Biomedical subjects
Publications and source records attributed to N Tait.
A case of Cholangitis Glandularis Proliferans (CAGP) in association with a cholangiocarcinoma of the common bile duct as described. This is the eighth case of CAGP described and the second association with cholangiocarcinoma.
We identified 10 patients with symptoms beginning before the age of 20 years in a group of 69 patients with proven chronic pancreatitis. Six of the 10 patients were women. There was a family history of pancreatitis in three patients and alcohol exposure in seven patients. Three patients were dependent on narcotics at the time of presentation. Six of the 10 patients had pancreatic duct dilatation to 10 mm or more in diameter during observation. These six patients underwent pancreaticojejunostomy, with clinical improvement in five patients. The median time of follow-up was 19 years from presentation. No patient developed diabetes and one developed malabsorption. Only three patients were free of pain, but four other patients had only mild episodes that rarely required hospital admission. One patient died of metastatic abdominal carcinoma of unknown origin 51 years after developing familial pancreatitis. Chronic pancreatitis beginning at a young age is sufficiently common to merit special awareness. It is compatible with prolonged survival, and pancreaticojejunostomy may help if the pancreatic duct reaches sufficient size. The disease does not seem to burn out with time.
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Two cases of Dieulafoy's ulcer are reported. Diagnosis was delayed but successful surgical treatment was achieved once the lesion was located by palpation.
Between January 1981 and July 1991, 61 patients with hepatic haemangiomata were examined at Westmead Hospital. There were 14 males (22%) and 47 females (78%). The age range was 26-85 years with a median of 49 years. Forty-one had abdominal symptoms but these could be attributed to a haemangioma in only seven cases. There was at least one subcapsular lesion in 17 (28%). Six of the seven symptomatic lesions were subcapsular and five of these were giant haemangiomata (i.e. more than 4 cm in greatest diameter). One large symptomatic lesion was intrahepatic. No association was observed between hepatic haemangiomata and other hepatic or extrahepatic diseases. Haemangiomata were resected from six patients, four of whom were symptomatic. Symptoms improved in all four but did not resolve completely in any. Follow-up ranged from nil in five patients to 108 months in one. The median follow-up was 12 months after initial diagnosis. Ten patients showed evidence of change in their lesions or symptoms while under observation. Only three had worsening symptoms or suspected change in size of a haemangioma. This study highlights the benign, static nature of most hepatic haemangiomata. When this lesion is suspected, the diagnosis should be confirmed with ultrasound (US) and labelled red blood cell scanning (RBCS). Referral for evaluation by a specialist hepatobiliary surgery unit is necessary when symptoms are intolerable, increasing size is definitely demonstrated or the diagnosis is uncertain and cannot be established without specialized investigations. Bleeding into or from these lesions is rare.
Iatrogenic injuries to the extrahepatic biliary tract continue to occur and result in significant morbidity. Over the last 10 years, 26 patients have been referred to Westmead Hospital for management of iatrogenic biliary tract injuries. Of these injuries, 22 occurred during cholecystectomy, three during hepatectomy and one during a pancreaticoduodenectomy. The principles of avoidance and repair are discussed. It is concluded that these injuries, although uncommon, continue to occur and that the best treatment results are achieved in specialized hepatobiliary units.
Amongst 17 patients with hepatic focal nodular hyperplasia (FNH) encountered at Westmead Hospital between 1981 and 1990, FNH was found in association with hepatocellular carcinoma (HCC) in three (3/17), one male and two females, one of whom also had peliosis and an hepatic adenoma. FNH was also found in association with other conditions which may affect hepatic function, structure or circulation, including chronic obstructive airways disease (2), congestive cardiomyopathy (1), chronic active hepatitis (1), granulomatous hepatitis (1), coeliac artery stenosis (1) and metastatic malignant melanoma (1). This report, derived from our experience with FNH over 10 years draws attention to a possible link between FNH, hepatic malignancy and conditions which may disturb the hepatic circulation. We suggest that patients with FNH should be investigated thoroughly and an aggressive management policy should be adopted.
Leucovorin enhances the cytotoxicity of fluorouracil (5-FU) in patients with colorectal cancer and may increase the efficacy of combination chemotherapy regimens containing 5-FU. To determine the maximum tolerated dose of 5-FU with leucovorin for use in combination with cyclophosphamide and doxorubicin, we conducted a phase I/II trial in 20 patients. The doses of leucovorin (200 mg/m2 on days 1-5), cyclophosphamide (500 mg/m2 on day 1), and doxorubicin (40 mg/m2 on day 1) were held constant, while the dose of 5-FU was escalated in cohorts of patients beginning at 150 mg/m2 on days 1-5. Cycles were repeated every 3 weeks. Significant mucositis, diarrhea, and myelosuppression were infrequently observed in patients receiving up to 250 mg/m2 5-FU on days 1-5. In contrast, at a dose of 300 mg/m2 on days 1-5, three of six patients had granulocyte count nadirs of less than 500/microL during the first cycle of therapy, and two of these three had platelet counts of less than 25,000/microL. In addition, two patients treated at this dose had significant mucosal toxic effects, and three had insufficient recovery to permit a second course by day 22. Among 14 patients with assessable breast cancer, there were one complete and nine partial responses (response rate 71%). Leucovorin modulation of 5-FU can be safely incorporated into combination chemotherapy with cyclophosphamide and doxorubicin and provides a highly active regimen for treatment of metastatic breast cancer. Further study will be required to determine whether the addition of leucovorin significantly enhances the activity of this regimen.
