Biomedical subjects
Publications and source records attributed to I Taylor.
Endothelin-1 is a small vasoconstrictor peptide that was first identified in 1988. Here we review the evidence implicating ET-1 in tumorigenesis. In particular, we concentrate on the role of ET-1 in mitogenesis, apoptosis, angiogenesis, tumour invasion and metastasis, and discuss the potential for endothelin-system modulation as an adjuvant therapeutic strategy.
BACKGROUND: Liver resection is the treatment of choice for patients with solitary colorectal liver metastases. In recent years, however, radiofrequency ablation has been used increasingly in the treatment of colorectal liver metastases. In the absence of randomized clinical trials, this study aimed to compare outcome in patients with solitary colorectal liver metastases treated by surgery or by radiofrequency ablation. METHODS: Solitary colorectal liver metastases were treated by radiofrequency destruction in 25 patients. The indications were extrahepatic disease in seven, vessel contiguity in nine and co-morbidity in nine patients. Outcome was compared with that of 20 patients who were treated by liver resection for solitary metastases and had no evidence of extrahepatic disease. Most patients in both groups also received systemic chemotherapy. RESULTS: Median survival after liver resection was 41 (range 0-97) months with a 3-year survival rate of 55.4 per cent. There was one postoperative death and morbidity was minimal. Median survival after radiofrequency ablation was 37 (range 9-67) months with a 3-year survival rate of 52.6 per cent. CONCLUSION: Survival after resection and radiofrequency ablation of solitary colorectal liver metastases was comparable. The latter is less invasive and requires either an overnight stay or day-case facilities only.
BACKGROUND: Postoperative portal vein infusion (PVI) of 5-fluorouracil (5-FU) is a well tolerated and widely applicable treatment for colorectal cancer that might have an enormous public health impact, even if it produced survival benefits of just a few per cent. Very large trials are required to detect such differences, and the Adjuvant X-ray and 5-FU Infusion Study (AXIS) is the largest such trial yet reported. METHODS: Consenting patients with presumed colorectal cancer were randomized to surgery with or without 7 days of PVI (1 g 5-FU plus 5000 units heparin in 1 litre 5 per cent dextrose infused over each 24-h period). In addition, patients with rectal cancer could be randomized to radiotherapy or no radiotherapy to be given either before or after surgery. RESULTS: Between November 1989 and December 1997, 3583 patients were randomized with respect to PVI. The survival hazard ratios (95 per cent confidence interval (c.i.)) in all patients randomized and in the curatively resected subgroup (71.2 per cent of patients) were 1.00 (0.92 to 1.11) and 0.94 (0.83 to 1.06) respectively. Tests for heterogeneity suggested a greater treatment benefit for patients with colonic cancer than for patients with rectal cancer with respect to disease-free survival (hazard ratio 0.79 versus 1.03; P = 0.07), and there was a non-significant trend with respect to overall survival (hazard ratio 0.87 versus 1.03; P = 0.17). No survival benefit was seen in the 761 patients randomized with respect to radiotherapy; although not statistically significant, the impact on local recurrence rates was similar to that reported in the literature. CONCLUSION: No overall benefit of PVI was established in AXIS when colonic and rectal cancers were considered together, but the evidence suggesting a differential treatment effect according to site of cancer in AXIS was strongly supported by a meta-analysis incorporating the previous trials. Combining the data gave hazard ratios of 0.82 and 1.00 for colonic and rectal tumours respectively (test for interaction, P = 0.024), equating to an absolute survival benefit for patients with colonic cancer of 5.8 (95 per cent c.i. 2.8 to 8.5) per cent, a level close to that seen for prolonged systemic therapy.
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Progress in colorectal surgery over the last few years is evident by the growing number of randomised controlled trials reported. We have scrutinised such trials reported over the last year across the entire spectrum of colorectal disease and have presented the significant findings in this trials report.
