Primary malignant tumor of the breast. Monitoring after treatment

The appropriate follow-up of primary breast cancer patients is a controversial topic: an intensive surveillance is the rule for many oncologists, but the beneficial effect of this attitude has never been demonstrated. Two consensus conferences focused on this issue, both discouraged the routine use of laboratory tests, chest X-ray, radionuclide bone scan or liver echography which involve a high financial cost. For these routine investigations the sensitivity to detect recurrence is less than 5%. History and physical examination remain the best methods to detect a recurrence, and mammogram is helpful for detecting recurrent disease in the treated breast or a new primary cancer in the controlateral breast, which both are curable. The purpose of intensive follow-up is earlier detection of recurrence in order to treat as early as possible, but two randomized studies failed to demonstrate a survival benefit in 2600 patients. However with current treatments, only a follow-up study including a very large number of patients could detect a survival difference. The demonstration of an intensive follow-up benefit is similar in screening studies where it is recommended to use the most predictive, the less toxic and the less expensive test. Serum C.A. 15.3 level which best anticipates diagnosis in follow-up is one of the best candidates to be used in a randomized study.     

Clinical decision-making in early breast cancer

OBJECTIVE: This in-depth review of the multidisciplinary approach to early breast cancer treatment (in situ, stage I and II) will update the surgeon about the indications, risks, and benefits of breast surgery, radiation therapy, adjuvant chemotherapy and hormonal therapy, and the importance of breast reconstructive surgery. SUMMARY BACKGROUND DATA: Breast cancer will occur in one of eight women in the United States during their lifetime and is the second leading cause of death in women from cancer. The practice of multidisciplinary breast cancer treatment has become the standard of care for the majority of breast cancer patients. If the surgeon is to retain the primary coordinating role in breast cancer management, then he or she must fully understand all modalities of oncology therapy and know how to deploy them to benefit individual patients. CONCLUSIONS: This article provides a framework for making clinical decisions about the appropriate combination and sequence of treatment for various presentations of early breast cancer.     

Diet supplemented with yoghurt or milk fermented by Lactobacillus casei DN-114 001 stimulates growth and brush-border enzyme activities in mouse small intestine

Adjuvant and neoadjuvant therapeutic principles have in recent years received increasing attention in the management of patients with carcinoma of the upper gastrointestinal tract. A series of randomized prospective trials has demonstrated that adjuvant postoperative radiation or chemotherapy does not result in a convincing survival advantage after complete tumor resection in gastric or esophageal cancer. The available data on the role of neoadjuvant preoperative therapy in these patients as yet permit no conclusion. While neoadjuvant therapy may reduce the tumor mass in a substantial portion of patients, a series of randomized controlled trials has shown that, compared to primary resection, a multimodal approach does not result in a survival benefit in patients with loco-regional, i.e. potentially resectable, tumors. In contrast, in patients with locally advanced tumors, i.e. tumors for which complete removal with primary surgery appears unlikely, neoadjuvant therapy increases the chance for complete tumor resection on subsequent surgery. However, only patients with objective histopathologic response to preoperative therapy appear to benefit from this approach. Compared to preoperative chemotherapy alone, combined radio-chemotherapy increases the rate of response, particularly in squamous cell esophageal cancer, but may also increase postoperative morbidity and mortality. Neoadjuvant therapy should therefore currently only be performed in experienced centers within the context of prospective clinical trials. The identification of factors that would allow prediction of response to neoadjuvant or adjuvant therapy is the focus of ongoing studies.     

Is there an association between hormone replacement therapy and breast cancer?

The fear of breast cancer has been suggested as a potential reason why only a relatively small percentage of postmenopausal women who would benefit from hormone replacement therapy (HRT) are current users. The equivocal results from a large number of epidemiologic studies make it difficult to evaluate whether an association does indeed exist between the use of HRT and the incidence of breast cancer. The inability to provide conclusive evidence for or against this relationship may be attributed to methodologic problems in these studies, including small sample sizes, lack of information on specific hormonal preparations (e.g., dose and type), failure to control for the type of menopause, and surveillance bias. In an attempt to generalize results from different studies in a systematic manner, several meta-analyses have been conducted of the effects of estrogen replacement therapy (ERT) or HRT on the risk of breast cancer. This article summarizes the data from these meta-analyses and incorporates data from studies published after these meta-analyses that have addressed this question. Data from ongoing studies that use a randomized, controlled, longitudinal design on large numbers of women are necessary before a possible association between the use of HRT and breast cancer can be ascertained.     

