Mycobacterium vaccae (SRL172): a potential immunological adjuvant evaluated in rat prostate cancer

OBJECTIVE: To evaluate the potential of heat-killed Mycobacterium vaccae (SRL172) as a nonspecific immunostimulant and as an adjuvant to whole tumour cell vaccination in the rat model of prostate cancer. MATERIALS AND METHODS: SRL172 was used as a vaccine in the prevention and treatment of subcutaneous tumours in rats. Prevention experiments were conducted using subcutaneous MAT-LyLu tumours in Copenhagen rats, comparing vaccination with SRL172 alone, SRL172 plus autologous cells, and bacille Calmette-Guèrin (BCG) plus autologous cells before tumour implantation. Treatment experiments were conducted using subcutaneous MAT-LyLu tumours in the Copenhagen rat and subcutaneous PAIII tumours in the Lobund-Wistar rat. Tumours were induced by subcutaneous injection with tumour cells. Animals were then vaccinated with autologous cells, autologous cells plus SRL172, or SRL172 alone. RESULTS: SRL172 was effective as an adjuvant to autologous whole tumour cell vaccination in the prevention of MAT-LyLu tumours and the survival benefit was equivalent to that provided when the adjuvant was live-attenuated BCG. SRL172 alone did not reduce tumour take or tumour growth in this model and neither strategy was effective in delaying the growth of established MAT-LyLu tumours. In the Lobund-Wistar rat vaccination with autologous whole tumour cells and SRL172 significantly delayed the growth of established tumours. CONCLUSION: Mycobacterium vaccae deserves further evaluation as an adjuvant to whole tumour cell vaccination in a phase I clinical trial in patients with prostate cancer.     

First clinical trial of cat soft-tissue sarcomas treatment by electrochemotherapy

Electrochemotherapy combines bleomycin and local electric pulses that allow cell permeabilization and free access of bleomycin to its intracellular target. We report the first veterinarian clinical trial of electrochemotherapy in 12 cats with spontaneous large soft-tissue sarcomas that suffered relapse after treatment with conventional therapies. Permeabilizing electric pulses were delivered using external surface electrodes, as well as new needle-shaped electrodes that were designed to be inserted in tumours for more effective treatment of several-centimetre-thick tumour nodules. The electric pulses were applied to the tumours several times from 4 to 15-30 min after a bolus intravenous injection of 0.5 mg kg(-1) bleomycin. Tolerance to treatment was excellent without general side-effects. The cats showed local inflammatory reactions for a few days and disease stabilization lasted from 2 weeks to 7 months. One partial regression was observed, and the general absence of nodule volume decrease can be explained by local fibrotic reactions. Histological analysis of biopsies also revealed massive tumour cell death. The cats' lifespan increased (P<0.001), with a mean survival time of 6.1 months (maximum 18 months) compared with 0.8 months (maximum 1.5 months) for a group of 11 untreated control cats displaying similar carcinological features. Electrochemotherapy is clearly effective as a salvage treatment for large spontaneous solid tumours in adverse clinical situations and this is promising for future applications.     

Selective in vitro replication of herpes simplex virus type 1 (HSV-1) ICP34.5 null mutants in primary human CNS tumours--evaluation of a potentially effective clinical therapy

Primary tumours of the central nervous system (CNS) are an important cause of cancer-related deaths in adults and children. CNS tumours are mostly glial cell in origin and are predominantly astrocytomas. Conventional therapy of high-grade gliomas includes maximal resection followed by radiation treatment. The addition of adjuvant chemotherapy provides little improvement in survival time and hence assessment of novel therapies is imperative. We have evaluated the potential therapeutic use of the herpes simplex virus (HSV) mutant 1716 in the treatment of primary brain tumours. The mutant is deleted in the RL1 gene and fails to produce the virulence factor ICP34.5. 1716 replication was analysed in both established human glioma cell lines and in primary cell cultures derived from human tumour biopsy material. In the majority of cultures, virus replication occurred and consequential cell death resulted. In the minority of tumour cell lines which are non-permissive for mutant replication, premature shut-off of host cell protein synthesis was induced in response to lack of expression of ICP34.5. Hence RL1-negative mutants have the distinct advantage of providing a double hit phenomenon whereby cell death could occur by either pathway. Moreover, 1716, by virtue of its ability to replicate selectively within a tumour cell, has the potential to deliver a 'suicide' gene product to the required site immediately. It is our opinion that HSV which fails to express ICP34.5 could provide an effective tumour therapy.     

