Christopher Christophi

The renin–angiotensin system and malignancy

The renin-angiotensin system (RAS) is usually associated with its systemic action on cardiovascular homoeostasis. However, recent studies suggest that at a local tissue level, the RAS influences tumour growth. The potential of the RAS as a target for cancer treatment and the suggested underlying mechanisms of its paracrine effects are reviewed here. These include modulation of angiogenesis, cellular proliferation, immune responses and extracellular matrix formation. Knowledge of the RAS has increased dramatically in recent years with the discovery of new enzymes, peptides and feedback mechanisms. The local RAS appears to influence tumour growth and metastases and there is evidence of tissue- and tumour-specific differences. Recent experimental studies provide strong evidence that drugs that inhibit the RAS have the potential to reduce cancer risk or retard tumour growth and metastases. Manipulation of the RAS may, therefore, provide a safe and inexpensive anticancer strategy.

Disturbances of the microcirculation in acute pancreatitis

Severe acute pancreatitis is characterized by pancreatic necrosis, resulting in local and systemic inflammation. Pancreatitis affects both the systemic and pancreatic vasculature. This review focuses on the underlying processes involved in the changes of microvascular anatomy following acute pancreatitis.

Review of experimental animal models of acute pancreatitis

The underlying mechanisms involved in the pathogenesis of acute pancreatitis are ill understood. The mortality rate of this disease has not significantly improved over the past few decades. Current treatment options are limited, and predominantly aimed at supportive therapy. A key feature of severe acute pancreatitis is the presence of extensive tissue necrosis with both local and systemic manifestations of inflammatory response syndromes. A better understanding of the underlying pathophysiology of severe acute pancreatitis may lead to more targeted therapeutic options, potentially leading to improved survival. Animal models of acute pancreatitis are therefore an essential investigative tool for these aims to be achieved. This review discusses the suitability of recent non-invasive models of acute pancreatitis such as hormone-induced, alcohol-induced, immune-mediated, diet-induced, gene knockout and L-arginine; and invasive models including closed duodenal loop, antegrade pancreatic duct perfusion, biliopancreatic duct injection, combination of secretory hyperstimulation with minimal intraductal bile acid exposure, vascular-induced, ischaemia/reperfusion and duct ligation.

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.

Monitoring response to therapy in melanoma by quantifying circulating tumour DNA with droplet digital PCR for BRAF and NRAS mutations

We assessed the utility of droplet digital PCR (ddPCR) to evaluate the potential of using circulating tumour DNA (ctDNA) as a post therapy monitoring tool in melanoma by comparing it to serum LDH levels and RECIST scores. ddPCR was shown to be reliable in distinguishing mutant from wild type alleles with no false positives. Subsequently, we quantified ctDNA (V600EBRAF,V600KBRAF or Q61HNRAS) in 6 stage IV melanoma patients across several time points during their treatment course. All tested patients had detectable ctDNA, which exhibited dynamic changes corresponding to the changes in their disease status. The ctDNA levels fell upon treatment response and rose with detectable disease progression. In our group of patients, ctDNA was more consistent and informative than LDH as a blood-based biomarker. In addition, BRAF mutant ctDNA as detected by ddPCR could be used diagnostically where the tumour block was unavailable. In conclusion, this study demonstrates the applicability of using ddPCR to detect and quantify ctDNA in the plasma of melanoma patients.

Aneurysms of the splenic artery – A review

Splenic artery aneurysm is the third most common intra-abdominal aneurysm with a prevalence as high as 10% in some studies. Widespread use of abdominal imaging has resulted in the increasing detection of asymptomatic incidental aneurysms. In this manuscript we review the changing incidence, risk factors and evolving therapeutic options in the era of minimally invasive therapy and have developed a treatment algorithm for practical use. Aneurysms with a low risk of rupture may be treated conservatively but require regular imaging to ascertain progress. Available evidence suggests that splenic artery aneurysms that are symptomatic, enlarging, more than 2 cm in diameter or those detected in pregnancy, childbearing age or following liver transplantation are at high risk of rupture and should undergo active treatment. Prophylactic screening should be reserved for those with multiple risk factors, such as pregnancy in liver transplant recipients. All false aneurysms should also be treated. The primary therapeutic approach should be endovascular therapy by either embolization or stent grafting.

Hyperbaric oxygen therapy for malignancy: a review.