Myxoid solitary fibrous tumours are a rare morphological sub-type of the rare solitary fibrous tumours. This case report appears to be the first reported ischiorectal occurrence of this rare tumour.
AIMS: To assess outcome in patients treated by a multidisciplinary team, with a combination of liver resection and RF ablation. METHODS: Sixteen unselected patients (f=9; m=7) with colorectal liver metastases who were not suitable for surgery alone, were treated as follows: six had RF ablation at open laparotomy, three patients had synchronous ablation and resection while seven patients had RF ablation after liver resection. Standard liver resection techniques were used. RF was performed using internally cooled, single or cluster electrodes with a high power (200 W) generator. All patients were followed with regular contrast enhanced CT and survival noted. RESULTS: A total of 27 tumours with diameters 1.2-10 cm were treated. Two minor complications were recorded. 2/6 (33%) who had intraoperative RF had incomplete ablation due to large tumour size (6 and 10 cm respectively). Further RF ablation sessions were carried out successfully. 11/16 (69%) are alive at 2 years of whom 7 (44%) have no evidence of residual or recurrent liver disease. CONCLUSION: In our study, RF ablation extends the therapeutic envelope, is an effective local treatment of liver metastases and improves life expectancy.
BACKGROUND: and aims: Positron emission tomography (PET) using (18)F labelled 2-fluoro-2-deoxy-D-glucose ((18)FDG) is an established imaging tool, although the recent development of a biologically stable thymidine analogue [18F] 3'-deoxy-3-fluorothymidine ((18)FLT) has allowed PET to image cellular proliferation by utilising the salvage pathway of DNA synthesis. In this study, we have compared uptake of (18)FLT and (18)FDG with MIB-1 immunohistochemistry to evaluate the role of PET in quantifying in vivo cellular proliferation in colorectal cancer (CRC). PATIENTS AND METHODS: Patients with resectable, primary, or recurrent CRC were prospectively studied. Thirteen lesions from 10 patients (five males, five females), median age 68 years (range 54-87), were evaluated. Patients underwent (18)FDG and (18)FLT PET scanning. Tracer uptake within lesions was quantified using standardised uptake values (SUVs). Histopathological examination and MIB-1 immunohistochemistry were performed on all lesions, and proliferation quantified by calculating a labelling index (% of MIB-1 positively stained nuclei within 1500 tumour cells). RESULTS: Histology confirmed adenocarcinoma in 12 of 13 lesions; the remaining lesion was reactive. All eight extrahepatic lesions were visualised using both (18)FLT and (18)FDG. Three of the five resected liver metastases were also avid for (18)FLT and showed high proliferation, while the remaining two lesions which demonstrated no uptake of (18)FLT had correspondingly very low proliferation. There was a statistically significant positive correlation (r =0.8, p<0.01) between SUVs of the tumours visualised with (18)FLT and the corresponding MIB-1 labelling indices. No such correlation was demonstrated with (18)FDG avid lesions (r =0.4). CONCLUSIONS: (18)FLT PET correlates with cellular proliferation markers in both primary and metastatic CRC. This technique could provide a mechanism for in vivo grading of malignancy and early prediction of response to adjuvant chemotherapy.
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OBJECTIVE: To evaluate the efficiency of the criteria proposed by the National Referral Guidelines at selecting patients with lower gastrointestinal tract cancer for urgent outpatient assessment when compared with the standard method for prioritization. PATIENTS AND METHODS: Consecutive patients aged 50 and over referred to a colorectal unit were offered urgent or non-urgent outpatient appointments on the basis of the contents of the referral letter. Clinical information obtained during the outpatient consultation was used to identify those patients that satisfied the guideline criteria for urgent referral. Patients were investigated and the findings recorded. RESULTS: Of 247 patients who completed their investigations 18 were found to have lower gastrointestinal tract cancer. Urgent outpatient appointments were offered to 115 patients of whom 14 had cancer (P = 0.0067, sensitivity=78%). A total of 119 patients satisfied the guideline criteria for urgent referral, including 17 of the patients who were found to have cancer (P < 0.0001, sensitivity=94%). CONCLUSION: The criteria used in the guidelines provide an effective method for selecting patients with cancer for urgent assessment. Application of the guidelines by general practitioners can be recommended.