The presence of antibodies against HIV peptides in the sera of alloimmune mice and thalassemic patients is due to a polyclonal activation mechanism

The effect of Photofrin-based photodynamic therapy (PDT) and adjuvant treatment with serum vitamin D3-binding protein-derived macrophage-activating factor (DBPMAF) was examined using a mouse SCCVII tumour model (squamous cell carcinoma). The results show that DBPMAF can markedly enhance the curative effect of PDT. The most effective DBPMAF therapy consisted of a combination of intraperitoneal and peritumoral injections (50 and 0.5 ng kg-1 respectively) administered on days 0, 4, 8 and 12 after PDT. Used with a PDT treatment curative to 25% of the treated tumours, this DBPMAF regimen boosted the cures to 100%. The DBPMAF therapy alone showed no notable effect on the growth of SCCVII tumour. The PDT-induced immunosuppression, assessed by the evaluation of delayed-type contact hypersensitivity response in treated mice, was greatly reduced with the combined DBPMAF treatment. These observations suggest that the activation of macrophages in PDT-treated mice by adjuvant immunotherapy has a synergistic effect on tumour cures. As PDT not only reduces tumour burden but also induces inflammation, it is proposed that recruitment of the activated macrophages to the inflamed tumour lesions is the major factor for the complete eradication of tumours.     

L-type calcium current in catecholamine-induced cardiac hypertrophy in the rat

CONCLUSIONS: Intra-arterial infusion chemotherapy via the celiac axis combined with external beam radiotherapy might be an effective method for palliative and perioperative multimodal treatment in pancreatic cancer. To improve the dismal prognosis in resectable and nonresectable pancreatic cancer, the results of multimodal palliative, adjuvant, and neoadjuvant therapies were reviewed and put into perspective with the results of two intra-arterial palliative and adjuvant treatment studies conducted at our department. The benefits and pitfalls of each method were outweighed, resulting in a concept for performing intra-arterial chemotherapy with radiotherapy in nonresectable stage UICC-III pancreatic cancer that eventually will be developed as a combined neoadjuvant/adjuvant treatment of all potentially resectable ductal pancreatic carcinomas.     

Exposure of macrophage-like cells to titanium particles does not affect bone resorption, but inhibits bone formation

Endocrine tumours of the pancreas, even in case of liver involvement, are generally characterized by a slower evolution and a better prognosis, if compared with ductal carcinoma. This fact gives reason to a radical surgical approach, whenever possible, and to the research of any effective adjuvant treatment. For this purpose, hepatic transarterial chemoembolization (TACE) has been proposed in recent years for the treatment of metastatic endocrine tumours. Out of 80 patients suffering from endocrine tumours of the pancreas, observed between January 1985 and December 1996, 28 (35%) presented liver metastases at the time of diagnosis. Twelve of these patients were submitted to palliative resection of pancreatic tumour and one or more cycles of TACE. Overall survival was 50% (6/12); median survival was 35.4 months (range 4-75). These results suggest that chemoembolization, combined with surgical resection of primary malignancy, appears to be able to control the disease for a certain time and to increase the survival rate.     

Evaluation of tryptamine in an impinger and on XAD-2 for the determination of hexamethylene-based isocyanates in spray-painting operations

We have investigated the relationship between immunohistochemically determined p53 status and outcome in 277 women with node-positive primary breast cancer who, following tumour excision and axillary clearance, were randomised to receive either 6 cycles of cyclophosphamide/methotrexate/S-fluorouracil (CMF) (n = 130) or no such post-operative treatment (n = 147). Follow-up data (median = 9 years) were available on all patients. A significant association was found between p53 status and survival. Patients with p53-positive tumours had a less favourable outcome than those with p53-negative disease. Women receiving adjuvant CMF chemotherapy had a significantly more favourable outcome compared to those who did not. The effect was seen both in women with p53-positive and p53-negative tumours; multivariate analysis showed relative risks for overall survival attributable to chemotherapy of 2.3 (95% CI 1.2-4.3) for women with p53-positive tumours and of 2.1 (95% CI 1.4-3.0) for those with p53-negative tumours. Thus, adjuvant chemotherapy with CMF is associated with a survival benefit in women with node-positive breast cancer irrespective of immunohistochemically determined p53 status.     

