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.

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.

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.

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.

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

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.

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.

Immunological aspects of head and neck cancer: biology, pathophysiology and therapeutic mechanisms.

Advanced cancer and head and neck cancer, in particular, remains a major clinical challenge with its associated morbidity and inevitable mortality. Local control of early disease is achievable in many solid tumours with current surgical and radiotherapeutic techniques but metastatic disease is associated with poor outcome and prognosis. It is known that, by the time of presentation, many patients will already have occult microscopic metastatic disease, and surgery and radiotherapy will not result in long-term survival. What little effect modern chemotherapeutic agents have on microscopic disease is, however, limited by systemic toxicity and multi-drug resistance. Immune surveillance is postulated to be operative in man. There is evidence, however, that patients with progressive tumour growth have failure of host defences both locally and systemically. Various possible defects and tumour escape mechanisms are discussed in the review. Immunotherapy and, in particular adoptive T cell therapy and DC therapy, show promise as putative tumour-specific therapy with clinical benefits. These techniques are undergoing development and evaluation in phase 1 clinical trials. Preliminary data suggest that the treatments are well tolerated. Unfortunately, there is limited evidence of significant and prolonged improvements in clinical outcome. Further developments of beneficial protocols (adjuvants, mode and frequency of vaccination etc) and multicentre studies of the use of immunotherapy in cancer are now required.

The role of gastrin in colorectal carcinogenesis.

Colorectal cancer is one of the leading causes of cancer-associated death in the United States and United Kingdom. In England and Wales, it is the second most common cancer in women and the third most common in men. Currently, treatment options for this debilitating disease are limited and surgical resection is the only curative treatment available. Despite rapid advances in surgery, as well as in adjuvant therapies such as radiotherapy and chemotherapy, there has been only a relatively modest improvement in mortality. The majority of colorectal cancers are epithelial-derived adenocarcinomas and arise from benign adenomas through the gain of mutations in key genes. Gastrin, an important polypeptide hormone, responsible for gastric acid secretion has been found to be involved in tumourigenesis in the gastrointestinal tract. When aberrantly expressed, the gastrin and gastrin/CCK-2 receptor genes can mediate powerful down stream events; the gastrin gene can impart anti-apoptotic properties while the gastrin/CCK-2 receptor can activate the transcription of a number of factors including ligands of the epidermal growth factor (EGF) receptor, the REG protein and matrix metalloproteinases (MMPs). In colonic tumourigenesis, gene expression of both gastrin and the gastrin/CCK-2 receptor is activated within epithelial cells at an early stage of the adenoma-carcinoma sequence. This review details the role played by gastrin in the adenoma-carcinoma sequence of colorectal carcinogenesis.

Immune suppression and isolated severe head injury: a significant clinical problem.

In the developed world, trauma is the principal cause of death under the age of 40 and is the third largest overall killer. In the UK, approximately 25,000 people die each year as a result of major injury, 25% as a result of head injuries alone. Despite improved diagnosis and management, infection remains the commonest complication in those patients surviving the initial injury. Some 5% are reported to die as a result of septic complications. Prolonged periods of intensive care and respiratory support predispose to infective respiratory complications. These patients in the absence of significant systemic injury and, as a result of severe head injury, are unable to mount an effective immune response. This literature review examines the changes that have been reported to occur in the immune system following isolated severe head injury and explores the relationship these changes may have to the increased development of infective complications.

Inflammatory bowel disease: dysfunction of GALT and gut bacterial flora (II).

The precise cause(s) of Crohn's disease and ulcerative colitis are unknown. From animal models and human studies it is well established that gut bacterial flora are essential for inducing the bowel inflammation. Animal models, when kept in a germ-free environment, do not develop colitis until the gut flora is reconstituted. It is not clear whether the bacterial antigens (Ags) from the normal flora or some other pathogenic bacterial Ags induce/propagate the inflammatory process in inflammatory bowel disease (IBD). Despite extensive research it has not been possible to identify any specific bacteria or virus as a credible cause of IBD. Recent understanding of quorum sensing molecules (QSMs) secreted by bacteria helps to explain the community behaviour in bacterial species. When QSMs reach a defined concentration, they activate bacterial proliferation and a number of virulence genes. Also, these molecules have been found to modulate the immune system to the advantage of the gut bacteria. They have not been well studied, however, in the gut. Inappropriate secretion of QSMs may alter the gut-associated lymphoid tissue (GALT) and, thereby, deregulate the immune tolerance normally present. Usefulness of probiotics and their immune modulating effects are being increasingly reported. Probiotics are also being used in the treatment of IBD. The interaction between the epithelial cells and the gut flora is very important as this is the first line of contact; this interaction may determine the induction of tolerance and mucosal integrity or immune activity, tissue inflammation and abnormal permeability. The latter is documented in patients with IBD and their healthy relatives. This may be an important factor in disruption of mucosal integrity and GALT dysfunction.

