Oncological emergencies: clinical importance and principles of management.

Oncological emergencies are common conditions associated with significant morbidity and mortality. Delay in diagnosis and treatment can result in unfavourable outcomes. Cancer itself, cancer-related hormones or cytokines, or treatment effects can cause emergency problems. Febrile neutropaenia, frequently associated with chemotherapy, can lead to life-threatening conditions. Treatment requires systematic evaluation and early empirical antibiotics. Hypercalcaemia of malignancy is the most common metabolic emergency in cancer patients. Non-specific clinical features may cause delay in diagnosis and increase morbidity and mortality. Treatment includes active fluid resuscitation, diuretics and intravenous bisphosphonates. Superior vena cava syndrome is usually caused by external compression. Computerised tomography is useful to confirm diagnosis, evaluate the extent of disease and guide invasive tissue diagnosis. Treatment and prognosis depend on the underlying malignancies. Spinal cord compression is a true emergency due to risk of permanent neurological impairment. Localised back pain is the most common presenting symptom while late presentation of neurological deficit is associated with irreversible outcomes. Magnetic resonance imaging is the investigation of choice. Treatment includes corticosteroids, radiotherapy and/or decompressive surgery.

The effects of smoking on fracture healing.

Tobacco smoking is the single most avoidable cause of premature death worldwide. In fracture healing, it has been found to be a contributory factor to delayed union, and smokers are significantly disadvantaged, as healing times are often prolonged. The orthopaedic surgeon is likely to be knowledgeable about the detrimental effects of smoking on healing bones, as the problem has been known for some time. Smoking adversely affects bone mineral density, lumbar disc degeneration, the incidences of hip fractures and the dynamics of bone and wound healing. Clinical trials and demographic studies have been more widespread than biochemical analyses, and have reported poor prognosis for fracture patients who smoke. Scientific research has elucidated some of the negative impacts of tobacco use and investigations involving several animal models in cellular and humoral analyses have shown damage caused by various toxicological processes. Cessation of the habit perioperatively, therefore, is routinely advised to improve outcomes for patients. The current review describes some of the consequences of tobacco smoking in fracture healing.

Treatment of established breast cancer in post-menopausal women: role of aromatase inhibitors.

Endocrine therapy plays a crucial and historically important role in the treatment ofwomen with hormone-responsive breast cancer. Tamoxifen has been the standard endocrine treatment for advanced and early-stage breast cancer for almost three decades. However, patients receiving tamoxifen may either fail to respond or develop disease recurrence following completion of therapy. The aromatase inhibitors (Als) have become the new and alternative modalities of endocrine treatment for post-menopausal women with oestrogen receptor-positive breast cancer, as a result of promising data from randomised trials in metastatic and locally advanced breast cancers. Recently, the results from several large, randomised, controlled adjuvant trials have provided further evidence that the use of Als, either as initial treatment or sequentially after tamoxifen, improves disease-free survival and, in certain patients, overall survival. With relatively short-term follow-up, the use of Als has been shown to be safe and welltolerated. Nevertheless, some detrimental adverse effects, particularly skeletal-related events or cardiovascular disease, remain important issues of concern and warrant continued monitoring and follow-up. The optimal use of Als, the appropriate timing of treatment, and the superiority of individual agents are under investigation. Use of Als in women with chemotherapy-induced amenorrhoea should be cautious due to the possibility of return of ovarian function. Cost-effectiveness and quality of life remain issues of interest since the high and ever increasing incidence of breast cancer has contributed to significant healthcare costs and patients with breast cancer following appropriate treatment are living longer but not necessarily being cured of their diseases.

Principles of proteomics and its applications in cancer.

During the past decade, genomic analyses have been introduced into cancer studies with variable success. It has become recognised, however, that genomic techniques in isolation are insufficient to study the complex pathways of carcinogenesis; this has led to the application of proteomic techniques, which allow for the reliable analysis of complex mixtures of proteins. This article reviews the basic principles of proteomics, methods currently used in proteomics including two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS), and the application of proteomics in cancer research. Currently, proteomic technology has been used in two main areas of cancer research: early diagnosis and treatment (included prediction of response to treatment and targeting novel cancer agents). The initial results from both in vitro and in vivo studies are impressive. These technologies, particularly when combined with genomic analyses, will provide valuable insights into the molecular basis of carcinogenesis and the development of more effective anti-cancer therapies.