Adjuvant medical therapy for colorectal cancer

In the mid-1980s, trials of adjuvant therapy for colon cancer in the United States had a "no treatment" arm, which reflected the belief that effective adjuvant chemotherapy did not exist for patients with surgically resected disease at high risk for recurrence. However, with the observation in the early 1990s that postsurgical adjuvant 5-FU plus levamisole reduced tumor recurrence and ultimately increased overall survival in stage III colon cancer, the potential of effective adjuvant chemotherapy was realized. Questions about the duration of adjuvant chemotherapy, the specifics of chemotherapy schedule/drug selection, and its use in stage II colon cancer are beginning to be clarified in large, randomized adjuvant therapy trials. In rectal carcinomas, combined modality postoperative pelvic irradiation plus chemotherapy for stage II and III disease has been shown to reduce both local and systemic recurrences and to prolong survival compared with that in patients treated with local surgery and radiation. Again, large randomized trials are attempting to clarify both the optimal chemotherapeutic agents and schedules to be used and also whether preoperative combined modality therapy can improve the resectability rate, rate of sphincter preservation, and survival. Future trials will examine new agents shown to be effective in advanced disease as well as monoclonal antibodies, such as MoAb 17-1A, that may have selective activity in minimal disease. Improvement in overall survival remains the ultimate endpoint of future adjuvant therapy trials; however, trials will also critically examine toxicity, quality of life, pharmacoeconomics, and genetic and biologic correlates that may help select more appropriate candidates for adjuvant therapies.     

Inequality in infant morbidity: causes and consequences in England in the 1990s. ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood

Leiomyosarcomas (LMS) of the heart are exceptional primary malignant tumours with a catastrophic prognosis and a mean survival measured in months. Extensive radical surgical resection clearly remains the most appropriate treatment. We report three cases observed over a 3-year period, consisting of an LMS of the inferior vena cava, an LMS of the pulmonary artery trunk and an LMS of the left atrium. The first case was treated by radical resection and reconstruction by autologous vein graft of the cavorenal junction, the second case was treated by extensive resection and prosthetic reconstruction of the pulmonary artery bifurcation and the third case was treated by a first radical resection of the left atrium, requiring total cardiectomy and orthotopic heart transplantation for local recurrence at the sixth month. The survical was significantly improved compared to other treatment options (chemotherapy, radiotherapy). The first patient is still alive without recurrence at two years; the second died 12.5 months after the surgical procedure and the medium-term follow-up of the transplanted patient revealed cerebral and hepatic metastases nine months after transplantation. The authors review the literature concerning these extremely rare malignant tumours. Recent progress of diagnostic investigations, such as spiral CT with reconstruction, MRI, positron emission tomography (PET), are now able to establish the diagnosis more rapidly and therefore allow more radical surgical resection. This resection, possibly combined with venous reconstruction, must be associated with adjuvant therapies. Heart transplantation should be considered among the treatment options for leiomyosarcomas of the heart, in order to improve the poor prognosis of these lesions affections a young population.     

