Biomedical subjects
Publications and source records attributed to D J Sherlock.
Monthly intravenous pegylated liposomal doxorubicin (PLD) 50 mg m(-2), although well tolerated, showed almost no activity in this phase II study of 16 patients with advanced hepatocellular carcinoma with a response rate of 0%, stable disease 19%, median time to progression of 2.4 months, 1-year survival of 25% and median survival of 6.5 months.
Despite improvements in treatment, the 5-year survival for metastatic colorectal cancer remains poor. Novel approaches such as gene immunotherapy are being investigated to improve treatment. Retroviral gene transfer methods have been shown to transduce primary human T lymphocytes effectively resulting in the expression of therapeutic genes. However, a number of defects have been identified in T lymphocytes isolated from patients bearing tumour, which may have critical implications for the development of gene-targeted T cells as an anticancer therapy. To address this issue, primary T lymphocytes were isolated from patients with advanced colorectal cancer and tested for their ability to be transduced and to express subsequently a chimeric immune receptor consisting of a single-chain antibody fragment antigen-binding moiety specific for carcinoembryonic antigen (CEA) fused to the T cell receptor (TCR) CD3zeta chain. In 10 out of 10 patients, T lymphocytes were transduced, expanded in the absence of selection and tested for functional activity against CEA-expressing tumour cells. In each case, functional-specific cytotoxic activity was observed. Negligible activity was found in control cultures. This study highlights the feasibility of patient-derived T lymphocytes as a source of immune cells for autologous gene immunotherapy approaches.
BACKGROUND: This paper reports a 7-year experience of cryoablation for colorectal and non-colorectal liver metastases. METHODS: A retrospective review was undertaken of patients treated in two adjacent UK centres in the north-west of England. RESULTS: Over a 7-year period (1993-2000), 57 patients underwent cryotherapy for malignant hepatic tumours (41 colorectal, 16 non-colorectal). In the patients with colorectal metastases, preoperative carcinoembryonic antigen (CEA) levels fell significantly, from a mean of 444.1 to 6.22 micro g/l (P = 0.002). One patient died, two developed cryoshock and six had cardiorespiratory complications. All patients with colorectal metastases subsequently received 5-fluorouracil-based chemotherapy. The remaining 16 patients with non-colorectal tumours (seven neuroendocrine metastases, five hepatocellular carcinomas, three sarcomas, one cholangiocarcinoma) all received cryotherapy alone, with no major complications. The median survival for patients with non-colorectal metastases was 37 months, compared with 22 months for those with colorectal metastases (P = 0.005). CONCLUSION: Hepatic cryotherapy is effective and safe, as demonstrated by the significant reduction in postoperative CEA concentration and the low risk of complications. However, this initial short-term success was not reflected in 5-year survival rates. Cryotherapy for non-colorectal metastases had a greater long-term survival benefit and is a useful means of controlling symptoms.
Primary malignant mesenchymal tumors of the liver are extremely rare. We report a case of a primary liposarcoma in the right hepatic lobe of a 50-year-old man. Sonography showed a poorly defined, lobulated, infiltrating echogenic tumor with shadowing. Within the tumor were hyperechoic and hypoechoic foci thought to represent areas of hemorrhage and necrosis. Color Doppler sonography showed the mass to be avascular. A low-attenuation mass of fat density was confirmed on CT. The resected tumor was reasonably well circumscribed, with demonstrable infiltration of the liver parenchyma. Histologic analysis showed liposarcoma with high-grade sarcomatous features.
The shortage of paediatric liver donors has led to the use of reduced size hepatic allografts. Between July 1987 and July 1990, 30 reduced size orthotopic liver transplantations were performed in 24 children aged between 3 months and 7 years. All patients were in advanced chronic or acute liver failure and were considered unlikely to survive for long enough for a size-matched donor to become available. The most common indication was biliary atresia. The median intraoperative blood loss was 75 (range 13-1015) ml kg-1. Nine patients have died and seven have undergone retransplantation, four successfully. Seven patients had portal vein hypoplasia with a high graft failure rate due to ischaemic infarction. There was significant morbidity from biliary tract complications, leading to further operations in four cases. The 1-year actuarial survival rate was 62 per cent.
A modification of the technique of liver transplantation by the face-à-face venacavaplasty is described and the use in four patients reported. This technique enables livers with a small vena cava to be inserted in an anatomic fashion and should help increase the use of such grafts where disparity between vessel size exists.
Over a 10-year period from 1980, 46 patients with liver injuries were referred after primary admission to other hospitals. Previous surgery had been performed in 40 cases and the predominant reasons for referral were uncontrollable bleeding and postoperative sepsis with biliary leakage. Of 30 such cases, 19 were treated by liver resection; all were of a limited nature and no major hepatectomies were performed. Only two deaths occurred in these patients and this low mortality rate supports our conservative approach to liver trauma. Other reasons for referral were late biliary stenosis, complicated penetrating injury and intrahepatic haematoma. Three cases were referred with postoperative hepatic failure; two responded to resection of infected necrotic tissue and liver transplantation was attempted in the third. Injuries to liver segments 6 and 7 were those most frequently referred for assistance with bleeding, and all patients were safely transferred after intra-abdominal packing. This injury is particularly suitable for resection by segmentectomy rather than a formal hepatectomy, which has been associated with a high mortality rate in trauma cases. Further patients with intractable injuries might be salvaged by liver transplantation.