Surgical sepsis: dysregulation of immune function and therapeutic implications.

Sepsis is defined clinically as the systemic inflammatory response of the host to the documented systemic infection. The pathophysiological disturbance involves both the innate and adaptive immune systems encompassing cellular immunity, humoral components and the complement system. Dendritic cells (antigen-presenting cells) are key cells involved in the regulation of the immune response in sepsis, in particular in activating T cells and especially inducing the production and secretion of specific cytokines. These are the main mediators in establishing prominent disturbances of inflammation in patients with sepsis. The clinical features of the sepsis syndrome may vary from minor clinical disturbances to severe multiple organ failure and death of the host. Appropriate therapeutic strategies for patients with sepsis utilise conventional therapy and new novel forms of treatment, which are showing promise for the future.

Inflammatory bowel disease: dysfunction of GALT and gut bacterial flora (I).

Gut-associated lymphoid tissue (GALT) is the largest lymphoid organ in the body. This is not surprising considering the huge load of antigens (Ags) from food and commensal bacteria with which it interacts on a daily basis. Gut-associated lymphoid tissue has to recognise and allow the transfer of beneficial Ags whilst concurrently dealing with and successfully removing putative and overtly harmful Ags. This distinctive biological feature of GALT is believed to be crucial to good health. Deregulation or dysfunction of GALT is thought to predispose to inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease. The exact mechanism(s) underlying the pathogenesis of IBD is (are) poorly understood and the immunological defects in GALT are poorly documented. Advances in immunology have highlighted the importance of dendritic cells (DCs), which are the key Ag presenting cells in tissues and lymphoid compartments. Their crucial role in GALT, in health and disease is discussed in this review. Interaction of DCs with T cells in the gut produces a subset of T lymphocytes, which have immunosuppressive function. Inappropriate Ag uptake and presentation to naïve T cells in mesenteric lymph nodes may lead to T cell tolerance in GALT. These various complex factors in the gut are discussed and their possible relevance to IBD evaluated.

Breast cancer in women aged 35 and under: prognosis and survival.

BACKGROUND: Breast cancer comprises 22% of all cancers occurring in females but only 2% of cases occur in women aged 35 years and less. The presentation, behaviour and prognosis of breast cancer in such women, when compared with older women, are unclear and conflicting results have been reported. This study has audited clinical and pathological features in patients aged 35 years and under with breast cancer. METHODS: One hundred and thirteen patients were identified. The details of clinical staging, local and distant disease recurrence and overall survival were obtained for all patients. Histological sections of tumours were examined for type, grade, size, presence of surrounding intraductal carcinoma, presence of vascular space invasion, lymph node involvement and oestrogen receptor (ER) status. RESULTS: Histological examination of the tumours revealed that 94% were invasive ductal carcinoma. In 73% of the cases the tumours were grade 3, 49% of patients who underwent axillary surgery had lymph node involvement and 20% of tumours expressed ERs. The overall 5-year survival was 64%. Predictors of a poorer survival (univariate analysis) were: increasing tumour size, absence of ERs, presence of lymphovascular space invasion, axillary lymph node involvement and detectable metastases at the initial presentation. Multivariate analysis revealed that only lymphovascular space invasion was an independent predictor of a poor survival. CONCLUSION: Breast cancer in young (< or = 35 years) women is biologically aggressive, compared with older women. Factors predicting survival and overall survival rates, however, were comparable with those previously reported for older women with breast cancer.

What is achieved by mammographic surveillance after breast conservation treatment for breast cancer?

