Evaluation of patient reported outcome measures and costs of managing osteoarthritis of the hip.

The number of hospital admissions for a hip prosthesis increased by more than 91% between 2002 and 2019 in Belgium (1), making it one of the most common interventions in hospitals. The objective of this study is to evaluate patient-report- ed outcomes and hospital costs of hip replacement six months after surgery. Both generic (EQ-5D) and specific (HOOS) PROMs of general hospital patients undergoing hip replacement surgery in 2021 were conducted. The results of these PROMs were then combined with financial and health management data. The mean difference (SD) in QALYs between the preoperative and postoperative phases is 0.20 QALYs (0.32 QALYs). The average cost (SD) of all stays is €4,792 (€1,640). Amongst the five dimensions evaluated in the EQ-5D health questionnaire, the 'pain' dimension seems to be associated with the greatest improvement in quality of life. As regards Belgium, the 26,066 arthroplasties performed in 2020 might constitute a gain of 123,000 years of life in good health. The relationship between QALYs and costs described in this study posits a ratio of €23,960 per year of life gained in good health. Given that in Belgium more than 3% of the hospital healthcare budget is devoted to hip prostheses, it would seem relevant to us to apply PROM tools to the entire patient population to assess treatment effectiveness more broadly, identify patient needs and, also, monitor the quality of care provided.

[Medical human resources planning in Europe: A literature review of the forecasting models]. / La planification des médecins en Europe : une revue de la littérature des modèles de projection.

BACKGROUND: Healthcare is a labor-intensive sector in which half of the expenses are dedicated to human resources. Therefore, policy makers, at national and internal levels, attend to the number of practicing professionals and the skill mix. This paper aims to analyze the European forecasting model for supply and demand of physicians. METHODS: To describe the forecasting tools used for physician planning in Europe, a grey literature search was done in the OECD, WHO, and European Union libraries. Electronic databases such as Pubmed, Medine, Embase and Econlit were also searched. RESULTS: Quantitative methods for forecasting medical supply rely mainly on stock-and-flow simulations and less often on systemic dynamics. Parameters included in forecasting models exhibit wide variability for data availability and quality. The forecasting of physician needs is limited to healthcare consumption and rarely considers overall needs and service targets. Besides quantitative methods, horizon scanning enables an evaluation of the changes in supply and demand in an uncertain future based on qualitative techniques such as semi-structured interviews, Delphi Panels, or focus groups. Finally, supply and demand forecasting models should be regularly updated. Moreover, post-hoc analyze is also needed but too rarely implemented. CONCLUSION: Medical human resource planning in Europe is inconsistent. Political implementation of the results of forecasting projections is essential to insure efficient planning. However, crucial elements such as mobility data between Member States are poorly understood, impairing medical supply regulation policies. These policies are commonly limited to training regulations, while horizontal and vertical substitution is less frequently taken into consideration.

Evaluation of cost and length of stay, linked to complications associated with major surgical procedures.

INTRODUCTION: A lot of studies have demonstrated the possibility of reducing the number of post-operative complications in the domain of major surgical procedures with the use of medical preventive techniques. However, complications following surgical procedures are unfortunately frequent and are a major problem, not only because of the impact for the patient, but also because of economic consequences that they provoke. The aim of the present study is to evaluate the extra length of stay and the extra cost, born by the hospital and the social security, linked to complications, incurring after major surgical procedures. MATERIAL AND METHODS: Study based on the data from 13 Belgian hospitals for the year 2012. Complications were extracted through medical discharge summaries. The cost born by the social security was assessed on the basis of the billing data, hospital cost are taken from cost accounting studies. RESULTS: The rate of complication for all the hospitals is 6.6%. About 30.3% of inpatient stays having a major or extreme severity of index had a complication during the stay, 1.8% of stays with a minor or moderate severity of index had a complication. The extra length of stay is 19.38 days when the stay has had a complication (p < 0.001). The additional mean cost borne from the hospital perspective is €21 353.07 and €8 026.65 for the social security. This additional mean cost varies greatly from one hospital to another. DISCUSSION/CONCLUSION: The present study has shown that the actual financing do not cover real hospital costs in the field of major surgical procedures having caused complications. Results should encourage Belgian authorities to propose and finance preventive measures in order to reduce these complications, which represent major economic impacts, not only for authorities but also for hospitals.