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The absence of perivascular nerves in tumour vessels suggests that endothelium derived vasoactive substances [nitric oxide (NO) and endothelin-1 (ET-1)] may be key factors in controlling tumour blood flow during tumour growth and metastasis. We have studied the ultrastructural distribution and immunoreactivity of different NO synthase (NOS) isoforms and ET-1 in human colorectal metastatic liver tumour tissues using pre-embedding peroxidase-anti-peroxidase and post-embedding immunoelectron microscopic triple gold labelling techniques. Dramatically lower NOS 1 immunoreactivity was observed in tumour vascular endothelium (1-3% and 15-20% in tumour and normal groups, respectively). As compared to control groups there were significantly less NOS3 immunopositive EC in metastatic tumour vessels (45-50% and 1-3% in normal and tumour groups, respectively). A striking rise in NOS2 was observed in tumour vessel endothelium (< 1% in normal and 65-70% in tumour vessel endothelium). ET-1 immunoreactivity levels were also significantly higher in tumour vessel endothelium (85-90% in tumour, 15-20% in normal group). This increased expression of NOS2 and ET-1 immunoreactivity was accompanied by the increased expression of three NOS isoforms and ET-1 immunoreactivity in liver parenchymal cells. These data suggest that metastatic tumour vessel endothelium is characterized by increased expression of NOS2 and ET-1 and by decreases in NOS1 and NOS3. These characteristics are associated with the overexpression of all three NOS isoforms and ET-1 immunoreactivity in non-vascular cells.
BACKGROUND: There is no consensus as to the most appropriate treatment for the varied and often complicated presentations of hydatid disease in Britain. We looked at our own results over a 12-year period to see if a consistent and logical plan had emerged. PATIENTS AND METHODS: 70 patients presenting between 1986 and 1998 were analysed retrospectively, with regard to their presentation, diagnosis, treatment and outcome, with particular reference to the use of chemotherapy, and to the difficulties of post-treatment assessment by serology and imaging. RESULTS: 37 patients had been treated previously. 35 had hepatic cysts and 26 multiple cysts. 4 patients were treated by surgery alone, 44 by chemotherapy and surgery, and 14 by chemotherapy alone. The combined use of albendazole and praziquantel pre-operatively reduced significantly the number of cysts that contained viable protoscolices: 1/25 versus 5/8 that received albendazole alone (P = 0.00013). During the 12-year period, it became our policy to aim for 3 months drug treatment (albendazole throughout with praziquantel for 2 weeks), re-assess and proceed either to surgery or to continue with chemotherapy. CONCLUSIONS: It is possible to construct an algorithm for the management of patients with hydatid disease by chemotherapy and surgery, but the assessment of results by indirect techniques remains difficult.
Endothelin-1 (ET-1) is a vasoconstrictor peptide which stimulates proliferation in vitro in different cell types, including colorectal cancer cells. Raised ET-1 levels have been detected both on tissue specimens and in the plasma of patients with cancers. To investigate the role of ET-1 in colorectal cancer: (i) ET-1 plasma levels in patients with colorectal cancer were measured by radioimmunoassay: group 1 = controls (n = 22), group 2 = primary colorectal cancer only (n = 39), group 3 = liver metastases only (n = 26); (ii) ET-1 expression in primary colorectal cancer specimens (n =10) was determined immunohistochemically and (iii) the effect of intraportally infused antagonists to the two ET-1 receptors, ET(A) and ET(B), on the growth of liver metastases in a rat model was assessed. ET-1 plasma levels were significantly increased in both patients with primary tumour and patients with metastases, compared to controls (P < 0.01, 3.9 +/- 1.4, 4.5 +/- 1.5, vs. 2.75 +/- 1.37 pg/ml, respectively). Immunohistochemically, strong expression of ET-1 was found in the cytoplasm, stroma and blood vessels of cancers, unlike the normal colon where only the apical layer of the epithelium, vascular endothelial cells and surrounding stroma were positively stained. In the rat model, there was significant reduction in liver tumour weights compared to controls, following treatment with the ET(A) antagonist (BQ123) 30 min after the intraportal inoculation of tumour cells (P < 0.05). These results suggest ET-1 is produced by colorectal cancers and may play a role in the growth of colorectal cancer acting through ET(A) receptors. ET(A) antagonists are indicated as potential anti-cancer agents.