Target volume and indications of radiotherapy in breast carcinoma

Breast-conserving surgery is now commonly used to treat breast cancer. While mastectomy has been the traditional treatment for ductal carcinoma in situ, it is felt to be excessive in most cases. A great effort has been made to identify pathobiological characteristics of DCIS that can be used to identify patients best suited for wide local excision vs. wide local excision and breast irradiation. Mastectomy and conservative surgery plus irradiation offer a similar outcome in patients with early stage invasive breast cancer. Radiotherapy has not been shown to improve survival but is able to reduce significantly the rate of local recurrence, which is regarded as a very undesirable outcome. There is still controversy concerning the necessity of irradiation of the breast in all patients. Analysis of predictors of outcome cannot identify a subgroup of patients with a very low risk for local breast recurrence who might not require radiation therapy. In premenopausal, node-positive breast cancer patients XRT has a beneficial effect not only on locoregional but also on systemic recurrences. Radiotherapy has to be integrated for a pre- or postoperative consolidation in new treatment concepts for locally advanced breast cancer which use primary chemotherapy and immediate or subsequent breast radiation. Radiation of internal mammary chain and supraclavicular fossa after conservative surgery does not lead to an increase in clinically important skin or pulmonary complications. Its role is being evaluated in current multicentre studies.     

Role of adjuvant chemotherapy in the treatment of invasive carcinoma of the urinary bladder

PURPOSE: The standard treatment for patients with muscle-invasive carcinoma of the urinary bladder is radical cystectomy. While radical cystectomy cures many patients with this tumor, almost 50% of them will develop metastatic disease. Adjuvant chemotherapy has been proposed for these patients in an attempt to reduce the probability of relapse and to improve survival. To assess whether adjuvant chemotherapy does benefit patients with muscle-invasive bladder cancer, we reviewed all phase II and III studies published in the English literature over the last 20 years. METHODS: A review of all published reports was facilitated by the use of Medline computer search and by manual search of the Index Medicus. RESULTS: Several comparative, nonrandomized studies have indicated that adjuvant chemotherapy may prolong disease-free survival. Four randomized studies have been conducted and all had a suboptimal patient accrual. Three studies used a cisplatin-containing combination chemotherapy and included primarily patients with non-organ-confined transitional-cell carcinoma (TCC) of the bladder. All three studies indicated that adjuvant chemotherapy improved disease-free survival and two of them also showed improvement in event-free survival and overall survival, respectively. CONCLUSION: Published series have been unable to establish an undisputed benefit of adjuvant chemotherapy over radical cystectomy alone for muscle-invasive bladder cancer. The interpretation of the available data is compromised by several methodologic and statistical problems. Thus, adjuvant chemotherapy cannot be considered as a standard treatment for all patients with muscle-invasive carcinoma of the bladder. Well-designed prospective randomized studies are needed to clarify the role of adjuvant chemotherapy in this disease. However, outside a protocol setting, there is some evidence that patients with extravesical disease or with lymph node involvement may benefit from adjuvant treatment with cisplatin-based combination chemotherapy. No data support such an approach for patients with muscle-invasive but organ-confined bladder cancer.     

Respective roles of radiotherapy and chemotherapy in adjuvant treatment of cancer of the breast: theoretical importance and feasibility of chemoradiotherapy