[Cost evaluation of organ harvesting in a Belgian academic hospital]. / Evaluation du coût de revient des prélèvements d'organes effectués dans le cadre de l'activité de transplantation d'un centre universitaire belge.

INTRODUCTION: The aim of this study is (1) to describe the characteristics of the organ harvesting activity conducted in 2012 at the Erasme's Hospital, Brussels University Hospital, (2) to highlight the different combinations " type of donor/types of organ's retrieved " in relation to organ harvestings carried out within the hospital, and (3) to calculate the organ harvesting's cost of acts. METHODS: The study is conducted according to the hospital perspective. It assesses the consumption of medical and nursing staff resources, disposable material costs, medical device costs, drugs costs, sterile instruments and biomedical equipment costs, of the 34 organ harvesting procedures that has been conducted this year. Costs are calculated by procedure, by donor's type, by organ and by combinations. RESULTS: Total cost is 99.442 €, with an average cost per donor of 3.016 €, 3.292 € for DBD postmortem donor (Donor Brain Death) and 2.456 € for DCD type (Donor Cardio-Circulatory Death). The average cost per organ leading to a transplantation is 1.842 € for DCD type and 1.297 € for DBD. CONCLUSION: The results show that there is as many costs as the number of organ harvesting's combinations. Integrate the revenue generated by organ harvestings could establish whether funding sources cover the costs generated by this activity or if a reform of the nomenclature should be considered.

INTRODUCTION: Les objectifs de ce travail sont (1) de décrire les caractéristiques de l'activité de prélèvement d'organes réalisée en 2012 par l'Hôpital Erasme, Cliniques Universitaires de Bruxelles, (2) de mettre en évidence les différentes combinaisons " type de donneur/types d'organes prélevés " rencontrées dans le cadre des prélèvements d'organes effectués au sein de l'institution, et (3) de calculer le coût de revient des actes de prélèvement d'organes. Matériel et méthodes : L'évaluation du coût est menée du point de vue du fournisseur de soins. Elle évalue la consommation des ressources en personnel médical et soignant, produits médicaux courants, dispositifs médicaux de viscérosynthèse, spécialités pharmaceutiques, instruments stériles et équipements biomédicaux, de 34 procédures de prélèvement d'organes. Les coûts sont calculés par type de donneur, par organe et par combinaison de prélèvement. Résultats : Le coût total calculé s'élève à 99.442 €, avec un coût moyen par donneur vivant à 3.016 €, par donneur post-mortem de type DBD (Donor Brain Death) à 3.292 €, et de type DCD (Donor Cardio-Circulatory Death) à 2.456 €. Par organe prélevé ayant abouti à la transplantation, le coût moyen est de 1.842 € lorsqu'il provient d'un donneur de type DCD, et de 1.297 € s'il provient d'un donneur de type DBD. CONCLUSION: Les résultats montrent qu'il y a autant de coûts de prélèvement que de combinaisons de prélèvement. Intégrer les recettes générées par les prélèvements permettrait d'établir si les sources de financement couvrent les frais engendrés par cette activité, ou si une réforme de la nomenclature devrait être envisagée dans ce secteur d'activité.

[Medical supply planning : dynamic registry of physicians, sixth reform of the State and numerus clausus]. / Planification de l'offre médicale : cadastre dynamique des médecins, sixième réforme de l'Etat et numerus clausus.

INTRODUCTION: The last few years have seen major changes in the Belgian medical planning. The paper aims to describe them and to assess how they will affect the medical demography. METHOD: Grey literature review and federal and federated entities legislation summary. RESULTS: A new dynamic register allows a better knowledge of medical workforce in all sectors of labour market. Recent legislation evolutions induce fragmentation of competences related to human resource for health planning : federal authorities are responsive for the fixation of number of GP and specialists and community authorities for registration of health professionals and fixation of sub-quotas in different branches of specialised medicine. Finally, the French Community has setting up a multiple selection system of medical students that have to past an 'orientation test', a possible reorientation after January examinations and then a numerus fixus at the end of the first academic year. CONCLUSIONS: Dynamic register improves the knowledge of medical workforce repartition. However, the assessment of its volume shows methodological limitations. From an operational viewpoint, the fragmentation of competences will ask coordination effort from all authority levels to avoid impairment in planning process. Finally, French Community has to consider evaluation and ambitious revision of medical workforce planning in their region.

