High-grade transformation in splenic marginal zone lymphoma with circulating villous lymphocytes: the site of transformation influences response to therapy and prognosis.

In a series of 48 patients with splenic marginal zone lymphoma (SMZL) with circulating villous lymphocytes, we describe the clinical and laboratory features of nine cases that transformed to high-grade B-cell lymphoma. These patients had a significantly greater incidence of peripheral lymph node involvement at diagnosis when compared to SMZL patients who did not transform (P < 0.03). While transformation in the bone marrow is frequently refractory to therapy and associated with poor outcome in SMZL, lymph node transformation responds well to chemotherapy with durable progression-free and overall survival.

Failure of dietetic referral in patients with gastrointestinal cancer and weight loss.

This study examined whether staff working within a cancer centre treating patients with gastrointestinal malignancy routinely identified individuals from outpatients for referral to a dietitian. A nutrition screening tool is employed only for in-patient admissions. Height, current and usual weight were recorded prospectively in all patients referred for consideration of treatment. First appointment with the dietitian, first hospital admission, demographic and clinical details were obtained from hospital records. Time from first appointment to referral to a dietitian was examined. Between September 2002 and March 2004, 920 patients were included. Five hundred and seventeen patients had lost weight, of whom 223 patients had lost between 5% and 10% and 294 patients had lost more than 10% of their pre-morbid weight. Three hundred and twenty-seven patients (36%) were referred to dietitians. Twenty eight (9%) of referrals were made by staff in outpatients. Two hundred and ninety-nine were referred during or after an inpatient admission but only 39% of these occurred within the first seven days following admission. One third of patients with more than 10% weight loss were not referred for dietary assessment, even following admission. The likelihood of referral was significantly associated with the degree of weight loss (univariate analysis hazard ratio (HR) 1.75, 95% Confidence Interval (CI) 1.4-2.19, multivariate HR 1.65, 95% CI 1.22-2.23) and was independent of factors such as performance status and clinical setting. Few patients were identified early in their treatment for referral to a dietitian. Since most chemotherapy is now given on an outpatient basis, patients are unlikely to be referred if they do not require admission. This study suggests that an out-patient dietetic screening tool is urgently required. Such screening is likely to result in considerable improvements to the clinical care of cancer patients with weight loss.

Dose-related endocrine effects and pharmacokinetics of oral and intramuscular 4-hydroxyandrostenedione in postmenopausal breast cancer patients.

4-Hydroxyandrostenedione (CGP32349; 4-OHA) is a clinically effective treatment for advanced postmenopausal breast cancer by both the parenteral and p.o. routes, as a result of its inhibition of aromatase and consequent suppression of plasma estrogen levels. Thirty patients were randomized to treatment with 250 mg 4-OHA orally once, twice, and 4 times daily for 2 weeks and 29 of these plus a further 11 patients were then randomized to treatment with 250 or 500 mg i.m. every 2 weeks to determine the optimal dose for each route according to the suppression of serum estradiol levels. There was no significant difference between the 3 oral doses in their suppression of estradiol levels indicating that the maximum required p.o. dose of 4-OHA is probably 250 mg daily. Suppression by the parenteral dose of 250 mg every 2 weeks was marginally suboptimal but clinical considerations of response and tolerability indicate this as the optimal dose for i.m. injection. 4-OHA had no effect on serum levels of androstenedione, testosterone, or 5 alpha-dihydrotestosterone when given by either route but p.o. treatment with 4 doses of 250 mg daily reduced sex hormone-binding globulin levels by a mean of 34%. Serum levels of estrone as measured by gas chromatography-mass spectrometry were suppressed to approximately 40% of baseline by parenteral treatment. The half-life of 4-OHA p.o. was approximately 3 h, whereas the apparent half-life of injected drug was between 5 and 10 days after a more rapid clearance during the first 4 days after injection.

A preliminary clinical study of gossypol in advanced human cancer.