Concomitant radiochemotherapy is of potential interest in the treatment of early stage breast cancer. Radiotherapy improves local control after both conservative surgery and mastectomy and in this last case also improves overall survival. Some questions however still exist concerning the role of the delay between surgery and radiotherapy on the efficacy of this treatment. Over 6 months, the benefit due to radiotherapy could be reduced. Adjuvant chemotherapy leads to improved survival in all categories of patients with breast cancer, either with or without axillary-node involvement. Anthracyclin-containing regimens seem to be the most efficient, but their superiority on "historical" standard regimens such as cyclophosphamide-methotrexate-5-fluorouracil has never been fully established. Chemotherapy and radiotherapy have synergistic effects. Used simultaneously, their effect on residual disease after surgery could be increased. Moreover, this therapeutic modality enables reduction of treatment duration as well as the delay between surgery and radiotherapy. Some studies have demonstrated the good tolerance of concomitant radiotherapy and FNC (5-fluoro-uracil, mitoxantrone and cyclophosphamide) or CMF. Three French randomized trials testing the value of concomitant vs sequential radiotherapy + chemotherapy are ongoing. However, careful and critical interpretation of survival data will be required to consider concomitant chemoradiotherapy as a standard adjuvant treatment of early stage breast cancer.     

Chemotherapy in non-small cell lung cancer: a review

Lung cancer, of which non-small cell carcinoma is the most common, has been a significant therapeutic challenge for decades and will remain so for decades to come. Despite its prevalence, progress in the management of non-small cell lung cancer has been relatively slow. This is in part due to the pessimism of most physicians treating this disease, which has resulted in a relatively lackadaisical attitude with regards to clinical trials when compared to other solid tumours like breast or colorectal cancers. Nevertheless, the past decade has seen significant progress, specifically with regards to the management of locally advanced disease. Chemotherapy, though shown to be biologically active in non-small cell lung cancer, is considered an ineffective palliative tool in the setting of metastatic disease due to its toxicities and the "less than encouraging" response rates generated by the cisplatin-based combination regimen which is generally considered to be the most active currently available. The advent of new active agents such as paclitaxel and vinorelbine which are potentially less toxic may change this view. Conversely, the response rate of locally advanced disease to chemotherapy is significantly higher and this has resulted in numerous multimodality trials of neoadjuvant chemotherapy prior to surgery and/or radiation. To date, a number of randomised trials have shown that this approach can result in significant survival benefit for patients with locally advanced disease. An alternative approach makes use of the potential synergism between certain chemotherapeutic agents (such as cisplatin) and radiation when used concurrently. However, data on concurrent chemoradiotherapy in locally advanced disease have been largely based on single-arm studies and are inconclusive. Three randomised trials on concurrent chemoradiotherapy have been shown benefit for the use of combined modality in locally advanced disease. Hence, treatment of locally advanced disease should include chemotherapy as part of the combined modality approach. However, the optimal sequencing of these modalities would require well-designed randomised trials to determine.     

Trends in the use of radiation and chemotherapy in the initial management of patients with carcinoma of the uterine cervix

PURPOSE: The Commission on Cancer of the American College of Surgeons conducts Patient Care Evaluation studies to describe practice patterns and trends in disease management. This report surveys changing strategies in the initial treatment of patients with invasive cancer of the uterine cervix. METHODS AND MATERIALS: Using a standard data collection form designed by a multidisciplinary committee of specialists, cancer registrars at 703 hospitals submitted anonymous data on 11,721 total cervical cancer patients diagnosed in 1984 and 1990. RESULTS: Between the two study years, the use of radiation as all, or a component, of the initial course of therapy declined from 70 to 60.3%, coincident with a 32.3% increase in the use of hysterectomy alone and a 33.7% reduction in the use of radiation alone. The percentage of all patients receiving combined hysterectomy and radiation (preoperative or postoperative) remained virtually unchanged--10.2% in 1984, and 9.3% in 1990. However, women who were treated by hysterectomy in 1990 were less likely to receive radiation as part of their treatment than patients treated by hysterectomy in 1984. Among patients treated by radiation without hysterectomy, the use of intracavitary brachytherapy techniques substantially exceeded interstitial brachytherapy techniques in both study years. Among patients treated by local radiation without hysterectomy, the frequency of adjunctive chemotherapy use increased from 6.9% in 1984 to 24.8% in 1990, with chemotherapy and radiation increasingly administered concurrently rather than sequentially. Although differences based on age, histology, race/ethnicity, and insurance status were observed, these general management trends were seen in all groups. CONCLUSIONS: Changes in the utilization of radiation and surgery may reflect the increasing surgical involvement of gynecologic oncologists in the management of early stage cervical cancer, rather than significant alterations in the demographics of the disease. Although brachytherapy is recognized as an important component of radiation treatment, some patients may not receive the potential benefit of this modality. Despite controversy concerning its efficacy, the use of adjuvant systemic chemotherapy to supplement local treatment modalities appears to be increasing rapidly.     