Over 12 years, 22 patients with the Budd-Chiari syndrome were treated surgically. Eighteen underwent a mesenterico-caval shunt (MCS); two, a side-to-side portacaval shunt; one, a mesenterico-atrial shunt (MAS); and one, a liver transplantation (OLT). One patient died after operation from the precipitating condition, and two MCS grafts that thrombosed were restored. All 21 surviving patients remain well, free from ascites, and all shunts are patent after a mean follow-up of 5.6 +/- 1 years, five patients with more than 10 years' follow-up. This long-term survival achieved by portasystemic shunts suggests that they have a major role in the treatment of the Budd-Chiari syndrome. The authors prefer the mesenterico-caval shunt using a jugular graft. This ensures a total portasystemic shunt, avoids subhepatic surgery, and reduces the long-term risk of prosthetic graft thrombosis. The MAS was reserved for cases with complete caval thrombosis. Patients with significant degrees of caval compression were satisfactorily decompressed by MCS. In patients not promptly treated, the disease progresses to cirrhosis, and such patients must be evaluated for transplantation similarly to those with other hepatopathies.
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Malignant change occurring at the site of a stoma in two patients with proved Crohn's disease is described. Patients with ulcerative colitis have an increased risk of colonic malignancy and Crohn's disease is also associated with both small and large bowel carcinoma. Most previous reports of stomal carcinoma have been associated with ulcerative colitis although Crohn's disease seems to carry a greater risk of associated small bowel carcinomas. This is the first report of stomal carcinoma complicating Crohn's disease. Epithelial dysplasia is associated with gastrointestinal carcinomas in both ulcerative colitis and Crohn's disease and a dysplasia-carcinoma sequence has been suggested as the origin of these tumours. In both our patients with stomal adenocarcinoma, dysplasia was identified in adjacent tissues, which suggests a similar mechanism. Malignant change should be suspected if epithelial dysplasia is discovered in a biopsy specimen from the mucosa of an ileostomy in Crohn's disease, and this risk is increased if the dysplasia is of a high grade.
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The development of a malignant soft tissue tumour (malignant fibrous histiocytoma) in a surgical wound is reported. Although rare, this occurrence has important diagnostic implications and the management is discussed.
Intestinal handling of water and electrolytes and motility were monitored in conscious dogs with chronic 25-cm Thiry-Vella loops of proximal jejunum. Absorption/secretion was quantitated using a neutral isosmotic perfusate containing [14C]polyethylene glycol as a recovery marker. Under basal conditions the animals absorbed water, Na+ and Cl-, while there was no net action on K+. Intravenous serotonin infusion (30 micrograms/kg/min) increased circulating levels of serotonin to a mean of 1556 +/- 191 ng/ml within 15 min of the commencement of the infusion. The infusion induced a significant secretion of water (mean -73 +/- 7 microliters/min) and electrolytes (sodium -10.4 +/- 0.7 muEq/min; potassium -0.8 +/- 0.05 muEq/min; chloride -12.4 +/- 1.0 muEq/min) in the dogs and all showed signs of hyperserotoninemia (salivation, loose bowel movements, tachypnea). After administration of ketanserin (33 micrograms/kg/min), a significant reduction in secretion was demonstrated (water +20.8 +/- 16.1 microliters/min; sodium 7.2 +/- 3.0 muEq/min; potassium -0.02 +/- 0.1 muEq/min; and chloride -1.9 +/- 2.8 muEq/min) as well as reduced motor activity. A similar antisecretory effect was demonstrated with atropine infusion (20 micrograms/kg/min), although this drug had a far more significant effect on the gastrointestinal motility recorded in the loop. Infusion of methysergide (33 micrograms/kg/min) did not significantly affect secretion (water -111.4 +/- 59.0 microliter/min; sodium -17.4 +/- 9 muEq/min; potassium -0.9 +/- 0.4 muEq/min; chloride -20.3 +/- 7.0 muEq/min). These results suggest possible actions which may make ketanserin useful in the treatment of symptoms of the carcinoid syndrome.
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58 (37 per cent) of the 155 patients over the age of 60 years presenting with appendicitis at East Birmingham Hospital from 1970 to 1982 were found to have perforated appendices; the corresponding proportion under the age of 60 was 346 out of 3608 patients (10 per cent), the difference being statistically significant (P less than 0.001). The delay before surgery and the length of in-patient treatment were significantly longer in the group who perforated, and the mortality was greater, although not achieving significance. Examination of the yearly incidence reveals neither an increasing trend of appendicitis in elderly patients, nor an increase in the perforation rate over the period studied. Delay, at all stages, appears to be the major factor responsible for the higher rate of perforation in this age group; only by an increased awareness of appendicitis in the elderly can this risk be minimized.
A case of malignant transformation in established secondary hyperparathyroidism presenting as tertiary hyperparathyroidism is reported. Although rare, this occurrence has important medical and surgical implications.
A prospective study of emergency operations was performed over three months in a district general hospital. Before starting surgery surgeons completed a questionnaire recording clinical details together with time of admission and were asked to state whether in their opinion the case could be safely deferred until the next morning assuming operating time was available. Of 251 operations performed, forms were completed for 244. According to the surgeons, 62 could have been safely deferred, and subsequent independent analysis indicated a further 24 could also have been safely postponed, giving a total of 86 cases (35%). Of the remainder, 71 were started between 2300 and 0900, and of these 51 (71%) were major operations requiring an experienced surgeon. The results suggest that, although the volume of nocturnal major surgery could not be reduced, the introduction of a daily emergency theatre session for cases seen during the day and those which could be deferred from the previous night would appreciably reduce the overall workload of nocturnal surgery at present done by the resident junior staff. This study will have important implications if, as has been suggested, the number of junior medical staff on call at night for emergencies is reduced.