Biomedical subjects
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Hypercalcaemia is one of the most common disorders occurring in patients with cancer and may have disabling symptoms. The mechanisms underlying hypercalcaemia associated with malignant disease, the symptoms attributable to and the treatment of this disorder are discussed in this paper.
A number of studies have shown that older people are less distressed by the diagnosis of cancer than their younger counterparts. This may be because older people have fewer dependants and they are less likely to suffer financial difficulties and to experience disruption to their daily routine following the diagnosis. It is surprising, therefore, that many elderly patients do not receive the biologically optimal treatment of their disease, even when comorbid medical conditions are taken into account. This appears to reflect an age bias amongst professionals involved in the management of cancer. There is a paucity of studies examining the perspective of elderly patients themselves regarding factors they consider important in their management. Elderly patients with cancer are not an homogeneous group in terms of their views about management. The vast majority of elderly patients, in common with younger patients, consider that giving the most effective treatment for breast cancer is just as important for older patients as it is for younger patients and that, in making a decision about the best treatment for them, the surgeon should only take account of the biological aspects of the disease. Clinicians, therefore, should avoid making assumptions about what patients wish simply on the basis of the age of the patient. Although there is a recent trend towards more elderly patients participating in oncology treatment trials, there is a great dearth of information about the acceptability and effectiveness of psychosocial interventions in elderly patients.
Breast cancer in older women continues to be a clinical problem and therapeutic challenge. The clinical presentation, biological characteristics and survival rates are comparable between older and younger women with breast cancer. Treatment of breast cancer in older women should aim to ensure satisfactory control of locoregional disease and prolongation of survival, for as long a period as possible. Optimal surgical therapy should be as for younger patients and adjuvant therapies may be required (considering side-effects and benefits). However, randomized trials are required to clarify the role of adjuvant treatments in older patients.
OBJECTIVE: To evaluate the ability of positron emission tomography (PET) with 18F-fluoro-2-deoxy-D-glucose (18F-FDG) to determine noninvasively axillary lymph node status in patients with breast cancer. BACKGROUND: The presence of axillary lymph node metastasis is the most important prognostic factor in women with breast cancer. It signifies the presence of occult metastatic disease and indicates the need for adjuvant therapy. The only reliable way in which this important prognostic information may be obtained is by performing axillary dissection, which may be associated with significant complications and delay in discharge from the hospital. PET with 18F-FDG can visualize primary cancers in the breast and metastatic tumor deposits. METHODS: Fifty patients with untreated breast cancer had clinical examination of their axilla performed (graded as positive or negative), followed by PET of the axilla and midthorax. PET data were analyzed blindly and graded as positive or negative, depending on the presence or absence of axillary nodal metastases. Cytopathologic assessment of the axillary nodes was carried out within 1 week of PET, by fine-needle aspiration cytology in 5 patients and axillary dissection in 45; the excised specimens were examined by a single pathologist. RESULTS: The overall sensitivity of PET in 50 patients was 90% and the specificity was 97%. Clinical examination of the same patients had an overall sensitivity of 57% and a specificity of 90%. In the 24 patients with locally advanced breast cancer (T3, T4, TxN2), PET had a sensitivity of 93% and a specificity of 100%. In T1 tumors (seven patients), the sensitivity and specificity were 100%. PET had a high predictive value (>90%) and accuracy (94%) in staging the axilla. CONCLUSIONS: PET is a sensitive and specific method of staging the axilla in patients with breast cancer. It may obviate the need for axillary surgery in women with small primary tumors, define the women likely to benefit from axillary dissection, or allow radiotherapy to be substituted for surgery, particularly in post-menopausal women.
OBJECTIVES: Recently, it has been postulated that patients with ulcerative colitis have altered natural cytotoxicity, in particular natural killer (NK) and lymphokine-activated killer (LAK) cell activities. These cellular mechanisms have been postulated to play an etiological role in the pathogenesis of the disease process. We have shown previously that the essential fatty acids (EFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) specifically inhibit natural cytotoxicity. Our aim was to evaluate the role of omega-3 EFA in the modulation of natural cytotoxicity and disease activity in patients with distal procto-colitis. METHODS: In this pilot study patients were randomized into two groups. Each patient received either fish oil extract (EPA, 3.2 g, and DHA, 2.4 g) (n = 9) or sunflower oil (placebo) (n = 9) daily in a double-blind manner for 6 months. Monthly assessments of disease activity (clinical and sigmoidoscopic scores) and histological evaluation of mucosal biopsies were carried out. Also, the circulating levels and activities of NK and LAK cells, using flow cytometric analysis (CD16+ CD56+) and in vitro 51 chromium release assays (K562), respectively, were monitored. RESULTS: After 6 months' supplementation with EFA, there was improvement in the clinical activity compared with pretreatment evaluation. There was significant reduction in the sigmoidoscopic and histological scores in the EFA group compared with the placebo group. Essential fatty acid supplementation for 6 months also induced significant reduction in the circulating numbers of CD16+ and CD56+ cells and the cytotoxic activity of NK cells, compared with the placebo group. CONCLUSIONS: This pilot study has demonstrated that omega-3 fatty acids can suppress natural cytotoxicity and reduce disease activity in patients with distal procto-colitis. These findings suggest a therapeutic strategy for managing patients with inflammatory bowel disease.