Hormone therapy of metastasizing breast carcinoma

In patients with metastatic breast cancer, cure is almost always an exception, irrespective of the therapy given. Thus the preservation of the quality of life or palliation in case of symptoms must be the principal goal. Only a small group of patients with their tumour showing a highly aggressive behaviour should be considered for primary chemotherapy. Aggressive tumour growth is then characterized by negative hormonal receptors, short disease-free interval and predominant visceral tumour growth. For all other patients there is not enough advantage to justify the clearly higher toxicity of a primary chemotherapy. This majority of patients with metastatic breast cancer can profit to a higher degree from hormonal treatment. Irrespective of the type of the hormonal therapy, the response rate is positively correlated with postmenopausal status, high hormonal receptor expression, al long disease-free interval, no previous adjuvant therapy and higher age. Advantages and problems of the various forms of hormonal manipulations are discussed. The recommended sequence of therapy represents only a handrail that needs to be adjusted carefully, according to the individual situation, the needs and expectations of the patient and in due knowledge of the toxicity of each hormonal substance. Combinations of different hormonal agents do not yield an additional benefit and should therefore be dropped for a sequential approach.     

Management of arthritis

Over the last 25 years the diagnostic approaches and therapeutic strategies of breast cancer have dramatically changed. The relationship between diagnosis and therapy has gradually become more complex due to the ever more sophisticated diagnostic tools (mammographic screening, digital mammography, magnetic resonance, SPECT scan and FDG-PET), which have improved resolution limits and accuracy, and also due to the different therapeutic planning applied to breast cancer in these years (conservative surgery, neo-adjuvant chemotherapy, axillary dissection or not). Thus, in this paper, we have briefly analyzed the many open questions in breast cancer management and the clinical challenges of present diagnostic tools in relation to pre-, peri- and postoperative phases, and to therapeutic strategies in general. The main goal of mammographic screening is to detect early invasive cancers and to treat them at the first useful moment. However, at which age should one begin screening, and what is the impact on overall survival, the cost-effectiveness, and, most of all, the best operative approach to suspect lesions? Can digital mammography give a better quality of imaging with respect to conventional mammography? Does unexpected multicentricity and/or multifocality, which is sometimes showed by magnetic resonance, have any clinical relevance? Is this technique really better than traditional methods for the identification of local recurrence? Is scintimammography able to improve the low diagnostic accuracy of mammography on non-palpable breast lesions? Moreover, at present, the need for axillary dissection and its therapeutic and staging value is deeply debated: however, clinical detection of axillary metastases is not a reliable diagnostic tool and there are no conventional radiologic techniques to be used: recently nuclear medicine imaging has provided various approaches, such as SPECT scan with different tracers, FDG-PET, or lymphoscintigraphy with gamma probe sentinel biopsy: there are not only methodologic but also phylosophic differences in using these techniques. Neo-adjuvant chemotherapy has allowed a dramatic reduction of primary breast cancer with a replanning of the surgical approach to large breast tumours but, at the same time, has posed new questions such as the adequacy of diagnostic pre- and perioperative revaluation. Finally, does postoperative follow-up take advantage of intensive diagnostic programs and are there therapeutic margins which would improve survival of patients with metastatic disease? This paper is an attempt to analyze the answers given in the literature. Nevertheless, at present, this matter is globally in progress and a scientific debate will provide, in the near future, a new promising scenario for breast cancer management.     