Blood monocytes and tumor-infiltrating macrophages in human breast cancer: differences in activation level as assessed by lysozyme content.

The lysozyme content of tumor-infiltrating macrophages (TIM) from human breast carcinomas has been compared with that of blood monocytes both from breast cancer patients and tumor-free controls. Cells were identified as macrophages or monocytes with the use of rosetting reactions to detect receptors for the Fc portion of IgG and differentiation antigens, and lysozyme was detected by an immunoperoxidase technique on cytocentrifuge preparations of rosetted cells. Significantly more monocytes from patients with breast cancer contained lysozyme than monocytes from comparable controls, suggesting the presence of activated circulating blood monocytes. Conversely, TIM were virtually devoid of lysozyme. This lack of enzyme was not due to methodologic factors and may represent defective antitumor activity.

T-lymphocyte and B-lymphocyte subpopulations infiltrating human mammary carcinomas.

Both T- and B-lymphocytes were found in human primary mammary carcinomas and were distributed in widely varying amounts, but in most tumors, T-lymphocytes predominated. A small percentage of the T-lymphocytes expressed receptors for the Fc portion of IgG (Fc gamma R), but very few had receptors for C3 (C3+) (comparable to the findings in blood). A prominent subset of lymphocytes had Fc gamma R and were C3+, and most of these were surface immunoglobulin (slg)-bearing cells. The majority of lymphocytes from this subset were Fc+ C3+, and only a small percentage were Fc+ C3- (in contrast to the findings in blood). IgD and IgM were the predominant classes of findings in blood). IgD and IgM were the predominant classes of immunoglobulin found on the B-lymphocytes. The different preparative techniques did not result in a selective loss of lymphocyte subsets, but collagenase digestion did lead to a loss of expression of the C3 receptor on the lymphocyte surface, which was recoverable when lymphocytes were reincubated at 37 degrees C. No evidence was found for blocking of the C3 receptor by immune complexes with activated complement.

Dendritic cell biology, dysfunction and immunotherapy in gastrointestinal cancers.

Gastrointestinal (GI) cancers make up a significant proportion of newly diagnosed malignant disease. The five-year survival for these GI cancers is poor. Anti-cancer host defences are thought to play a role in these cancers, albeit they are suboptimal. Novel immunotherapies are being introduced to treat such patients. This review describes basic cell biology of dendritic cells, as they are thoughtto play a key role in generating effective anti-tumour responses. Dendritic cell dysfunction in patients with various cancers is documented and immunotherapy using dendritic cells in a range of GI cancers is described and discussed

Neoadjuvant chemotherapy in women with large and locally advanced breast cancer: chemoresistance and prediction of response to drug therapy.

Patients with large and locally advanced breast cancer (LLABC) present with a therapeutic challenge and undergo multimodality treatment. Many such patients receive neoadjuvant chemotherapy (NAC) prior to surgery. However, a number of these patients do not respond well to NAC and only a percentage (usually less than 30%) obtains a complete or optimal response. A range of mechanisms are believed to be involved in this chemoresistance, including ATP binding cassette (ABC) transporter overexpression, dysregulation of apoptosis and possibly increased numbers of cancer stem cells. The chemoresistant processes may be due to more than one mechanism. The ability to predict a response to NAC would be beneficial, targeting expensive and toxic drug treatment to those likely to respond and providing a therapeutic strategy for further post-operative chemotherapy. Currently, many biomarkers have been studied with a view to establishing a predictor of response. However, no single biomarker appears to be effective. Genomics is a novel biotechnological process which is being used to predict response to drug therapy; this work is currently at an early stage of development

Vaccination therapy in malignant disease.

Improvement in survival among patients with early malignancy is well established in various cancers. However, long-term survival in those with advanced malignancy has changed little and this poses a major therapeutic challenge to clinicians. Anti-cancer immunotherapy is a novel approach, which is still experimental, but offers a new therapeutic strategy. In this review, we discuss the basic immunological interplay between the host immune system and the tumour, mechanisms of anti-tumour immune responses induced by immunotherapy and key in vivo pilot studies of active specific immunotherapy in various sold cancers, carried out during the last five years.