Patients with large primary breast cancers are being treated with neo-adjuvant chemotherapy. Studies in animals have shown that responses to chemotherapy can be increased by dietary manipulation of tumour cell metabolism. Also dietary supplementation with the amino acid L-arginine, resulted in an increase in tumour metabolic activity expression of the nuclear activation antigen, Ki67, in patients with breast cancer. Therefore, we have carried out a randomised, double blind, placebo controlled trial to determine if L-arginine supplementation is beneficial in patients with breast cancer, undergoing neo-adjuvant chemotherapy. 96 patients were randomised to receive L-arginine (30 g/day) for three days (n = 48) or placebo (n = 48) prior to undergoing chemotherapy (doxorubicin, cyclophosphamide, vincristine, prednisolone), 6 pulses at 21-day intervals. Clinical and pathological responses were assessed in both groups of patients following completion of chemotherapy. The clinical response rate was 77% (23% complete and 54% partial responses) in the L-arginine treated group, compared with 71% (15% complete and 56% partial) in the placebo group of patients (p = ns). However, in patients with tumours less than 6 cm in initial diameter, there was a significant increase in the better histopathological responses in the L-arginine group, when compared with the placebo group of patients (88% vs 52%, p = 0.04). This may have important implications for clinical practice.
Seventy-seven patients with locally advanced breast cancer were treated with multimodality therapy comprising of six pulses of neo-adjuvant chemotherapy (doxorubicin, cyclophosphamide, vincristine and prednisolone) at 21-day intervals, followed by surgery (breast conservation or mastectomy) with appropriate axillary surgery, radiotherapy and adjuvant tamoxifen. The serum concentrations of acute phase proteins, C-reactive protein (CRP), á-1-anti-trypsin, albumin and transferrin were measured in serum taken prior to commencement of treatment. Patients were followed up for a median of 31 months and their clinical and histological responses and overall survival recorded. Univariate analyses revealed that tumour stage (p=0.01), clinical lymph node status (p=0. 02) and pre-treatment levels of serum albumin (p=0.002) and á-1-anti-trypsin (p=0.06) predicted overall survival. Using the Cox proportional hazards model reduced pre-treatment levels of serum albumin (p<0.00001), progressive lymph node involvement with tumour (p<0.005), and advancing tumour stage (p<0.01) were independent prognostic indicators for a poorer survival in patients with locally advanced breast cancer receiving neo-adjuvant chemotherapy.
The aim of this study was to ascertain whether apoptotic counts have prognostic significance in colorectal cancer and if such counts are related to the expression of proteins implicated in cell cycle regulation. Material from a cohort of patients aged 45 years or less with colorectal carcinoma was re-examined to determine apoptotic and mitotic counts by light microscopy, in addition to assessing p53, c-myc, and bcl-2 protein status by immunohistochemistry. The apoptotic index in the 74 patients who were alive or who had died of colorectal carcinoma ranged from 1.2 per cent to 12.3 per cent and exhibited independent prognostic significance, with high counts predicting better survival (P = 0.02). Mitotic counts were not related to survival, despite a close correlation with apoptosis (r = 0.85). Tumours regarded as not staining with the CM1 antibody for p53 protein demonstrated higher apoptotic counts, compared with those that stained (medians 5.2 and 4.0 per cent, respectively; P = 0.03), but p53 expression was found not to be related to survival. The 68 tumours which stained for c-myc appeared to exhibit higher mitotic counts than those that did not. bcl-2 was detected in only four tumours. The latter two proteins exhibited no apparent relationship to the apoptotic index or survival. Although these results indicate a potential role for apoptotic counting in prognostic prediction in colorectal tumours, this is an uncommon group of patients who exhibited some atypical features. The likelihood of a proportion of cases arising within hereditary non-polyposis colorectal cancer syndrome may limit the application of the findings to a more general population with cancer of the colon and rectum. Further work is required, including critical measurement of reproducibility and assessment of the relative impact of this parameter compared with 'traditional' prognostic markers.