Differentiating therapy in acute myeloid leukemia

Differentiating therapy is a new antineoplastic strategy which has received increasing attention due to the remarkable activity of the vitamin A derivative, all-trans retinoic acid (ATRA) in patients with acute promyelocytic leukemia (APL). Although it has been known for years that a variety of agents, including retinoids, could induce leukemic cells to differentiate in vitro, it was not until the initial report from Shanghai in 1988 that laboratory studies translated into clinical activity and benefit in patients. Since this initial report, a number of studies have confirmed that the majority of patients with both newly diagnosed and previously chemotherapy-treated patients with APL achieve complete remission (CR) with ATRA. In addition, the characteristic life-threatening coagulopathy resolves quickly. Several limitations to this approach have emerged, including the development of retinoid resistance, hyperleukocytosis and the retinoic acid syndrome, a constellation of findings including unexplained fever, fluid retention, pleuropericardial effusions and pulmonary infiltrates. Although ATRA is very effective in inducing CR, its benefits compared to conventional chemotherapy are only now being addressed. The first prospective randomized trial comparing ATRA plus chemotherapy to chemotherapy alone was terminated early because of an improved event-free survival for patients receiving ATRA. The benefit was attributable to a difference in relapse rate. A large, intergroup, prospective, randomized trial comparing conventional chemotherapy to ATRA for induction and ATRA to observation for maintenance has recently completed accrual and will provide insight into the emerging role of ATRA in patients with APL. ATRA represents the first example of a specific form of antileukemic therapy targeting a specific genetic abnormality and may serve as a paradigm for the development of differentiating therapy for patients with other hematologic malignancies.     

Systemic therapy for breast cancer

Currently available information suggests that the optimal duration of adjuvant therapy for breast cancer patients with no involved axillary nodes is 5 years, though controversy about this recommendation persists. In postmenopausal patients, disease-free survival appears to be improved by the addition of combination chemotherapy to tamoxifen. Recently reported studies indicate that there is no benefit to dose escalation of cyclophosphamide in adjuvant therapy and that the risk of secondary leukemia may be increased. The combination of paclitaxel and doxorubicin has been reported in single-institution studies to produce high response rates but may also be cardiotoxic. Recent reports indicate that a pharmacokinetic interaction between these two drugs may cause these clinical findings. New agents that may be of utility in the management of advanced or primary breast cancer include novel hormonal agents, notably the aromatase inhibitors, and the bisphosphonates.     

Prediction of recurrence for advanced breast cancer. Traditional and contemporary pathologic and molecular markers

Approximately 50% of patient with breast cancer ultimately develop metastases, among which only 10% to 15% of patients live 5 years or more. Patients with locally advanced (stage III) breast cancer have a 5-year survival rate of approximately 20% to 30%. Thus, despite high remission rates obtained with current therapies, the poor long-term results associated with the apparent plateau of response achievable with systemic therapies emphasize the necessity of identifying accurate prognostic factors for this group of patients. This will allow an informed discussion with the individual patient. In addition, prognostic information could be used to guide the therapy and also to identify those subgroups of patients who may benefit with less-aggressive therapies. Furthermore, in the context of randomized studies, prognostic factors can be used to stratify patients. Prognostic factors have been extensively studied in early-stage breast cancer. In comparison, only a few studies exist on biologic prognostic factors in advanced breast cancer. Based on the limited information available, it appears that the biologic factors prognostic for locally advanced breast cancer are similar to those reported for early-stage breast cancer. Apparently, certain factors have a prognostic value irrespective of the stage of the disease at the time of presentation. This would then suggest that certain factors maintain their significance as the breast cancer progresses from an overtly local to a systemic disease. It is already well recognized that histologic grade is a significant prognostic factor for early-stage as well as metastatic breast disease. Hormone receptors have been reported to be of prognostic value at all stages of disease. Proliferation rate assessed by a variety of techniques as well as determination of the Nottingham Primary Prognostic Index provides important information about the rate of the growth of the tumor. Thymidine labeling index and S-phase fraction also provide information in regard to response to chemotherapy. DNA ploidy has been reported to be of significance in prediction of response to adjuvant chemotherapy and to a lesser extent to hormone therapy. The value of DNA ploidy in relation to survival in advanced breast cancer, however, remains controversial. Other prognostic factors such as oncogenes, tumor suppressor genes, and growth factors have also shown some predictive value in advanced breast cancer. Similar to what has also been suggested in early breast cancer, much research still needs to be done to clarify the role of currently available prognostic factors and to identify new, more powerful discriminants.(ABSTRACT TRUNCATED AT 400 WORDS)     