Pearson marrow pancreas syndrome: a molecular study and clinical management

Breast cancer is the commonest malignancy in women and although identification of this multi-system disease has increased, the survival rates have not dramatically altered over the past four decades. Optimium treatment of patients with breast cancer is a subject of great debate and traditionally may be divided into surgery, radiotherapy, chemotherapy and hormone manipulation. Halsted's radical mastectomy, although initially superseded by more mutilating surgery involving removal of tumour, breast, pectoral muscles and axillary contents, has given way to more conservative surgery and breast conservation, so now removal of the tumour with a marginal of healthy tissue is possible. Additional loco-regional radiotherapy has added to the increasing number of treatment options available to both doctor and patient. Systemic adjuvant therapy, primarily hormonal therapy, is used with the aim of decreasing the incidence of recurrence and distant tumour development. Through the process of randomized controlled trials these new therapeutic treatments have shown to be effective in the treatment of locoregional disease. Surgery in patients with advanced systemic disease is limited, however radiotherapy is of considerable importance and can be used to treat or palliate sites of metastases. In recent years trials have assessed chemotherapeutic regimens. However, limited number of patients and adequate randomization have hindered the confident acceptance of these results. Cyclophosphamide, methotrexate and 5 fluorouracil still remain the standard chemotherapeutic regimen, however many new drugs are currently undergoing trials and these or combinations of these may prove to be of future clinical use. Dramatic advances in cell and molecular biology have allowed the development of novel breast cancer therapies. Specific oncogenes and loss of tumour suppressor genes have been associated with decrease patient survival, with the presence of lymph node metastases and with decreased relapse free survival. Growth factor receptor blockers and tyrosine kinase inhibitors may be developed to specifically eradicate breast cancer cells. Immunotherapy and gene therapy may produce effective therapies. Trials utilizing cytokines and trials increasing the immunogenicity of tumours have already reported promising results. Surgery, chemotherapy, radiotherapy and hormone manipulation are the major treatment arms of breast cancer therapy. However, breast cancer still accounts for 20 percent of all female cancer deaths and the overall survival of patients has remained relatively static over the past forty years. From our increasing understanding of the pathological processes involved in the development and spread of breast cancer, new pharmaceutical, immunological and gene therapies may dramatically increase the cure rate of this serious disease.     

One hundred years of orthopedics in the Netherlands. VIII. Pediatric orthopedics

Orthopaedic disorders in children differ in type from those in adults: most frequent are congenital anomalies and disorders of growth and development. The special nature and relative rarity of these conditions justify the separate development of this branch of the discipline. Fractures almost always heal normally after closed reduction and immobilization in a plaster cast; fractures close to epiphyseal discs and in joints require special attention. Slipping of the upper femoral epiphysis necessitates surgical fixation of the epiphysis. Benign bone tumours occur relatively often and mostly require no surgical intervention. The prognosis of solid malignant bone tumours has improved since the introduction of (neo)adjuvant chemotherapy and limb-sparing surgery. In case of difference in leg length, the length of both legs is predicted with the aid of roentgenological measurements. Inhibition of the growth of the longer leg gives rise to fewer complications than lengthening of the short leg. The essence of the treatment of growth disorders due to abnormal ossification of the cartilage is to monitor the natural repair process and to intervene if permanent malformation threatens.     

Secretion of parathyroid hormone by abnormal human parathyroid glands in vitro

Radiation survival curves for Lewis lung tumours in the lungs ranging in size from 0-5 to 20 mm3 have been obtained, and a size-dependent variation in hypoxic fraction was found. Cell-survival studies following treatment of various sizes of s.c. tumours indicated that the effects of 60Co gamma-rays and the chemotherapeutic agents 1,3-bas(2-chloroethyl)-1-nitrosourea (BCNU) and cyclophosphamide are all size-dependent. Large pulmonary nodules which had regressed but had not been cured by cyclophosphamide regrew with a radiosensitivity that was characteristic of previously untreated tumours. The results give additional experimental support to the clinical interest in early adjuvant therapy of micrometastases, and sequential combined modality therapy for larger tumours.     