A pilot study with long term follow up of hyperbaric oxygen pretreatment in patients with locally advanced breast cancer undergoing neo-adjuvant chemotherapy.

Work in an animal cancer model suggests that pretreatment with hyperbaric oxygen can improve tumor vascularity rendering chemotherapy more effective. Accordingly 32 subjects with locally advanced breast carcinoma (>5cm diameter) entered into a randomized clinical trial where a course was administered of six intravenous pulses of cyclophosphamide 1000mg/m2 i.v., doxorubicin 50mg/m2 i.v. and vincristine 1.5mg/m2 i.v. In the case group this was preceded by ten, once daily, sessions of hyperbaric oxygen therapy (HBO2) administered either at 2.4 or 2.0 atmospheres absolute. Eleven out of 15 subjects tolerated a full course of HBO2 and chemotherapy. All 17 control subjects tolerated a full course of chemotherapy. Tumor extravascular extracellular or edema fluid was reduced after HBO2 but there was no reduction in tumor cell volume and no indication of increased vascularity on MRI. Clinical and pathological responses to chemotherapy were the same in both groups and there was no evidence of neovascularisation. Five year survival in those who tolerated the trial regime was 73% and did not differ between the groups. This mortality was cancer related.

Positron emission tomography using [(18)F]-fluorodeoxy-D-glucose to predict the pathologic response of breast cancer to primary chemotherapy.

PURPOSE: To determine whether [(18)F]-fluorodeoxy-D-glucose ([(18)F]-FDG) positron emission tomography (PET) can predict the pathologic response of primary and metastatic breast cancer to chemotherapy. PATIENTS AND METHODS: Thirty patients with noninflammatory, large (> 3 cm), or locally advanced breast cancers received eight doses of primary chemotherapy. Dynamic PET imaging was performed immediately before the first, second, and fifth doses and after the last dose of treatment. Primary tumors and involved axillary lymph nodes were identified, and the [(18)F]-FDG uptake values were calculated (expressed as semiquantitative dose uptake ratio [DUR] and influx constant [K]). Pathologic response was determined after chemotherapy by evaluation of surgical resection specimens. RESULTS: Thirty-one primary breast lesions were identified. The mean pretreatment DUR values of the eight lesions that achieved a complete microscopic pathologic response were significantly (P =.037) higher than those from less responsive lesions. The mean reduction in DUR after the first pulse of chemotherapy was significantly greater in lesions that achieved a partial (P =.013), complete macroscopic (P =.003), or complete microscopic (P =.001) pathologic response. PET after a single pulse of chemotherapy was able to predict complete pathologic response with a sensitivity of 90% and a specificity of 74%. Eleven patients had pathologic evidence of lymph node metastases. Mean pretreatment DUR values in the metastatic lesions that responded did not differ significantly from those that failed to respond (P =.076). However, mean pretreatment K values were significantly higher in ultimately responsive cancers (P =.037). The mean change in DUR and K after the first pulse of chemotherapy was significantly greater in responding lesions (DUR, P =.038; K, P =.012). CONCLUSION: [(18)F]-FDG PET imaging of primary and metastatic breast cancer after a single pulse of chemotherapy may be of value in the prediction of pathologic treatment response.

Vaccination and malignant disease: promising therapeutic approach.

Immunotherapy of cancer is now entering its second century. Much of our understanding of the complex interaction between tumours and the host immune system has come about because of technological and immunobiological advances in very recent years. For some malignancies, such as bladder cancer and malignant melanoma, immunotherapy is becoming an accepted form of adjuvant therapy. However, for most types of cancer, immunotherapy remains experimental and the majority of surgeons will have had little experience of immunotherapy in the clinical setting. This review provides a background to the scientific basis of immunotherapy, how different forms of immunotherapy are delivered and how their effects are monitored.

The cognitive effects of recombinant interleukin-2 (rIL-2) therapy: a controlled clinical trial using computerised assessments.