INTRODUCTION: Ces dernières années, la planification de l'offre médicale belge a connu des bouleversements majeurs. Cet article propose de les décrire et d'en apprécier l'impact pour le futur de la démographie médicale. METHODE: Revue de la littérature grise et des textes législatifs nationaux et de la Communauté française. RESULTATS: La mise en place d'un cadastre dynamique a permis de mieux connaître la force de travail des médecins au sein des différents secteurs d'activité sur le marché de travail. Les récentes évolutions législatives montrent un morcellement accru des compétences en termes de planification : le Fédéral étant compétent pour la fixation des quotas de généralistes et de spécialistes, et les Communautés pour l'enregistrement des professionnels de santé et des sousquotas par disciplines. Enfin, la Communauté française a mis en place un système d'hyper-sélection des candidats aux études de médecine soumis successivement au test d'orientation, à la session de janvier suivi d'une éventuelle réorientation, et à la session de juin accompagnée de l'épreuve de classement du numerus fixus. CONCLUSIONS: La mise en place du cadastre dynamique améliore grandement la connaissance de la répartition de la force de travail médicale. Cependant, l'évaluation de son volume pose d'importantes questions méthodologiques. D'un point de vue opérationnel, le morcellement des compétences demandera des efforts de coordination entre les différents niveaux de pouvoir pour ne pas porter préjudice au processus de planification. Enfin, la Communauté française ne pourra faire l'économie d'une évaluation et d'une révision ambitieuse de la planification des médecins sur son territoire.

[Evaluation of adverse events caused by intravesical BCG instillations: Has the strain used a potential implication?]. / Évaluation des effets indésirables des instillations endovésicales par BCG : implication potentielle de la souche utilisée ?

INTRODUCTION: Intravesical instillations of BCG represent an established treatment of high-risk non-muscle-invasive bladder cancer but also carry considerable toxicity. The aim of this work was to identify adverse effects, their impact on the treatment and the possible involvement of the BCG strain used. MATERIAL AND METHODS: To evaluate adverse events in terms of incidence, severity and moment of occurrence, we performed a retrospective analysis of all patients treated with BCG in our institution from 1998 to 2012. RESULTS: One hundred and forty-six patients were retained for analysis, 140 (95.9%) finished their first induction cycle. Thirty patients (20.6%) had to stop the treatment because of BCG-related adverse events, 80% of which happened during the first 3 BCG cycles (12 instillations). The strain used may have had a significant impact: 16 out of 42 patients (38.1%) treated with Connaught (Immucyst®) and 14 out of 104 patients (13.5%) treated with Tice (Oncotice®) had to stop treatment because of BCG related adverse events (P=0.0019) with an odds ratio of 2.83 (IC 95%: 1.52-5.23). CONCLUSION: BCG-related adverse events generally occur at the beginning of the treatment and therefore do not limit the use of BCG maintenance therapy. Good instillation practice and, in our series, the shift from Connaught to Tice strain enabled to significantly reduce BCG-related adverse events through time. The potential implication of the BCG strain used should be evaluated in prospective trials.

What can we learn from international comparisons of costs by DRG?

OBJECTIVES: The objective of this study was to compare costs data by diagnosis related group (DRG) between Belgium and Switzerland. Our hypotheses were that differences between countries can probably be explained by methodological differences in cost calculations, by differences in medical practices and by differences in cost structures within the two countries. METHODS: Classifications of DRG used in the two countries differ (AP-DRGs version 1.7 in Switzerland and APR-DRGs version 15.0 in Belgium). The first step of this study was to transform Belgian summaries into Swiss AP-DRGs. Belgian and Swiss data were calculated with a clinical costing methodology (full costing). Belgian and Swiss costs were converted into US$ PPP (purchasing power parity) in order to neutralize differences in purchasing power between countries. RESULTS: The results of this study showed higher costs in Switzerland despite standardization of cost data according to PPP. The difference is not explained by the case-mix index because this was similar for inliers between the two countries. The length of stay (LOS) was also quite similar for inliers between the two countries. The case-mix index was, however, higher for high outliers in Belgium, as reflected in a higher LOS for these patients. Higher costs in Switzerland are thus probably explained mainly by the higher number of agency staff by service in this country or because of differences in medical practices. CONCLUSIONS: It is possible to make international comparisons but only if there is standardization of the case-mix between countries and only if comparable accountancy methodologies are used. Harmonization of DRGs groups, nomenclature and accountancy is thus required.