One unique feature of tumors is the presence of hypoxic regions, which occur predominantly at the tumor center. Hypoxia has a major impact on various aspects of tumor cell function and proliferation. Hypoxic tumor cells are relatively insensitive to conventional therapy owing to cellular adaptations effected by the hypoxic microenvironment. Recent efforts have aimed to alter the hypoxic state and to reverse these adaptations to improve treatment outcome. One way to increase tumor oxygen tensions is by hyperbaric oxygen (HBO) therapy. HBO therapy can influence the tumor microenvironment at several levels. It can alter tumor hypoxia, a potent stimulus that drives angiogenesis. Hyperoxia as a result of HBO also produces reactive oxygen species, which can damage tumors by inducing excessive oxidative stress. This review outlines the importance of oxygen to tumors and the mechanisms by which tumors survive under hypoxic conditions. It also presents data from both experimental and clinical studies for the effect of HBO on malignancy.

Effect of ACE inhibitors and angiotensin II receptor antagonists in a mouse model of colorectal cancer liver metastases

Background and Aims:  Angiotensin converting enzyme inhibitors (ACE‐I) and angiotensin II type I receptor (AT1R) antagonists are commonly used as a treatment for hypertension. Recent experimental and population studies have suggested that these agents may exert an inhibitory effect on malignancy, possibly through anti‐angiogenic pathways. The aim of this study was to investigate the effect of an ACE‐I (captopril) and an AT1R antagonist (irbesartan) in colorectal cancer liver metastases.

Characterization of an animal model of hepatic metastasis

The experimental study of possible therapies for control of the growth of liver metastases requires the availability of a model which is technically feasible and appears to exhibit growth characteristics similar to human tumours. We report on the development of an intrasplenic injection model of liver metastases, and describe the histology, growth pattern and blood flow demonstrated by light microscopy, stereology and laser Doppler flowmetry. The hepatic metastases were induced in mice by intrasplenic injection of dimethylhydrazine (DMH) induced primary colonic carcinoma cells (106 cells in 1 mL). The growth and development of metastases was studied over a period of 3 weeks at predetermined time points. Tumour cells were visible in the hepatic sinusoids by day 7 by light microscopy. Macroscopically visible tumours with a diameter of 0.18 ± 0.02 cm (mean ± s.d.) were seen by day 10. By this time the tumours had derived a blood supply from the hepatic sinusoids adjacent to the tumour periphery. With further vascularization the tumours reached a diameter of 0.96 ± 0.50 cm by day 22. Metastatic growth was quantitated by stereological analysis of tumour volume in relation to non‐diseased hepatic tissue. Normal mouse liver had a mean volume of 1.13 ± 0.14 cm3. Tumour growth occurred in three phases. During the initial slow phase the volume of metastases increased from 0.03 ± 0.02 cm3 at day 10 to 0.22 ± 0.24 cm3 by day 16. Rapid tumour growth, occurring over the next 3 days, constituted the intermediate phase with metastatic volume reaching 1.21 ± 0.74 cm3 by day 19 (P= 0.0003 compared with day 16). This growth was followed by a plateau phase when the metastatic volume was 1.40 ± 0.55 cm3 at day 22. The volume of total liver and of tumour necrosis followed a similar growth pattern. A necrotic tumour volume of 0.004 ± 0.006 cm3 first seen on day 10 increased to 0.05 ± 0.06 cm3 by day 16, and to 0.25 ± 0.20 cm3 by day 22 (P=0.0022 compared with day 16). The blood flow in metastases measured by laser Doppler flowmetry was lower compared to the non‐diseased liver. Tumour blood flow, expressed as a percentage of normal liver blood flow, was 63.31 ± 26.28% at day 10 and diminished to 27.91 ± 8.99% by day 22, with an increase in tumour size and age. The decrease in flow was significant between days 13 and 16 (P= 0.0015). This intrasplenic mouse model of metastases is reproducible and should prove useful in the study of treatment of hepatic metastases.

Interstitial laser thermotherapy for liver tumours

Primary hepatocellular carcinoma (HCC) and metastases from colorectal cancer are the most common malignant liver tumours. Surgical resection is the optimum treatment in suitable patients. Interstitial laser thermotherapy (ILT) is gaining acceptance for the treatment of irresectable liver tumours and as a potential alternative to surgery. An understanding of the principles of therapy and review of clinical outcomes may allow better use of this technology.