It has been suggested that patients undergoing treatment with recombinant interleukin-2 (rIL-2) may develop cognitive impairment. 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) and chemotherapy alone. Assessments were carried out daily whilst patients were in hospital and regularly between cycles of treatment using state-of-the-art computerised cognitive assessment, as well as traditional psychometric tests. Rigorous discontinuation criteria were applied to ensure that the effect of time-related variables did not influence the results. One patient developed repeated transient psychotic episodes associated with rIL-2 infusions and another regularly became confused. Computerised cognitive assessments revealed that immunochemotherapy produced significant impairment in various tasks, especially reaction time, picture recognition and vigilance. These effects were not due to sleep deprivation or pyrexia. For most patients, cognitive functioning was restored to the baseline level within 10 days following the cessation of rIL-2. In conclusion, during infusions of rIL-2, some patients experience severe confusion and amnesia which resembles some of the major cognitive impairments associated with dementias such as Alzheimer's disease. Computerised cognitive assessment using the Cognitive Drug Research system provides a feasible, sensitive and reliable method of evaluating cognitive changes in patients with cancer. It could usefully be included in quality of life assessments in clinical trials where treatment-related cognitive changes need to be evaluated.

A phase III study of recombinant interleukin-2, 5-fluorouracil and leucovorin versus 5-fluorouracil and leucovorin in patients with unresectable or metastatic colorectal carcinoma.

135 patients with locally advanced or metastatic colorectal cancer were entered into a phase III trial evaluating the efficacy of chemoimmunotherapy [recombinant interleukin 2 (rIL2)/5-fluorouracil (5-FU) and leucovorin (LV)] versus chemotherapy alone (5-FU/LV). A cycle of chemoimmunotherapy comprised a constant intravenous infusion of rIL2 at a dose of 18 x 10(6) U/m2/24 h for 120 h, followed by three bolus injections of 5-FU (600 mg/m2) and LV (25 mg/m2) at weekly intervals. Patients receiving chemotherapy alone received 5-FU/LV at the same dose at weekly intervals for 6 weeks followed by a rest period of 2 weeks, constituting one cycle of therapy. A maximum of 6 months therapy was given in both arms of the study. The response rates (complete and partial responses) were 17% in patients receiving rIL2/5-FU/LV versus 16% in those in the 5-FU/LV arm of the study. Median survival and progression-free survival were comparable for the two groups of patients, although there was a trend for a prolongation of survival in patients receiving chemoimmunotherapy compared with chemotherapy alone, beyond 12 months. Retrospective subgroup analyses revealed a significantly increased survival in poor prognosis patients (ECOG 1) treated with rIL2/5-FU/LV when compared to those receiving chemotherapy alone. Therefore, further studies evaluating the dose and duration of chemoimmunotherapy in patients with metastatic colorectal cancer seem warranted.

Psychological factors can predict the response to primary chemotherapy in patients with locally advanced breast cancer.

This study evaluated the possible value of psychological variables in predicting clinical and pathological response to primary chemotherapy. 96 women with newly diagnosed large, or locally advanced, breast cancer (T2 > 4 cm, T3, T4, N2 and M0) participated in a prospective, randomised trial to evaluate the effects of relaxation training with guided imagery and L-arginine on response to primary chemotherapy. Before the first of six cycles of primary chemotherapy, women were assessed using the Hospital Anxiety and Depression Scale (HADS) and the Eysenck Personality Questionnaire (EPQ). The primary outcomes were clinical response (evaluated using standard International Union Against Cancer (UICC) criteria) and pathological response (graded by means of a previously published 5-point scale) following primary chemotherapy. Stepwise linear regressions were used to estimate the predictive value of age, menopausal status, clinical nodal status, tumour size at diagnosis, oestrogen receptor status, dietary supplementation (L-arginine versus placebo), personality (EPQ-L scores), mood (HADS scores) and a psychological intervention. HADS depression score was a significant independent predictor of pathological response to chemotherapy. HADS anxiety score was a significant independent predictor of clinical response. Because the original tumour size before chemotherapy (also a significant predictor of clinical and pathological responses) was taken into account in the analyses, the results cannot be explained in terms of psychobiological factors related to tumour size. This study supports the importance of psychological factors as independent predictors of response to primary chemotherapy in patients with breast cancer. If they can be replicated, these findings have major implications for the management of women with breast cancer. Psychological factors need to be assessed and evaluated in future trials of chemotherapy.

Sephadex G-10 columns do not retain selectively T or B lymphocyte subpopulations.