[The financial impact of missed appointments in a gastroenterology unit and evaluation of preventive strategies]. / Impact financier de l'absentéisme des patients dans une consultation de gastro-entérologie et évaluation des mesures préventives.

Objectives of the study were to evaluate the missed appointments rate in a consultation of gastroenterology of a general hospital situated in the south part of the country, to evaluate financial consequences and to evaluate preventive strategies. During this study, the missed appointments rate was 19.4%. The risk to have a missed appointment is higher for patients that come for the first time in the hospital, coming for a visit, having an appointment in the afternoon, having less than 26 years and that have taken an appointment a long time ago. The loss of income in gastro-enterology was 77 Euro and 32 Euro outside gastro-enterology for a loss of income of 109.20 Euro by patient. The estimated loss of income for 711 patients that have missed their appointment is 71,984 Euro. Two preventive strategies of reminders were tested: the telephone reminder and the mail reminder. The non-attendance rate was lower for patients with a mail reminder. The percentage of deferred or cancelled appointments is higher for patients with a telephone reminder. The low cost of a reminder (telephone or mail) should stimulate the hospital direction to develop a system of reminders to limit the non-attendance rate, at least for patients with a higher risk of non-attendance.

Comparison of cost-weights scales methodologies in the perspective of a financing system based on pathologies.

OBJECTIVES: Objectives of this article are to evaluate the possibility to create a CW scale by pathology on the basis of cost data from Belgian hospitals, to compare several methodologies to create this CW scale, and to evaluate the financial impact of a modification of the financing system on hospitals' income. METHODS: CW scales were elaborated according to various methodologies in order to isolate the scale allowing the most adequate financing system, i.e. approaching the real costs as much as possible. Twelve scales were created. They vary according to the type of data used, according to DRGs and severities of illness included within the scale, and according to the variable used in order to isolate outliers. RESULTS: For a similar case-mix, Hospitals H2 and H5 would see their financing increased through a prospective system based on the selected CW scale (No. 6). This modification would generate a reduction in financing going from -1 to -9% according to hospitals. CONCLUSIONS: The cost database created made it possible to create a CW scale according to a technique which could constitute the first step of a PPS if advantages of a such financing system were established. In the Belgian context, it would be probably judicious to envisage regional databases allowing diversified methodological approaches whose results would be confronted, discussed, and coordinated at the federal level.

[Are extra costs generated by patients justifiable? Methodology and results from a study carried out in a Belgian general hospital]. / Les surcoûts engendrés par certains patients sont-ils justifiables? Méthodologie et résultats d'une étude réalisée dans un hôpital général belge.

Cost outliers account for 6 to 8% of hospital inpatient stays and concentrate 22 to 30% of inpatient costs. Explanatory factors were highlighted in various studies. They are the lenght of stay, an intensive care unit stay, the severity of illness index related to DRG and social factors. Patients are not always explained by these factors. The objective of this study is to analyse cases not explained by those factors, through a detailed analysis of medical files. In the studied hospital, there are 6,3% high cost outliers and 1,1% low cost outliers. These stays were isolated on the basis of a rule based on percentiles. Extra costs generated by high cost outliers are 6.999 euro per stay. The extra lenght of stay for these patients is 20,42 days. Among the 454 patients high cost outliers, 334 patients are explained by factors extracted from a statistical analysis based on a logistic regression (intensive care unit stay, severity of illness index, lenght of stay and social factors). The analysis of medical files of the 120 not explained inpatient stays highlights new explanatory factors (coding errors, heterogeneity of DRGs, etc.). At the end of this study, the conclusion is that a statistical analysis combined with a precise analysis of medical files allowed to explain the majority of cost outliers. An explanation is however not necessarily synonymous with medical justification.