A total of 34 patients with advanced cancer were given weekly or daily escalating doses of oral gossypol, a cottonseed-oil constituent showing evidence of antineoplastic activity in pre-clinical studies. No major adverse events occurred and there was no evidence of haematological or biochemical disturbance. As determined by dose escalation in 17 patients, the dose-limiting toxicity was emesis in 16 patients. There was no evidence of tumour regression in any of the 20 patients assessed for response. We conclude that gossypol is safe but unlikely to be clinically useful in patients with advanced cancer.

Proliferative responses of normal human mammary and MCF-7 breast cancer cells to linoleic acid, conjugated linoleic acid and eicosanoid synthesis inhibitors in culture.

Potential mechanisms for the stimulation or inhibition of cell growth by linoleic acid (LA) and conjugated linoleic acid (CLA) were investigated by using eicosanoid synthesis inhibitors. Normal human mammary epithelial cells (HMEC) and MCF-7 breast cancer cells were incubated in serum-free medium supplemented with LA or CLA and cyclooxygenase (indomethacin; INDO) or lipoxygenase (nordihydroguaiaretic acid; NDGA) inhibitors. Linoleic acid stimulated the growth and [3H]thymidine incorporation of normal HMEC and MCF-7 cancer cells, while CLA was inhibitory. Supplementation with LA increased intracellular lipid peroxide concentrations in normal HMEC and MCF-7 cancer cells, whereas CLA did not affect lipid peroxide formation. Normal HMEC and MCF-7 cells supplemented with LA and INDO or NDGA resulted in growth inhibition. The treatment of normal HMEC with CLA and INDO or NDGA, and MCF-7 cells with CLA and INDO stimulated cell growth. However, the addition of CLA and NDGA to MCF-7 cells resulted in synergistic growth suppression suggesting that CLA effects were mediated through lipoxygenase inhibition. Although NDGA was more inhibitory of cell growth in the presence of LA or CLA than INDO, growth was associated with both prostaglandin and leukotriene production. Additional studies are warranted to elucidate the mechanism(s) whereby LA or CLA affect breast cell growth.

Dietary energy and fat content as factors in the nutrition of developing egg strain pullets and young hens. 3. Effects on hepatic lipogenic enzyme activity and body chemical composition during the first 20 weeks of lay.

One hundred and twenty six commercial White Leghorn pullets were housed in cages at 23 weeks of age and fed two laying diets that in energy and fat content. Changes in hepatic "citrate-cleavage" and "malic" enzyme activity and changes in liver and body chemical composition were measured each week during the first 20 weeks of lay. Average daily caloric intake was greater for the birds fed the high energy laying diets even though these birds consumed 11% less feed. While energy content of the laying diet failed (P = 0.05) to affect body weight gains, liver weight, liver fat content and hepatic enzyme activity, significant (P = 0.05) increases in abdominal fat pad weight and total body fat content were noted. The findings of significant alterations in total carcass composition in birds receiving the high energy laying diet support the conclusion that energy content of the layer diet will influence the carcass composition of modern day egg producing strains.

Dietary energy and fat content as factors in the nutrition of developing egg strain pullets and young hens. 4. Effect on growth, hepatic lipogenic enzyme activity and body chemical composition of White Leghorn pullets from hatch to 20 weeks of age.

Nine starting and rearing diets (three energy levels each with three fat levels) were fed to commercial White Leghorn chicks from hatch to 20 weeks of age. As noted in the earlier papers of this series, pullets fed the high energy rearing diets showed significant (P = 0.05) reductions in feed intake, however, average daily caloric intake was greater (P = 0.05) for pullets consuming the low energy rearing diets. Fat content of the diet had not influence on either daily feed (g.) or caloric (kcal.) intake. Energy content of the diets failed (P = 0.05) to affect parameters related to body growth and development, hepatic citrate-cleavage and "malic" enzyme activity and liver or body composition. Fat content of the diet depressed hepatic enzyme activity while no effect was noted on body weight, liver weight or body composition. The onset of sexual maturity altered lipid metabolism in the developing pullets. Significant (P = 0.05) energy level by fat level interactions were noted in only two of the 20 parameters studied in this experiment. In vitro assay of hepatic citrate-cleavage and "malic" enzyme activity proved to be of little value in predicting hepatic lipogenic activity and subsequent effects on liver and total body composition.