Alpha interferons--new therapeutic modalities

Interferons are naturally occurring substances. In fact, interferons are intercellular signalling proteins produced by cells in response to various biological and synthetic stimuli. Three major classes of interferons have been identified: interferons alpha, beta and gamma. Interferons originate from natural sources and are products of recombinant technology. Two forms of recombinant alpha-interferons, 2a and 2b, are available. Alpha-interferons are secreted and synthetised by leucocytes and lymphoblasts. The objective herein is to review the current therapeutic implications of alpha-interferons. Interferons alpha have antiviral, anticancer and immunomodulatory activities. Clinical trials have proved interferons alpha to be of special value as adjuvant therapy (first line drugs) for hairy cell leukemia, virus hepatitis B and C and condylomata acuminata. The efficacy of interferons alpha is now also being evaluated in other malignancies and virus diseases. For instance, interferons alpha are an important advanced modality in the management of chronic myelogenous leukemia and can be considered a first-line therapy option in patients who cannot receive or relapse following allogenic bone marrow transplant. Of course, further research is also required to evaluate combination therapies with interferons alpha and other agents. Presently malignancies have the broadest potential in application of interferons alpha therapy. Hairy cell leukemia responds to interferons alpha in up to 90% of patients, Kaposi's sarcoma, which occurs primarily in association with AIDS, benefit in up to 40% of patents, lymphomas respond in about 65% of patients whereas chronic myelogeneous leukemia in more than 80% of patients in early cases. The uses of interferons alpha in infectious diseases (condylomaty acuminata, rhinovirus infection, protozoal, parasitic and fungal intracellular infections) may also be significant. However, the cost of interferons alpha is too high. This makes interferons alpha a second line therapy, but not in patients where it is more effective than alternative treatment. Interferons alpha are cytokines (intercellular signalling proteins) which have antiviral, anticancer and immunomodulatory activities. Interferons alpha therapy represents an important advanced modality in the management of patients with hematological diseases, malignancies, lymphomas, solid malignant tumours and viral infections. Clinical trials have proved interferons alpha to be of special value as first line drugs for hairy cell leukemia, virus hepatitis B and C and condylomata accuminata. Interferons alpha are used as single primary therapy, adjuvant therapy and maintenance therapy. The limiting factor for the application of interferons alpha is the cost of treatment.     

Concurrent radiochemotherapy for patients with stage III non-small-cell lung cancer (NSCLC): long-term results of a phase II study

The distribution of estrogen and progesterone receptors (ER, PR) was assessed in the primary tumour in 1335 of 2704 (49%) consecutive new breast carcinoma patients (HORMREC). In a subgroup of 757 radically treated patients without systemic adjuvant treatment (RADOP) the relation of the ER and PR content to relapse and survival was evaluated. Three levels were defined for ER: ER-: <10 fmol/mg protein, ER+: moderate ER content >/= 10-99 fmol/mg protein, and high ER content >/= 100 fmol/mg protein. In 1288 patients of the HORMREC group who were evaluable for ER, 1061 (82%) had ER+ tumours, 685 (65%) of moderate content and 376 (35%) of high content, respectively. Among 917 patients, evaluable for PR, 723 (79%) tumours were PR+ (>/= 20 fmol/mg protein), of them 352 (49%) with a moderate content (>/= 20-99 fmol/mg protein) and 371 (51%) with a high content ( >/= 100 fmol/mg protein). The median ER content was significantly increased among the post-menopausal women as compared to the premenopausal women, whereas the median PR content showed no such differences. For the RADOP patients, no correlation between ER status and the first site of relapse was seen, whereas PR+ tumours tended to relapse more often locally than PR- tumours. In the univariate analysis the five-and 10-year tumour-related survival rates for all patients were not correlated with ER or PR positivity. One subgroup of patients with favourable outcome was identified on the basis of hormone receptors: Premenopausal women with tumours of moderately elevated ER content. In the multivariate analysis tumour size and axillary node status were the only independent predictors of survival. Measurements of hormone receptor status give weak prognostic information in radically treated patients with breast cancer as long as no adjuvant systemic treatment is applied. As todays' adjuvant treatment is based on the knowledge of hormone receptor status of the primary tumour, this information should be obtained routinely.     

Cases of multiple tumors in our clinic

Between 1989 and 1994, 719 patients had been treated with tumours at the Department of Surgery, Teaching Hospital of Semmelweis University Medical School, Budapest, Multiple tumours were found in 53 cases (7.37%), 49 of these being duplex and four triplex form. In men colorectal carcinoma was the most frequent while in women synchrone and metachrone breast cancers. Simultaneous breast tumors were most often found in senior patients (mean age 72.7) and metachrone ones at younger age (first tumor at 54.8 and the second one at 65.4 years of age, the following time being 10.6 years). Colorectal and gynecological tumours appeared with breast cancer in 5 cases. Regional colorectal tumours developed in five patients after radiotreatment of the pelvis. Familiar accumulation of colorectal cancer occurred in 4 cases. Lynch syndrome developed in 2 patients. The role of genetical factors is known in this group of illness, and they need to be screened. In this study the metachrone cancer in women occurred most frequently and only these patients received oncological treatment. The more effective treatment is supposed to enhance the number of multiplex tumours in which etiological factors also can play a role likewise mutagen effects of the first cancer therapies. The importance of collecting and processing these data is to referre to those risks, which should be considered in our everyday diagnostic work and postoperative care in these groups of patients.     