Financial consequences of hospital-acquired bacteraemia in three Belgian hospitals in 2003 and 2004.

The financial and human costs of hospital-acquired infections are increasingly recognised in many healthcare systems. This study seeks to quantify excess expenditures on hospital-acquired bacteraemia (HAB) in three Belgian general hospitals in 2003 and 2004. Patients with HAB were compared with patients in the same All Patient Refined Diagnosis Related Groups (APR-DRGs) without HAB. Patient level costs were estimated using a hospital costing system developed by the 'Université Libre de Bruxelles', and compared with DRG-based funding for the three hospitals. HAB incidence was consistent with the national rate for two of the three hospitals, but considerably higher for the third. Both severity of illness and mortality were higher in the HAB group. Nosocomial bacteraemia was associated with an increased length of stay of 30 days and of 6.1 days in intensive care units. When compared with uninfected patients in the same DRG, treatment of HAB patients cost an additional euro 16,709. At current funding rates, hospitals made a mean profit of euro 446 for uninfected patients, but a mean loss of euro 2,431 for patients with HAB. Our findings suggest that hospitals have a financial interest in reducing the rate of HAB, even in a system which funds such complications through severity adjustments in the APR-DRG system. Growing international interest in pay for performance and other funding schemes will only strengthen these financial incentives.

Costs associated with hospital-acquired bacteraemia in a Belgian hospital.

Studies from around the world have shown that hospital-acquired infections increase the costs of medical care due to prolongation of hospital stay, and increased morbidity and mortality. The aim of this study was to determine the extra costs associated with hospital-acquired bacteraemias in a Belgian hospital in 2001 using administrative databases and, in particular, coded discharge data. The incidence was 6.6 per 10000 patient days. Patients with a hospital-acquired bacteraemia experienced a significantly longer stay (average 21.1 days, P<0.001), a significantly higher mortality (average 32.2%, P<0.01), and cost significantly more (average 12853 euro, P<0.001) than similar patients without bacteraemia. At present, the Belgian healthcare system covers most extra costs; however, in the future, these outcomes of hospital-acquired bacteraemia will not be funded and prevention will be a major concern for hospital management.

What is the optimal regimen for BCG intravesical therapy? Are six weekly instillations necessary?

OBJECTIVE: For more than 20 years, BCG intravesical therapy schedule has included 6 weekly instillations. Very few studies have, however, analyzed the rationale of this regimen. We previously demonstrated that intravesical BCG induced an increased peripheral immune response against mycobacterial antigens as compared to pretreatment values. In the present work, we have studied the weekly evolution of this immune response induced by intravesical BCG instillations. MATERIALS AND METHODS: The evolution of the lymphoproliferative response of peripheral blood mononuclear cells against BCG culture filtrate (CF), tuberculin (PPD) and BCG extract (EXT) was tested before, every week during the BCG instillations and at 3 and 6 months follow-up in 9 patients with superficial bladder cancer treated with 6 weekly BCG instillations. Lymphoproliferation was measured by means of a tritiated thymidine incorporation test. RESULTS: A significant increase in the lymphoproliferative response against PPD, CF and EXT was observed in 9, 8 and 7 of the 9 patients, respectively, as compared to pre-BCG values. The maximal lymphoproliferation was achieved after 4 instillations in 4/5 patients initially reactive against mycobacterial antigens whereas 2 of 4 initially nonreactive patients required 6 instillations. At 6 months' follow-up, lymphoproliferation against BCG and the other mycobacterial antigens returned to pre-BCG values in all patients. In 3 patients who received additional instillations because of tumor recurrence within 1 year of follow-up, the maximum immune response was observed already after 2 instillations. CONCLUSION: In most patients, the maximal peripheral immune response is already observed after 4 weekly instillations. However, patients not previously immunized against mycobacterial antigens may require 6 weekly instillations to achieve a maximum stimulation level. Our data support the need to further evaluate the role of this status before starting BCG instillations. It could be of interest to study whether 6 BCG instillations are really necessary in patients previously immune against mycobacterial antigens.

Superficial bladder tumors and increased reactivity against mycobacterial antigens before bacillus Calmette-Guerin therapy.