Relationship between estrogen levels, use of hormone replacement therapy, and breast cancer

We sought to determine the strength of the evidence suggesting that estrogen and postmenopausal replacement hormones play a role in the development of breast cancer. We reviewed the existing English language literature in MEDLINE on hormones and breast cancer, including reports on cell proliferation and endogenous hormone levels, as well as epidemiologic studies of the relationship between the use of postmenopausal hormones and the risk of breast cancer in women. A factor that increases the probability that cancer will develop in an individual has been defined as a cancer cause. The Hill criteria for demonstrating a link between environmental factors and disease were used to review the evidence for a causal relationship between female hormones and breast cancer. We found evidence of a causal relationship between these hormones and breast cancer, based on the following criteria: consistency, dose-response pattern, biologic plausibility, temporality, strength of association, and coherence. The magnitude of the increase in breast cancer risk per year of hormone use is comparable to that associated with delaying menopause by a year. The positive relationship between endogenous hormone levels in postmenopausal women and risk of breast cancer supports a biologic mechanism for the relationship between use of hormones and increased risk of this disease. The finding that the increase in risk of breast cancer associated with increasing duration of hormone use does not vary substantially across studies offers further evidence for a causal relationship. We conclude that existing evidence supports a causal relationship between use of estrogens and progestins, levels of endogenous estrogens, and breast cancer incidence in postmenopausal women. Hormones may act to promote the late stages of carcinogenesis among postmenopausal women and to facilitate the proliferation of malignant cells. Strategies that do not cause breast cancer are urgently needed for the relief of menopausal symptoms and the long-term prevention of osteoporosis and heart disease.     

Popularity of less frequent follow up for breast cancer in randomised study: initial findings from the hotline study

OBJECTIVE: To compare the experiences of patients with breast cancer who were conventionally monitored with those in whom routine follow up was restricted to the time of mammography. DESIGN: Randomisation to conventional schedule of clinic visits or to visits only after mammography. Both cohorts received identical mammography and were invited to telephone for immediate appointments if they detected symptoms. SETTING: Combined breast clinic, Chelsea and Westminster Hospital. SUBJECTS: 211 eligible outpatients with a history of breast cancer. MAIN OUTCOME MEASURES: Acceptability of randomisation, interim use of telephone and general practitioner, satisfaction with allocation to follow up. RESULTS: Of 211 eligible patients, 196 (93%) opted for randomisation in the study. Of these, 55 were under 50 years, 78 were diagnosed fewer than five years before, 90 had stage T2-4 tumours, and 71 had involved axillary nodes. Patients who did not participate were more likely to be under 50 years, to be two to five years after diagnosis, and to have had aggressive primary disease. Twice as many patients in both groups expressed a preference for reducing rather than increasing follow up. No increased use of local practitioner services or telephone triage was apparent in the cohort randomised to less frequent follow up by specialists. CONCLUSIONS: Reducing the frequency of routine follow up has so far proved popular among patients with breast cancer at standard risk in this cohort. A multicentre study is needed to determine the effectiveness and cost-effectiveness of routine follow up with respect to disease outcomes.     

Central nervous system metastasis in breast cancer

BACKGROUND AND PURPOSE: Central nervous system (CNS) metastasis occurs in at least 30% of patients with breast cancer. Standard treatment is the same as in other solid tumors, though clinical behavior, and sensitivity to radiation therapy (RT) and to chemotherapy may differ considerably. Most of these patients die within a few months, but a substantial subgroup may survive a year or more. The last decade has given rise to new diagnostic methods, new surgical and radiotherapeutic techniques, and the clinical evidence of a chemotherapy permissive blood-brain barrier in CNS metastases. The literature was reviewed to assess the clinical impact of early diagnosis, recognition of prognostic factors, and of the recently developed therapeutic approaches. MATERIAL AND METHODS: Review of the literature on CNS involvement in breast cancer focusing on clinical studies on early diagnosis, new modes of treatment, and factors influencing outcome. RESULTS: Although randomized studies are still awaited, systemic chemotherapy seems a valuable alternative for RT of brain metastases in selected cases. In meningeal carcinomatosis, long survival may be independent of intraventricular chemotherapy. Neurotoxicity of intensive intraventricular treatment is considerable. In epidural metastasis, early diagnosis with prompt start of treatment remains the crucial factor for outcome. Radiation therapy is the mainstay of treatment of epidural metastasis, but new surgical techniques and even systemic chemotherapy should be considered in selected cases. CONCLUSIONS: Recognition of prognostic factors combined with appropriate use of various recently developed therapeutic possibilities will improve the clinical outcome including better local tumor control and less treatment-induced neurotoxicity in a considerable number of patients with CNS metastasis from breast cancer.     