Positron emission tomography (PET) has been successfully used to image colorectal cancer (CRC). This study evaluated the accuracy of 2-[(18)F]-fluoro-2-deoxy- D-glucose (FDG) PET for the detection and staging of recurrent CRC and the consequent impact on clinical management. Forty-two patients previously treated for CRC were investigated for suspected recurrence and, if recurrence was confirmed, the extent of disease was evaluated. All patients underwent whole-body FDG-PET and computed tomography (CT) scan and results were compared to assess sensitivity, specificity and diagnostic accuracy for each modality. We then assessed the FDG-PET directed alteration in clinical management from that planned on the basis of spiral CT results. FDG-PET was more sensitive (93%) than CT (73%) for detection of recurrence (specificity 58% and 75%, respectively). FDG-PET yielded a correct diagnosis in 35 (83%) out of 42 patients, while CT did so in 31 patients (74%). FDG-PET was more accurate than CT for staging local recurrence (sensitivity 100%, specificity 86% with FDG-PET vs 75% and 100%, respectively, with CT) and CRC liver metastases (sensitivity 100% vs 45%; specificity 100% for both). Overall, PET upstaged 8 out of 30 patients (27%) and altered patient management in 16 (38%) cases. This study confirms that FDG-PET is more sensitive than CT for the detection and staging of recurrent CRC. The results also indicate that FDG-PET is an accurate means of selecting appropriate patients for operative treatment. When applied to routine clinical practice, patient management is altered.
To gain a better understanding of the effects of chronic stimulation on mammalian muscles we needed to generate patterns of greater variety and complexity than simple constant-frequency or burst patterns. We describe here two approaches to the design of implantable neuromuscular stimulators that can satisfy these requirements. Devices of both types were developed and used in long-term experiments. The first device was based on a semi-custom Application Specific Integrated Circuit (ASIC). This approach has the advantage that the circuit can be completely tested at every stage of development and production, assuring a high degree of reliability. It has the drawback of inflexibility: the patterns are produced by state machines implemented in silicon, so each new set of patterns requires a fresh production run, which is costly and time-consuming. The second device was based on a commercial microcontroller (Microchip PIC16C84). The functionality of this type of circuit is specified in software rather than in silicon hardware, allowing a single device to be programmed for different functions. With the use of features designed to improve fault-tolerance we found this approach to be as reliable as that based on ASICs. The encapsulated devices can easily be accommodated subcutaneously on the flank of a rabbit and a recent version is small enough to implant into the peritoneal cavity of rats. The current devices are programmed with a predetermined set of 12 patterns before assembly; the desired pattern is selected after implantation with an electronic flash gun. The operating current drain is less than 40 microA.
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An elderly female patient presenting for phaco-emulsification and intra-ocular lens implant under local anaesthesia developed pulmonary oedema after surgery and underwent emergency tracheal intubation. The pulmonary oedema may have been caused by her omission of routine oral diuretic medication before surgery and having to lie flat for the procedure. The patient had not been fasted before surgery, as is accepted practice in many hospitals. This made emergency tracheal intubation potentially hazardous. The patient made a full recovery. The issues of pre-operative assessment, fasting and the withholding of diuretic medication before elective eye surgery under local anaesthesia are discussed.