A dose-response relationship has been suggested for medroxyprogesterone acetate in the treatment of advanced breast cancer. To determine the tolerability and efficacy of increasing doses of megestrol acetate in the treatment of metastatic breast cancer, we conducted a phase I/II study among 57 patients. Three patients each received 480, 800, and 1280 mg/d; 48 patients received 1600 mg/d. Of the 57 patients, 56 patients had had disease progression on prior hormone therapy, chemotherapy, or both. Twenty-seven patients had previously received standard-dose MA (160 mg/d). Among the 37 patients with measurable disease, high-dose megestrol acetate (HDMA) produced 6 (16%) complete responses (CRs) and 6 (16%) partial responses (PRs); 11 patients achieved stable disease (SD). HDMA resulted in improvement or stabilization in 12 of the 20 patients with evaluable, non-measurable disease. There were no responses among the 6 patients with liver metastases. Among the 27 patients who were previously treated with standard-dose MA, including 9 patients with primary treatment failure, HDMA resulted in 1 CR, 3 PRs, and 10 SD. Toxicities, which were mild and reversible, included fluid retention, hypertension, hyperglycemia, and mild congestive heart failure. Two patients had superficial phlebitis. The most profound side effect was weight gain which occurred in 43 patients (75%). This study suggests a dose-response relationship for MA in the treatment of advanced breast cancer. A randomized trial to determine the optimal dose is ongoing.
In 5 years, 64 solid hepatic lesions have been referred for diagnosis and management which have been found unexpectedly on organ imaging in well patients. We have called this lesion a "dystychoma". Patients have undergone a two phase investigation programme which allows a diagnosis without admission to hospital in about 50% of cases. About three quarters of patients (47/64) have had non-neoplastic lesions, and about half (33/64) have had haemangiomas. About one patient in four (17/64) has had a neoplasm, and the neoplasm has been malignant in about one in six (11/64) of all patients. We stress the need to pursue the diagnosis in these patients. There were no reliable clinical, biochemical or imaging characteristics which individually distinguished benign from malignant lesions. Age over 55 years, an enlarged liver or a palpable liver mass and a raised serum alkaline phosphatase were all significantly more frequent with malignant tumours. The risk of malignancy rose with the number of risk factors, and all patients with all three risk factors had malignant tumours. Only 11 of the 64 patients were judged to have benefited by significant increase in quality or quantity of life as a result of what was frequently inappropriate organ imaging. There is no strong argument for replacing history taking and physical examination by CT scanning, ultrasound examination or other organ imaging.
The extreme anorexia and cachexia associated with cancer and other disease states often have important physical and psychologic impact on both patients and their families. Weight gain resulting from megestrol acetate therapy in breast cancer patients suggests that progestins may be useful for alleviation of disease-associated appetite and weight loss. Early breast cancer experience, as well as preliminary data from a randomized, placebo-controlled trial of high-dose megestrol acetate in cancer anorexia and wasting, is therefore reviewed. Although the precise mechanism by which megestrol acetate exerts its effect remains unclear, weight gain was observed in 75% of patients in the high-dose study and in nearly all of those who remained on therapy for 6 weeks. It was concluded that, although megestrol acetate cannot be expected to directly affect the prognosis of patients with hormone-insensitive tumors, it may increase host resistance by improving nutritional status and/or enhancing the quality of life.
One of the prime nutritional concerns in cancer patients is cachexia and deteriorating nutritional status. Cachexia can occur as a result of either treatment or the tumor itself. The progressive malnutrition ultimately affects performance status and organ function. Tolerance to treatment may thus be decreased, which, in turn, may adversely affect toxicity and response. In addition, the deleterious effects of malnutrition on the immune system can increase susceptibility to infection. The weakness and fatigue related to muscle wasting and changes in metabolism affect physical appearance, leading to a loss of self-esteem. Thus, the vicious cycle of cachexia severely impacts on every aspect of daily life. Providing nutritional support and effective treatment may reverse the cachexia. Studies involving caloric supplements alone have not been encouraging. Conversely, studies using megestrol acetate have shown that cancer patients gain weight and that their sense of well-being improves. However, the mechanisms of weight gain remain unknown, and further studies are needed to determine the mechanisms by which appetite is stimulated or catabolism is inhibited or both. Nursing interventions to stimulate appetite and promote greater food intake, coupled with the use of agents that alter metabolism, such as megestrol acetate, may reverse the trend of cachexia and thus provide an increased sense of well-being and improved quality of life.