It has been suggested that recombinant interleukin-2 (rIL-2) may cause pyschological and psychiatric problems, although the effects of rIL-2 on its own have not been well documented. To evaluate these effects, 17 patients with advanced colorectal cancer took part in a randomised, parallel group study of rIL-2 with chemotherapy (5-fluorouracil and leucovorin) versus chemotherapy alone. Patients were assessed regularly by means of various psychometric tests including the Hospital Anxiety and Depression Scale, the Mood Rating Scale, the Mini-Mental State Examination, the Digit Symbol Substitution Test, the Trail-Making Test and the Benton Revised Visual Retention Test. Rigorous discontinuation criteria were applied to ensure that the effect of time-related variables did not influence the results. Compared with patients who were given chemotherapy alone, patients receiving immunochemotherapy reported reduced energy, impaired confidence, higher depressed mood and more confusion. Immunochemotherapy was rated as more distressing than chemotherapy alone and patients reported a greater incidence of appetite impairment, weight loss, poor concentration and fever. Cognitive assessments indicated that brain dysfunction can be caused by rIL-2. Compared with the control group, patients receiving immunochemotherapy showed significant impairment on Trail Making Test B and the Digit Symbol Substitution Test. One patient developed repeated transient psychotic episodes associated with rIL-2 infusions and another regularly became confused. These effects were not due to sleep deprivation or pyrexia. Treatment with rIL-2 should not be discarded on psychosocial grounds, although in each case the psychological morbidity and adverse effects on quality of life need to be balanced carefully against potential therapeutic benefits.
PURPOSE: The increased mortality of emergency vs. elective colonic surgery applies equally to the right and left colon. Recent interest has surrounded the application of expandable metal stenting in acute obstruction but has been confined to the left colon. We describe successful application of stenting in the right colon, allowing postponement of a particularly high-risk laparotomy. METHODS: A patient with acute bilateral iliofemoral thromboses simultaneously developed complete obstruction of the proximal transverse colon. After heparinization and under fluoroscopic control, a 10-cm-long, self-expanding Wall-stent (Schneider, Bulach, Switzerland), 22 mm in diameter, was manipulated across the obstruction. RESULTS: Immediate decompression with symptomatic relief ensued. The stent prevented obstruction during a 10-week period of anticoagulation, and repeat duplex scanning showed resolution of iliac thrombus. An elective right hemicolectomy was then performed. Postoperative course was uncomplicated, and histopathology confirmed a Dukes B carcinoma. CONCLUSIONS: This case, in which a potentially hazardous laparotomy was delayed until the operative risk improved, defines a new role for stenting in colonic obstruction and demonstrates an extension of its applicability to the right colon. Literature review found no other report of stent application in the right colon.
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In this third article in the series, the management of patients with symptoms arising as a consequence of metastatic disease involving peripheral nerves, the spinal cord and the brain are discussed. In particular, pain, spinal cord compression and symptoms due to either raised intracranial pressure or specific neurological deficits may substantially impair the quality of life in patients with advanced cancer. Pain control, using both medical and surgical treatments, are discussed. The principles underlying the diagnosis and treatment of metastases to the vertebral column and spinal cord, as well as intracranial deposits, are outlined.
In this second article in the series, obstruction of hollow viscera in patients with advanced malignant disease is discussed. The obstruction of such structures can be associated with the development of painful and incapacitating symptoms, often in patients who have a limited life expectancy. This obstruction may be caused by the primary tumour, compression from adjacent tumour-draining lymph nodes, the presence of metastases distant from the site of the primary tumour or to adhesions within the abdominal compartment (usually as a result of previous surgery). The organs most often affected are the oesophagus, the intestine (small and large), the biliary tree and the genito-urinary tract. Obstruction of each of these organs and its management is discussed in more detail below.