Ex-vivo gene therapy using cytokine-transduced tumor vaccines: molecular and clinical pharmacology

Whether the current generation of cytokine gene-transduced tumor vaccines will show clinical efficacy is under study. Fortunately, the large safety profile so far observed with gene-transduced tumor vaccines can allow outpatient testing in large populations of patients in the adjuvant therapy situation. This will allow large studies statistically powered to see potentially important adjuvant therapy effects in the range that are observed for tamoxifen in breast cancer. For example, the outpatient, adjuvant therapy safety context has been established in the use of GM-CSF gene-transduced autologous prostate cancer vaccines following radical prostatectomy. Similar adjuvant therapy clinical trial efforts are anticipated with allogeneic breast, colon, pancreatic, and ovarian cancer in addition to prostate, renal cell carcinoma, and melanoma. The reverse translation of early clinical data back to basic laboratory research also suggests the field of cytokine gene-transduced tumor vaccine research will remain vibrant. Efforts are currently being directed on optimizing DC activation with polycistronic constructs of cytokine genes, and overexpressing the most relevant tumor-associated peptides. As in the case of antineoplastic drug development, not all lead compounds will become approved drugs in medical oncology. Rigorous yet innovative clinical trial designs will be key to the accelerated identification of cytokine gene-transduced vaccines that improve survival in cancer patients.     

Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients

The mechanisms causing resistance to chemotherapeutic drugs in cancer patients are poorly understood. Recent evidence suggests that different forms of chemotherapy may exert their cytotoxic effects by inducing apoptosis. The tumor suppressor gene P53 has a pivotal role inducing apoptosis in response to cellular damage. In vitro investigations have shown intact p53 to play a critical role executing cell death in response to treatment with cytotoxic drugs like 5-fluorouracil, etoposide and doxorubicin. Recently, mutations in the P53 gene were found to confer resistance to anthracyclines in a mouse sarcoma tumor model, and overexpression of the p53 protein (which, in most cases, is due to a mutated gene) was found to be associated with lack of response to cisplatin-based chemotherapy in non-small cell lung cancer. Previous studies have shown mutations in the P53 gene or overexpression of the p53 protein to predict a poor prognosis, but also a beneficial effect of adjuvant radiotherapy or chemotherapy in breast cancer. In this study we present data linking specific mutations in the P53 gene to primary resistance to doxorubicin therapy and early relapse in breast cancer patients.     

Acute therapy of episodic and chronic cluster headache with sumatriptan s.c. Results of a one-year long-term study

Breast cancer is the commonest malignancy to affect women. The malignant process may present clinicians with problems in establishing the diagnosis expeditiously, accurately staging the disease and assessing tumour response to primary systemic chemotherapy. Considerable recent interest has focused on the application of imaging techniques that utilize tumour-specific gamma-ray-emitting radiopharmaceuticals to resolve these problems. The wide availability of gamma camera systems makes single photon-imaging techniques, using radiopharmaceuticals incorporating conventional isotopes, attractive options. However, results concerning the detection of the primary breast cancer and the staging of axillary lymph nodes suggest that these techniques would appear to offer no significant advantages, when compared with those obtained using standard diagnostic methods. Dual gamma-ray-emission imaging by positron emission tomography (PET) may offer an alternative solution. Studies performed show that PET can accurately detect primary breast cancers, stage locoregional lymph nodes and visualize distant tumour metastases. Furthermore, PET may be able to monitor early tumour response to chemotherapy agents. It would appear, therefore, that dual gamma emission might have an important role to play in the management of patients with breast cancer.