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N-methylformamide (NMF) (800-1,000 mg/m2 i.v. day 1) was given to 14 patients with measurable, advanced renal cell carcinoma in this Phase II trial. Treatment was repeated every 28 days. Significant toxicities included drug-induced hepatitis along with moderate nausea and vomiting. No objective responses were seen although several patients had stable disease with treatment for prolonged periods. NMF is not an active agent in renal cell cancer when administered by this schedule.
Sixteen patients [13 acute nonlymphocytic leukemia (ANLL), 2 acute lymphocytic leukemia, 1 chronic myelogenous leukemia in a blast crisis; median age, 40 yr; range, 25-78 yr; 9 male, 7 female] received 23 courses of carboplatin given as a bolus on a daily X 5 schedule. Six patients were given 7 courses of carboplatin at 200 mg/m2/day; 3 patients received 5 courses at 250 mg/m2; 9 patients received 11 courses at 300 mg/m2; 2 patients initially treated at 200 mg/m2 were given their 2nd course at 300 mg/m2. Significant hearing loss documented by audiometry occurred in five patients, including three of nine treated at 300 mg/m2. All five had prior or recent exposure to aminoglycoside antibiotics. Three patients developed cancer and acute leukemia group B grade 3 or 4 mucositis, and 18 of 23 courses were complicated by nausea and vomiting. Marrows were hypocellular or aplastic in all patients treated at the highest dose. No complete responses occurred, although two patients with ANLL treated at 300 mg/m2 achieved partial responses lasting 71 and 138 days. The t1/2 alpha [half-life (t1/2)], t1/2 beta, and total body clearance of ultrafilterable platinum were comparable to those previously described by us in patients receiving bolus doses of carboplatin of 22-77 mg/m2/day X 5. Carboplatin has activity in ANLL.
Cachexia can be a severe problem in the management of patients with cancer and other illnesses because it produces an ever-increasing spiral of anorexia, undernutrition, loss of tissue mass, muscle wasting, and increased susceptibility to infection and treatment toxicity. Megestrol acetate has been observed to produce weight gain in patients with hormone-sensitive tumors and has recently been noted to produce a similar degree of weight gain in those with hormone insensitive tumors. A review of our experience in a phase I-II study of escalating doses of megestrol acetate for advanced breast cancer revealed that weight gain occurred in more than 80% of all treated patients and in 90% of those patients who received treatment for 6 or more weeks. The median maximum weight gain was 5.5 kg, with a range of -5.6 to 44 kg. Subjective improvement in appetite occurred in most patients. These data provided the impetus for a series of further studies of the role of megestrol acetate in the control of cachexia, including a randomized study in cancer cachexia, AIDS cachexia, and anorexia nervosa. In addition, a number of laboratory trials seeking the mechanism of action have been initiated, as well as whole-animal studies to define the compartment of increased weight. Our data and the preliminary observation of weight gain in patients with hormone insensitive tumors suggest that megestrol acetate has a potential role in producing a possibly dose-related subjective improvement and an increase in appetite and weight. Further research is necessary to understand the mechanism of appetite stimulation and anabolic effect.
A dose-response relationship has long been suspected for progestin compounds in the treatment of breast cancer, but only recently have trials been implemented to investigate this issue. In 1985, we began a phase I-II study of high-dose megestrol acetate in dosages of 480 mg/d to 1,600 mg/d in heavily pretreated postmenopausal patients with advanced breast cancer. After establishing the safety of this therapy, we expanded our trial, which now includes 47 patients, 34 of whom have measurable disease. Of these 34 patients, 30 had disease progression on prior hormonal therapy and 29 had progression on chemotherapy. Six of the 34 patients had complete response and six had partial response for a median time on study of 10 months (range, 8 to 30 months). Ten patients had stabilization and 12 had progression. Thirteen patients had evaluable but nonmeasurable disease, and of these, ten had improvement or stabilization for a median period of 6 months (range, 2 to 18 months) and three had progression. Of 17 patients who had experienced disease progression while receiving standard-dose megestrol acetate, 13 (76%) achieved objective remissions or stabilization with high-dose therapy. The main side effects were weight gain and appetite enhancement, which were beneficial in 13 underweight patients. These data indicate that high-dose megestrol acetate is well tolerated and effective in patients with advanced breast cancer refractory to multiple previous therapies. While optimal dose levels for clinical use remain to be established by ongoing studies, our data suggest that doses higher than the standard dose may be more effective.