BACKGROUND: After breast conservation surgery for breast cancer, patients are followed up by regular clinical examination and mammography, at intervals which vary according to local practice. However, the optimum interval remains unclear with current guidelines suggesting mammography should be carried out every 1 to 2 years. This study has investigated this aspect and, in particular, whether mammography or clinical examination or both allowed an early detection of recurrence of the disease in the conserved breast. METHODS: A total of 695 patients who had undergone breast conservation surgery were identified from a database of prospectively recorded data during the period 1990 to 1995. Clinical examination and annual mammography were performed in accordance with local protocol. The results of clinical examination, mammography, and local recurrence rates were evaluated. RESULTS: A total of 2,181 mammograms were undertaken in the 695 patients studied. Local recurrence of disease in the conserved breast occurred in 21 patients (3%), at a mean follow-up of 3.5 years. The first identification of tumor recurrence was by clinical examination in 11 patients with local recurrence, and by the surveillance mammography in the other 10 patients with local recurrence. Overall, mammography detected the local recurrence in 13 of 20 (65%) patients who underwent this examination. In the other patients, the recurrence was detected on clinical examination only. In addition, in 52 patients, mammography was falsely positive, giving a false positive rate of 2.3%. Contralateral cancers in the opposite breast were detected in 2 patients. CONCLUSIONS: The detection of local disease after breast conservation surgery requires both clinical examination and mammography. In the context of our follow-up policy, in 52% of patients with local recurrence, this was first identified by clinical examination. Disease recurrence was identified in the other 48% of patients by mammographic surveillance. Overall, mammography will identify or confirm local recurrence in two thirds of women. However, in a small number of cases (2.3% in our series) mammography will give false positive results. New imaging modalities to assist in the diagnosis of local recurrence of disease after breast conservation surgery are required.

Dendritic cells (II): Role and therapeutic implications in cancer.

The potential to harness the effectiveness and specificity of the immune system underlies the growing interest in cancer immunotherapy. One such approach uses bone marrow-derived dendritic cells (DCs), phenotypically distinct and very potent antigen-presenting cells, to present tumour-associated antigens (TAAgs) and, thereby, generate tumour-specific immunity. Support for this strategy comes from animal studies that have demonstrated that DCs, when loaded ex vivo with tumour Ags or pulsed with peptides and administered to cancer-bearing hosts, can elicit T cell-mediated cancer destruction. These observations have led to clinical trials designed to investigate the immunological and clinical effects of Ag-pulsed DCs administered as a therapeutic vaccine to patients with cancer. In the design and conduct of such trials, important considerations include Ag selection, methods for introducing TAAgs into MHC class I and II processing pathways, methods for isolating and activating DCs, and route of administration. Although current DC-based vaccination methods are cumbersome and complex, promising preliminary results from clinical trials in patients with malignant lymphoma, melanoma, and prostate cancer suggest that immuno-therapeutic strategies, that take advantage of the unique properties of DCs, may ultimately prove both efficacious and widely applicable treatment in patients with cancer.

Inhibition of the contraction of collagen gels by extracts from human dermis.

Extracts from the human dermis were prepared and evaluated with respect to their ability to influence fibroblasts to contract collagen gels in vitro. The extract which had the most inhibitory effect on fibroblasts to cause contraction of collagen gels was extract D. It also inhibited fibroblast growth. Inhibition of contraction was not simply related to fibroblast cell numbers and the data suggests a specific effect upon the ability of fibroblasts to cause contraction. Other extracts were without significant effect.

Dendritic cells (I): Biological functions.

Dendritic cells (DCs) are potent antigen presenting cells (APCs) that possess the ability to stimulate naïve T cells. They comprise a system of leukocytes widely distributed in all tissues, especially in those that provide an environmental interface. DCs posses a heterogeneous haemopoietic lineage, in that subsets from different tissues have been shown to posses a differential morphology, phenotype and function. The ability to stimulate naïve T cell proliferation appears to be shared between these various DC subsets. It has been suggested that the so-called myeloid and lymphoid-derived subsets of DCs perform specific stimulatory or tolerogenic function, respectively. DCs are derived from bone marrow progenitors and circulate in the blood as immature precursors prior to migration into peripheral tissues. Within different tissues, DCs differentiate and become active in the taking up and processing of antigens (Ags), and their subsequent presentation on the cell surface linked to major histocompatibility (MHC) molecules. Upon appropriate stimulation, DCs undergo further maturation and migrate to secondary lymphoid tissues where they present Ag to T cells and induce an immune response. DCs are receiving increasing scientific and clinical interest due to their key role in anti-cancer host responses and potential use as biological adjuvants in tumour vaccines, as well as their involvement in the immunobiology of tolerance and autoimmunity.