Adamantinoma arising in the distal fibula treated with distal fibulectomy: a case report and review of the literature.

Adamantinoma is a rare primary bone tumor occurring in the mandible and the long tubular bones. The diaphysis of the tibia is the most common site of extragnathic presentation. Fibular involvement is rare and usually has coexisting tibial involvement. Adamantinoma arising in the distal fibular metaphysis has not been previously reported. This is a case of a teenage boy presenting with a cystic lesion of the distal fibula, initially diagnosed and treated as a unicameral bone cyst. Aggressive behavior ultimately led to a diagnosis of adamantinoma. He was treated with distal fibulectomy without surgical reconstruction with good functional outcome.

Evolution of a home health ethics committee.

In 1996, the Visiting Nurse Association of Boston established an Ethics Advisory Committee to address ethical issues that arise in patient care. This article describes the Committee's development from implementation of an ethics education plan for agency staff, to policy recommendations and consultation for ethical conflicts in patient care. Whether developing an ethics committee or evaluating your current one, this article can be helpful.

Correlation of CT with histopathological findings in patients with gastric and gastro-oesophageal carcinomas following neoadjuvant chemotherapy.

UNLABELLED: Gastric carcinoma is the fourth commonest cause of death from malignant disease in United Kingdom. In the Western hemisphere, it usually presents with advanced disease, which contributes to its very poor prognosis. Pre-operative (neoadjuvant) chemotherapy offers the possibility of down-staging such tumours and the potential to render tumours operable. Computed tomography (CT) plays a central role in the assessment of patients presenting with the disease, and in those who undergo chemotherapy, in evaluating their response. OBJECTIVE: This study was undertaken to evaluate the role of CT in predicting loco-regional spread of tumour following neoadjuvant chemotherapy in non-metastatic gastric and gastro-oesophageal cancers. METHODS AND MATERIALS: We correlated CT evidence of loco-regional spread with pathological findings following surgery in 21 patients who received pre-operative chemotherapy. RESULTS: Residual masses were seen on CT in 19 patients, and 15 contained active tumour, although in four patients no viable tumour was demonstrated at histopathology. The overall accuracy of CT in assessing loco-regional disease was disappointing with sensitivities, specificities, positive and negative predictive values of 57%, 43%, 75% and 33%, respectively. CONCLUSIONS: We conclude that CT is not accurate in identifying residual loco-regional spread and therefore should not preclude surgery in those patients who have received neoadjuvant chemotherapy.

FDG-PET in the prediction of survival of patients with cancer of the pancreas: a pilot study.

Carcinoma of the pancreas is an aggressive tumour with an extremely poor prognosis. Recent studies have shown that chemotherapy can improve survival as well as quality of life. Since the prognosis is generally poor, the identification of early responders to chemotherapy is important to avoid unnecessary toxicity in patients who are not responding. Response assessment by conventional radiographic methods is problematical because treatment induces fibrosis and makes tumour measurements difficult. The aim of this pilot study was to assess 18-fluoro-deoxy-glucose positron emission tomography (FDG-PET) as an early marker of the benefit of chemotherapy. Eleven patients with histologically proven adenocarcinoma of the pancreas were treated with protracted venous infusional 5-fluorouracil (PVI 5-FU) alone or PVI 5-FU and mitomycin C (MMC). FDG-PET scans were performed prior to and at 1 month following the commencement of chemotherapy. FDG uptake was compared with the tumour dimensions measured on a computer tomographic (CT) scan. Patients were followed up for relapse, death and symptomatic response. Three of the 11 patients had no measurable FDG uptake prior to chemotherapy. Of the eight patients who had measurable uptake prior to treatment, seven had a reduction in uptake at 1 month. Six out of the 11 patients had no measurable FDG uptake at 1 month. The overall survival (OS) in these patients ranged from 124 to 1460 days, with a median of 318.5 days. This was superior in comparison to patients who had residual FDG uptake at 1 month (median survival 318.5 days vs 139 days; P = 0.034) and there was a trend to improved symptoms (84% [5/6] vs 20% [1/5]; P = 0.13). There was no statistically significant correlation between best CT response and FDG uptake at 1 month. These results suggest that the absence of FDG uptake at 1 month following chemotherapy for carcinoma of the pancreas is an indicator of improved overall survival. This suggests that FDG-PET may be superior to response assessment by conventional radiographic methods and FDG-PET may have the potential to help make difficult treatment decisions in the management of pancreatic cancer. Larger prospective studies are required to confirm this finding.