The passage through Sephadex G-10 columns of lymphocytes prepared from different lymphoid compartments of man, guinea pig and rabbit, did not result in a selective loss of lymphocyte subsets, as assessed by various rosetting assays. This lack of T and B lymphocyte loss was seen irrespective of whether glass beads or a fine mesh net was used as a support for the Sephadex G-10 column.

Antibody-dependent cellular cytotoxicity and natural cytotoxicity: effect of pre-treatment of human lymphocytes with deionised water and ammonium chloride.

Deionised water is an efficient red blood cell lytic agent with no demonstrable deleterious effects on ADCC and natural cytotoxicity (blood and tonsil). Treatment with isotonic ammonium chloride, however, produces a significant reduction of both ADCC and natural cytotoxicity. This reduction is less pronounced if the treatment is carried out at 4 degrees C and is temporary, recovery occurring over a 24 h period of incubation at 37 degrees C.

Expression of the intermediate affinity interleukin-2 receptor by a human solid tumor-cell line - evidence for functional-activity.

Interleukin 2 (IL2) has well recognized pleiotropic effects on the activation, differentiation and proliferation of lymphoreticular cells, mediated via its specific membrane-bound receptors, but its effect on human solid tumour cells is poorly characterised. This study has used the A549 tumour cell line, derived from a human lung carcinoma, to demonstrate the presence of the interleukin 2 receptors (p70/75 beta and/or p55 alpha components) and to document functional activity. Immunohistochemical techniques demonstrated large amounts of the p70/75 beta chain of the interleukin 2 receptor, which is necessary for IL2 internalization, receptor signal transduction and mediation of the biological effects of IL2. In contrast, the p55 alpha chain was detected minimally and sparsely. In addition we documented the presence of IL2 in the nucleus of the A549 cells. The addition of exogenous rIL2 (10-500 IU/ml), to the culture medium of A549 cells over 48 hours resulted in a significant stimulation of DNA synthesis, as assessed by tritiated thymidine uptake. The results were; 9335+/-365, 12669+/-271, 12889+/-255, 19448+/-1427, 20189+/-1004 and 22586+/-1334 CPM, at 0 IU/ml, 10 IU/ml, 50 IU/ml, 100 IU/ml, 250 IU/ml and 500 IU/ml, respectively (means+/-SEM), and were significantly increased when compared with control cultures, p<0.001). These results may have important implications in our understanding of tumour-host interactions and in future strategies involving immunotherapy.

Differential responses of human tumor-cells to polyunsaturated Fatty-acids - stimulation of proliferation of a colon-tumor cell-line by docosahexaenoic Acid.

The potential differential effects of polyunsaturated fatty acids (5-100 mu g/ml) on four human tumour cell lines of different origin and a human fibroblast cell line were investigated. Following 6 days exposure to the fatty acids, gamma linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid, culture growth was almost completely abolished at the highest concentration used. At lower concentrations, the tumour cell lines exhibited a differential sensitivity to the inhibitory effects of the fatty acids on cell number (IC50, breast=lung>melanoma>colon). MRC-5 fibroblast cell numbers were significantly increased at low concentrations of gamma linolenate and eicosapentaenoate, but significantly reduced by docosahexaenoate. These effects on cell numbers were rapid in onset. Following only 2 days exposure to low concentrations of the fatty acids, cell numbers in the breast tumour cell line, MCF-7, were significantly reduced relative to controls. In contrast, the colon cell line, WiDR, was largely unaffected at this time, and in some cases, cell numbers were significantly increased. In the normal fibroblast cell line, cell numbers were significantly reduced by docosahexaenoate at concentrations greater than or equal to 20 mu g/ml. Following only 2 days exposure to PUFA, cell death in the breast cell cultures was maximally increased above controls by 20 mu g/ml of docosahexaenoate, whereas cell proliferation was unaffected at this concentration. In contrast, under these circumstances, cell proliferation in the colon cell cultures was significantly increased by this PUFA while there were only small increases in cell death. Our observations have highlighted the differential responses of human tumour cell lines to PUFAs and documented the stimulation of a colon cell line by certain PUFAs.

Potentiation of the response to chemotherapy in patients with breast cancer by dietary supplementation with L-arginine: results of a randomised controlled trial.

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.