Chemotherapy of metastatic soft tissue sarcoma

The chemosensitivity of bone sarcomas contrasts sharply with the comparative initial chemoresistance of soft tissue sarcomas. The lack of new effective cytotoxic agents, delayed treatment due to a clinical presentation which is often innocuous and the absence of a consensus about the role of adjuvant chemotherapy after adequate surgery account for the slow progress achieved in the treatment of these tumours and for such an appalling prognosis. Chemotherapy is still purely palliative except for certain specific metastatic lesions, and median overall survival is more often than not below 12 months. However, the optimization of the therapeutic index of the most active antimitotic drugs, the ever-increasing acceptance of the concept of a dose-effect for the majority of these lesions, the particularly promising objective response rates with intensive drug combinations and a better understanding of the development process of certain lesions and histologic subtypes make it possible to envisage a rapid improvement in their still far too dismal prognosis.     

Radiotherapy of epipharyngeal carcinoma: successes and limits as examples of new treatment strategies

In treating cancer patients, disease free survival and survival have been improved during the last decade by technical progress and new systemic therapies. In radiation therapy as well as in any other cancer treatment potential long-term side effects and complications need special attention. The success of doubling tumour control by radiation therapy in patients with head and neck tumours illustrates the needs of long-term follow-ups. Cost-effectiveness has to be considered, when treatment results of RT equal surgical results, as it is often the case in head and neck tumours as well as in other malignant diseases.     

Mechanisms of in vivo anti-neuroblastoma activity of human natural IgM

Normal human sera of healthy adults contain natural IgM antibodies which are cytotoxic for human neuroblastoma cells. In this study, we evaluated the anti-neuroblastoma activity of these natural IgM antibodies in nude rats bearing solid human neuroblastoma tumours. A single intravenous (i.v.) injection of purified cytotoxic IgM led to uptake of IgM in the tumours with massive perivascular complement activation and accumulation of neutrophil granulocytes after 24 h. Five consecutive i.v. injections of purified cytotoxic IgM into neuroblastoma-bearing animals resulted in complete growth arrest of even large established solid tumours which lasted for several weeks after discontinuation of the injections, whereas tumours of control animals continued to grow exponentially during the observation period. These studies suggest that natural anti-neuroblastoma IgM may have a potential as a novel therapeutic modality in the treatment of human neuroblastoma.     

Macular pattern dystrophy in patients with deafness and diabetes

Currently used and developing therapies for multiple sclerosis (MS) are dealing with the treatment of acute exacerbations, the prevention of relapses and of the progression of neurological handicap, the treatment of symptoms, and the repair of demyelinated lesions. New insights into the treatment of acute relapses as well as recent immunomodulatory and immunosuppressive agents tested in MS are exposed in this brief review. Interferon-beta (1a and 1b), copolymer 1 and new immunosuppressive therapies are particularly discussed with emphasis on their potential to alter the course of MS.     

Adjuvant therapies in combination with pancreatectomy for carcinoma of the pancreas

In the treatment of adenocarcinoma of the pancreas, surgical resection is the only curative strategy. However, the long-term survival rate after pancreatectomy remains poor, and most patients died of loco-regional and/or hepatic recurrence. Thus, we should perform effective adjuvant therapies in combination with surgery, in order to completely prevent these two types of cancer relapse. The present article is designed to introduce the recent reports on the adjuvant chemo-and/or radio-therapies for this cancer. As for loco-regional control, extended pancreatectomy plus chemoradiation seems to be most promising, and preoperative chemoradiation will be more popular in the near future. In order to decrease hepatic metastasis, our "2-channel chemotherapy", a continuous infusion of 5-FU via both hepatic artery and portal vein, is very promising. If postoperative survival is improved by combining these two types of regional therapy, the role of pancreatectomy will be enlarged and more widely understood in the near future.