Essential fatty acids (EFA) have been shown in animal studies to have a differential effect on various aspects of immune reactivity. However, there have been few studies in humans. Therefore, we elected to investigate the effects of a variety of EFA [gamma-linolenic acid (GLA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] in vitro on human blood lymphocyte reactivity, cytokine secretion and natural cytotoxicity. The proliferative response to polyclonal mitogens (phytohaemagglutinin, pokeweed mitogen, concanavalin A), as measured by [3H]thymidine incorporation into newly synthesized lymphocytes, was inhibited (P < 0.05) by all EFAs tested, in a dose-dependent manner (3-15 micrograms/ml). The greatest inhibition of proliferation was caused by EPA and DHA. Similarly, EPA, DHA and GLA significantly reduced cytotoxic activity [expressed as lytic units, using 51 chromium-release assays natural killer (NK) (K562 cells) and lymphokine-activated (LAK) (Daudi cells) cells] (P < 0.05) in a concentration-dependent manner (5-50 micrograms/ml), without affecting cell viability. EPA and DHA exhibited greater suppression than GLA. Furthermore, the inhibition of cell proliferation and suppression of natural cytotoxicity was associated with marked decrease in cytokine [interleukin-1 (IL-1), IL-2, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma)] production in vitro. Our findings demonstrate that EFAs (GLA, EPA, DHA) have the potential to inhibit significantly various aspects of human lymphocyte cell-mediated and humoral immune reactivities.
In summary, therefore, the provision of TPN to malnourished patients in the pre-operative period reduces the incidence of post-operative complications, but does not affect post-operative mortality. It is likely that the provision of nutrition by the enteral route is as effective as that by the parenteral route, and may have the extra benefit of resulting in a reduction in infectious complications when compared with patients receiving TPN. Furthermore, the use of enteral nutritional support in the post-operative period may also reduce both septic and major complications, but does not alter mortality. The use of specific combinations of nutrients appears to offer the greatest promise in the use of peri-operative nutritional support. The initial studies reported to date demonstrate reductions in post-operative morbidity, but again there are no benefits on mortality. However, further studies to determine the optimal combinations of nutrients for use in patients in the peri-operative period are urgently required.
BACKGROUND: Dietary supplementation with L-arginine enhances natural cytotoxicity in peripheral blood lymphocytes but its effect on infiltrating lymphoreticular cells within a tumour microenvironment is unknown. The effects of dietary supplementation with L-arginine on tumour-infiltrating lymphocytes (TILs) in patients with colorectal cancer were evaluated. METHODS: Eighteen patients received either a standard hospital diet (controls) or a standard diet supplemented with 30 g per day of L-arginine for 3 days before surgery. Tumour biopsies were taken at surgery and lymphocyte subsets (CD antigens) and macrophages examined immunohistochemically. RESULTS: Tumours from patients receiving L-arginine contained increased numbers of specific cell subsets within the tumour which expressed CD16 (P = 0.004) and CD56 (P = 0.001) surface markers, when compared with tumours from control patients. There were no differences in the total number of T and B cells, T helper and T suppressor cells. CONCLUSION: Dietary supplementation with L-arginine significantly alter the spectrum of TILs in human colorectal cancers in vivo. These findings have important implications for new strategies in anticancer treatment.
BACKGROUND: Considerable interest and concern have been expressed about junior doctors' hours. This study was carried out to evaluate the emotional and cognitive effects of a weekend on call in a surgical ward. METHODS: Ten surgical house officers were assessed, in counterbalanced design, on four Monday mornings, twice after a weekend off duty and twice after a weekend on call. Cognitive functioning was assessed using the Cognitive Drug Research computerized cognitive assessment system, and emotional state was evaluated by means of the Aberdeen Mood Rating Scale. RESULTS: Following a weekend on call, significant impairment in concentration, speed and power was observed, and the doctors felt less confident, less energetic and more confused. Impaired attention, working memory, long-term memory and confusion were most closely correlated with number of hours worked on Sunday, and tiredness and confusion were related to number of hours slept. CONCLUSION: A weekend on call has significant deleterious effects on cognitive performance and mood. The findings have implications for staffing levels and the design of duty rosters.
Growth factor receptor expression has been shown to be of prognostic significance in certain cancers, but its relevance in young patients with colorectal cancer is unknown. The aim of this study, therefore, is to determine the prognostic relevance of growth factor receptor expression [c-erbB-2, epidermal growth factor receptor (EGFR) and transforming growth factor beta receptor (TGF beta R)] in such patients. Ninety-two patients were evaluated. They were staged using the Jass staging system and the presence of metastases. The expression of EGFR and TGF beta R and the protein production of c-erbB-2 were detected using standard immunohistochemical techniques. The expression of EGFR and TGF beta R and the presence of the c-erbB-2 protein product were not identified as independent prognostic factors for survival. Furthermore, their expression did not correlate with established prognostic indicators such as Jass staging, the presence of extramural vascular invasion and the degree of tumour differentiation.