Phase I/II study of the anti-oestrogen zindoxifene (D16726) in the treatment of advanced breast cancer. A Cancer Research Campaign Phase I/II Clinical Trials Committee study.

We report a phase I/II study of the indole derivative, zindoxifene, an anti-oestrogen with intrinsic oestrogenic activity. We have treated 28 women with advanced breast cancer of whom 26 had received prior endocrine therapy. Oral zindoxifene doses ranged from 10 to 100 mg daily; doses were escalated in some patients. Twenty-five patients were assessed for response; the remaining three patients completed less than 3 weeks of treatment. There were no objective responses; disease stabilised in seven patients for up to 5 months and progressed in the remaining 18. Five patients (including three treated with tamoxifen) responded to subsequent endocrine therapy. Nausea, which was dose-limiting, affected half of the patients treated with 80 mg daily. Metabolites of zindoxifene were detectable in serum at all doses used, and sex hormone binding globulin (SHBG) levels showed a strong tendency to rise at the higher doses, indicating that zindoxifene is absorbed and has biological activity. We conclude that zindoxifene in the doses used in this study has only marginal therapeutic activity in the treatment of advanced breast cancer.

Prognostic significance of BCL-2 expression and bcl-2 major breakpoint region rearrangement in diffuse large cell non-Hodgkin's lymphoma: a British National Lymphoma Investigation Study.

The Bcl-2 protein is capable of preventing apoptosis, and in vitro evidence suggests a role in drug resistance. It is expressed and the gene is rearranged in a proportion of cases of large-cell non-Hodgkin's lymphoma (NHL), but the clinical significance of these findings is controversial. The purpose of this study was to determine the influence of both Bcl-2 expression and major breakpoint region (MBR) bcl-2 rearrangement in a large cohort of prospectively accrued patients with intermediate-grade B-cell NHL treated in a standardized manner. All patients with Working Formulation F, G, or H NHL treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy in British National Lymphoma investigation studies between July 1974 and April 1992 were considered for this study if the appropriate paraffin blocks were available. Paraffin sections from the diagnostic specimen were analyzed for evidence of MBR rearrangement using a polymerase chain reaction-based method, and for Bcl-2 expression using immunohistochemistry. Failure to achieve complete remission (CR), relapse, death from NHL, and deaths from all causes were used as end points to measure CR rate, actuarial relapse rate, actuarial survival from NHL, and actuarial overall survival. One hundred sixty-one suitable patients were identified and tested for the bcl-2 MBR translocation, with 27 (17%) found to be positive; 153 of these patients were tested with immunocytochemistry, and 84 (55%) showed evidence of Bcl-2 expression. For patients who achieved CR from the initial treatment, the relapse rate was significantly higher in those with Bcl-2 expression than in those without. In addition, multivariate analysis identified Bcl-2 expression as the only factor significantly related to relapse rate in the subjects measured. The cause-specific survival for NHL in the series as a whole was significantly lower in patients with Bcl-2 expression than in those without. MBR status had no significant influence on any of the outcome measures, but the number of MBR-positive patients was relatively small, and larger studies are required. In conclusion, in Working Formulation F, G, and H NHL of B-cell type, expression of Bcl-2 protein predicted independently for relapse.

