaluated these as markers for site of relapse. Experimental Design: One hundred colorectal cancer metastases were screened for mutations in 19 oncogenes, and further 61 metastases and 87 matched primary cancers were analyzed for genes with identified mutations. Mutation prevalence was compared between (a) metastases from liver (n = 65), lung (n = 50), and brain (n = 46), (b) metastases and matched primary cancers, and (c) metastases and an independent cohort of primary cancers (n = 604). Mutations differing between metastasis sites were evaluated as markers for site of relapse in 859 patients from the VICTOR trial. Results: In colorectal cancer metastases, mutations were detected in 4 of 19 oncogenes: BRAF (3.1%), KRAS (48.4%), NRAS (6.2%), and PIK3CA (16.1%). KRAS mutation prevalence was significantly higher in lung (62.0%) and brain (56.5%) than in liver metastases (32.3%; P = 0.003). Mutation status was highly concordant between primary cancer and metastasis from the same individual. Compared with independent primary cancers, KRAS mutations were more common in lung and brain metastases (P < 0.005), but similar in liver metastases. Correspondingly, KRAS mutation was associated with lung relapse (HR = 2.1; 95% CI, 1.2 to 3.5, P = 0.007) but not liver relapse in patients from the VICTOR trial. Conclusions: KRAS mutation seems to be associated with metastasis in specific sites, lung and brain, in colorectal cancer patients. Our data highlight the potential of somatic mutations for informing surveillance strategies. Clin Cancer Res; 17(5); 1122–30. ©2011 AACR.

The treatment of malignancy by hyperthermia

The use of hyperthermia for the selective destruction of tumours may be applied by a whole body, surgical perfusion or interstitial techniques. The main determinant of selectivity is tumour blood flow. The effects of hyperthermia may be augmented by step-down heating, manipulating pH changes and sensitisation by chemotherapy or specific pharmacological agents.

Lower gastrointestinal haemorrhage and superselective angiographic embolization.

Background:   Little information is available in the surgical literature regarding the use of superselective embolization for bleeding with its origin distal to the ligament of Treitz. The outcome of this treatment remains, to some extent, an unknown. The present paper evaluates the Alfred Hospitals experience using superselective transcatheter embolization in the treatment of acute lower gastrointestinal haemorrhage.

Pancreatic resection for metastatic melanoma

BACKGROUND The pancreas is an occasional site of metastases from melanoma. It may be the only location of metastatic disease, but more often the melanoma metastasis to other organs as well. Treatment options are somewhat limited, and the role of operative treatment is poorly defined. CASE OUTLINES Two patients presenting with abdominal pain were found to have pancreatic lesions. A 45-year-old woman had a pylorus-preserving pancreatoduodenectomy for a mass in the head of pancreas; concurrent liver nodules were treated by segmental liver resection. A 55-year-old man had a total pancreatectomy for multiple pancreatic tumours. Both patients gave a history of ocular melanoma, diagnosed >10 years previously. They had no evidence of malignancy elsewhere. Histology of resected specimens confirmed metastatic melanoma with features consistent with an ocular primary. All resection margins were clear of malignancy, and no lymph node metastases were detected. At 6 months follow-up there were no signs of tumour recurrence. DISCUSSION Complete surgical resection offers potential cure in selected patients with metastatic melanoma involving the pancreas, when there is no evidence of widespread disease.

18F‐FDG PET/CT influences management in patients with known or suspected pancreatic cancer

Background: The aims of this study were (i) to assess and validate the incremental information of positron emission tomography/computed tomography (PET/CT) over conventional staging investigations (CSI) and (ii) to assess the management impact of PET/CT in patients with known or suspected pancreatic cancer.

mRNA gene expression correlates with histologically diagnosed chemotherapy-induced hepatic injury

INTRODUCTION Chemotherapy-induced hepatic injuries (CIHI) are an increasing problem facing hepatic surgeons. It may be possible to predict the risk of developing CIHI by analysis of genes involved in the metabolism of chemotherapeutics, previously established as associated with other forms of toxicity. METHODS Quantitative reverse transcriptase-polymerase chain reaction methodology (q-RT-PCR) was employed to quantify mRNA expression of nucleotide excision repair genes ERCC1 and ERCC2, relevant in the neutralization of damage induced by oxaliplatin, and genes encoding enzymes relevant to 5-flurouracil metabolism, [thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD)] in 233 hepatic resection samples. mRNA expression was correlated with a histopathological injury scored via previously validated methods in relation to steatosis, steatohepatitis and sinusoidal obstruction syndrome. RESULTS Low-level DPD mRNA expression was associated with steatosis [odds ratio (OR) = 3.95, 95% confidence interval (CI) = 1.53-10.19, P < 0.003], especially when stratified by just those patients exposed to chemotherapy (OR = 4.48, 95% CI = 1.31-15.30 P < 0.02). Low expression of ERCC2 was associated with sinusoidal injury (P < 0.001). There were no further associations between injury patterns and target genes investigated. CONCLUSIONS Predisposition to the development of CIHI may be predictable based upon individual patient expression of genes encoding enzymes related to the metabolism of chemotherapeutics.

Not all hepatic carcinoids are metastases.