Magnetic resonance detects metabolic changes associated with chemotherapy-induced apoptosis.

Apoptosis was induced by treating L1210 leukaemia cells with mechlorethamine, and SW620 colorectal cells with doxorubicin. The onset and progression of apoptosis were monitored by assessing caspase activation, mitochondrial transmembrane potential, phosphatidylserine externalization, DNA fragmentation and cell morphology. In parallel, 31P magnetic resonance (MR) spectra of cell extracts were recorded. In L1210 cells, caspase activation was detected at 4 h. By 3 h, the MR spectra showed a steady decrease in NTP and NAD, and a significant build-up of fructose 1,6-bisphosphate (F-1,6-P) dihydroxyacetonephosphate and glycerol-3-phosphate, indicating modulation of glycolysis. Treatment with iodoacetate also induced a build-up of F-1,6-P, while preincubation with two poly(ADP-ribose) polymerase inhibitors, 3-aminobenzamide and nicotinamide, prevented the drop in NAD and the build-up of glycolytic intermediates. This suggested that our results were due to inhibition of glyceraldehyde-3-phosphate dehydrogenase, possibly as a consequence of NAD depletion following poly(ADP-ribose) polymerase activation. Doxorubicin treatment of the adherent SW620 cells caused cells committed to apoptosis to detach. F-1,6-P was observed in detached cells, but not in treated cells that remained attached. This indicated that our observations were not cell line- or treatment-specific, but were correlated with the appearance of apoptotic cells following drug treatment. The 31P MR spectrum of tumours responding to chemotherapy could be modulated by similar effects.

A randomized British National Lymphoma Investigation trial of CHOP vs. a weekly multi-agent regimen (PACEBOM) in patients with histologically aggressive non-Hodgkin's lymphoma.

BACKGROUND: Between 1987 and 1991, the British National Lymphoma Investigation randomized 459 patients with non-Hodgkin's lymphoma with a large-cell component to either CHOP or the PACEBOM regimen. PATIENTS AND METHODS: Four hundred fifty-nine eligible patients were included in this trial, four hundred one with diffuse large-cell lymphoma and fifty-eight with diffuse mixed-cell lymphoma according to the Working Formulation. Two hundred twenty-six patients were randomized to receive CHOP and two hundred thirty-three to receive PACEBOM. The two arms of the trial were well balanced for all potential prognostic factors. RESULTS: The complete remission rate with PACEBOM was 64% and with CHOP 57% (NS). At eight years, the actuarial cause specific survival (CSS) in the PACEBOM arm is 59% compared to 49% in the CHOP arm (P = 0.09). Patients < 50 years of age fared significantly better in the PACEBOM arm both for CSS and overall survival (P = 0.002) and the CSS was also significantly improved in stage IV disease (P = 0.02). CONCLUSIONS: The mature data from this trial suggest that an etoposide-containing multi-agent weekly regimen can be superior to CHOP.

A randomised comparison of a third-generation regimen (PACEBOM) with a standard regimen (CHOP) in patients with histologically aggressive non-Hodgkin's lymphoma: a British National Lymphoma Investigation report.

A combination of cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) has been a standard therapy for histologically aggressive non-Hodgkin's lymphomas for over 20 years, but several newer regimens, referred to as second or third generation, have been reported to give improved results in single-centre studies. Positive evidence from randomised trials has been lacking, and the British National Lymphoma Investigation therefore commenced a randomised comparison of CHOP vs a third-generation regimen, PACEBOM, in November 1987. A total of 459 eligible patients were entered into the trial: 226 in the CHOP arm and 233 in the PACEBOM arm. Overall, there was no significant difference in outcome between the two arms of the trial. In patients with stage IV disease there was an apparent improvement in survival for those treated with PACEBOM, but considerable caution must be exercised with such subgroup analysis.