To the Editor, Carcinoids are common gastrointestinal endocrine tumors. A primary hepatic carcinoid is extremely rare and is far more likely to be a metastasis than a true primary tumor. Appropriate investigations are required to exclude a metastasis prior to appropriate intervention. A 51-year-old-man presented with a 1-week history of upper abdominal pain and mild shoulder discomfort. There was no other significant history of note. Examination revealed tenderness in the right upper quadrant and a large abdominal mass. Abdominal ultrasound and computed tomography (CT) identified a 15 ¥ 13 cm low-attenuated mass occupying the right lobe of the liver. Serum bilirubin was slightly elevated at 22 mmol/L (3–17 mmol/L), with the remaining biochemical parameters within normal limits. Alpha-fetoprotein, carcinoembryonic antigen, hepatitis serology, and CT of the chest were normal. Ultrasound-guided fine-needle biopsy of the liver lesion was performed and revealed sheets of tumor cells with round nuclei and delicate cytoplasm. The cells showed areas of acinar arrangement and ribbon formation, with fine cytoplasmic granules suggestive of a neuroendocrine tumor. Subsequent upper and lower gastrointestinal endoscopy and a small bowel series failed to identify a primary gastrointestinal malignancy. At operation, there was a large mass occupying segments 4–8 of the liver. There was no evidence of tumor elsewhere. The patient underwent a right hepatic trisegmentectomy and made a complete recovery. Histopathological examination of the resected specimen revealed a well-circumscribed tumor in a noncirrhotic liver, clear of resection margins. The tumor comprised small uniform cells arranged in a pattern of nests, ribbons, trabeculae, and gland-like structures. Nuclei were round to oval with stippled chromatin and inconspicuous nucleoli. Mitoses were scant. Immunohistochemical staining was positive for neuroendocrine markers, chromogranin A and neuron-specific enolase (Fig. 1). The tumor had features consistent with carcinoid. The patient was admitted 1 year later with adhesive small-bowel obstruction requiring laparotomy and division of adhesions. There was no sign of intra-abdominal malignancy. At 11-year follow-up, there was also no clinical or radiological evidence of tumor recurrence or alternative sites of primary disease. Carcinoid tumors comprise 1–2% of all gastrointestinal malignancies and metastasize to the liver in approximately 5–10% of cases. Godwin et al., in a review of 2837 consecutive patients with carcinoid tumors, did not identify a single liver primary. Sixtyfour cases of primary hepatic carcinoid (including primary neuroendocrine carcinomas) have been previously described in the English literature. However, Soga recently reported 126 cases of primary neuroendocrine carcinomas of the liver, obtained from a Japanese patient database. These tumors occurred more commonly in women than in men (ratio 1.6:1), at a mean age of 49.5 years (range 8–83 years) at diagnosis. An abdominal mass and pain are the most common presenting features of a primary hepatic carcinoid. Evidence of excess hormone production occurs in fewer than a third of cases, with carcinoid syndrome the most common manifestation of endocrine excess when it occurs. Immunostaining for various hormones, par-

Correlations between histopathological diagnosis of chemotherapy-induced hepatic injury, clinical features, and perioperative morbidity.

BACKGROUND Chemotherapy has in some series been linked with increased morbidity after a hepatectomy. Hepatic injuries may result from the treatment with chemotherapy, but can also be secondary to co-morbid diseases. The aim of the present study was to draw correlations between clinical features, treatment with chemotherapy and injury phenotypes and assess the impact of each upon perioperative morbidity. PATIENTS AND METHODS Retrospective samples (n= 232) were scored grading steatosis, steatohepatitis and sinusoidal injury (SI). Clinical data were retrieved from medical records. Correlations were drawn between injury, clinical features and perioperative morbidity. RESULTS Injury rates were 18%, 4% and 19% for steatosis, steatohepatitis and SI, respectively. High-grade steatosis was more common in patients with diabetes [odds ratio (OR) = 3.33, P= 0.01] and patients with a higher weight (OR/kg = 1.04, P= 0.02). Steatohepatitis was increased with metabolic syndrome (OR = 5.88, P= 0.02). Chemotherapy overall demonstrated a trend towards an approximately doubled risk of high-grade steatosis and steatohepatitis although not affecting SI. However, pre-operative chemotherapy was associated with an increased SI (OR = 2.18, P= 0.05). Operative morbidity was not increased with chemotherapy, but was increased with steatosis (OR = 2.38, P= 0.02). CONCLUSIONS Diabetes and higher weight significantly increased the risk of steatosis, whereas metabolic syndrome significantly increased risk of steatohepatitis. The presence of high-grade steatosis increases perioperative morbidity, not administration of chemotherapy per se.

Surgical outcomes for duodenal adenoma and adenocarcinoma: a multicentre study in Australia and the United Kingdom.

Pancreaticoduodenectomy is often required in patients with duodenal adenoma and adenocarcinoma and these patients generally have soft pancreatic texture and small pancreatic ducts, the two most significant factors associated with post‐operative pancreatic fistula (POPF). The aims of the study were to evaluate the rate of POPF and long‐term outcomes for patients with duodenal adenoma and adenocarcinoma who underwent curative resection.