PURPOSE: The precise mechanism of action of bacillus Calmette-Guerin (BCG) in bladder cancer treatment remains poorly understood. Whether bladder tumor cells are destroyed by nonspecific mechanisms or targeted by specifically activated lymphocytes recognizing cognate antigens is unclear. To investigate a possible cross-reactivity between BCG and bladder cell tumors, we tested before BCG treatment the lymphoproliferation of peripheral blood lymphocytes against several mycobacterial antigens, including the secreted fibronectin binding antigen 85 complex from BCG (AG 85) in patients with superficial bladder tumors compared to control matched patients. MATERIALS AND METHODS: Using a whole blood assay, T cell response against purified protein derivative, BCG extract, whole BCG, purified AG 85, and the nonspecific mitogens pokeweed and phytohemagglutinin was investigated in 79 patients with superficial bladder tumors before BCG and in 39 control subjects without malignancy matched for age and sex. Neither group had a history of tuberculosis. Lymphoproliferation was measured with a tritiated thymidine uptake assay on day 7 of culture. RESULTS: Of the 79 patients with superficial transitional cell carcinoma, a significant lymphoproliferative response before BCG against PPD, BCG extract, whole BCG and AG 85 was observed in 65 (82.2%), 67 (84.81%), 30 (37.97%) and 49 (62.02%) patients, respectively. Of the 39 controls only 26 (64.1%), 23 (58.9%), 3 (7.7%) and 3 (7.7%) patients, respectively, had a significant lymphoproliferation against PPD, BCG extract, BCG and AG 85 (p >0.05, p = 0.004, p = 0.00001 and p = 0.00001, respectively). In terms of lymphoproliferative levels, patients with superficial transitional cell carcinoma also showed a significantly higher response against PPD (p = 0.000012), BCG extract (p = 0.000001), AG 85 (p = 0.000001), whole BCG (p = 0.00001) and pokeweed (p = 0.01) than controls but not against phytohemagglutinin. CONCLUSIONS: Patients with superficial transitional cell carcinoma demonstrate an increased lymphoproliferation against mycobacterial antigens before BCG compared to control subjects. Although a nonspecific activation of the immune system cannot be excluded at this stage, our data may suggest the possible existence of bladder cancer antigens cross-reactive with mycobacterial antigens responsible for boosting precursor cells witnessing previous contacts with mycobacteria. The implication of these findings in the antitumoral mechanism of action of BCG are under investigation.

Humoral response against heat shock proteins and other mycobacterial antigens after intravesical treatment with bacille Calmette-Guérin (BCG) in patients with superficial bladder cancer.

Few studies have analysed the antibody response during intravesical BCG immunotherapy for superficial bladder cancer. We have examined the evolution in serum antibody response against several heat shock proteins (hsp), including the recombinant mycobacterial hsp65 and the native protein P64 from BCG, GroEL from Escherichia coli (hsp60 family), recombinant mycobacterial hsp70 and the E. coli DnaK (hsp70 family), against purified protein derivative of tuberculin (PPD) and the AG85 complex of Mycobacterium bovis BCG, as well as against tetanus toxoid in 42 patients with a superficial bladder tumour, 28 treated with six intravesical BCG instillations and 14 patients used as controls. We also analysed the lymphoproliferative response of peripheral blood mononuclear cells against PPD in this population. Data of antibody responses at 6 weeks post BCG were available in all 28 patients, and at 4 month follow up in 17 patients. All patients who demonstrated a significant increase in IgG antibodies against PPD at 4 months follow up had a significant increase already at 6 weeks of follow up. In contrast, IgG antibodies against hsp increased significantly from 6 weeks to 4 months post-treatment. A significant increase in IgG antibodies against PPD, hsp65, P64, GroEL, and hsp70 at 4 months follow up was observed in 10/17, 8/17, 10/17, 4/17 and 8/17 patients. Native P64 protein elicited a higher antibody response than recombinant mycobacterial hsp65. No increase in antibody response was observed against Dnak from E. coli, against AG85 or tetanus toxoid after BCG therapy. An increase in IgG antibodies against P64 at 4 months follow up compared with pretreatment values was found to be a significant predictor of tumour recurrence (P<0.01). Further studies with a larger number of patients are needed to confirm the value of the antibody response against P64 as a clinical independent prognostic factor.

[The need of prolonged BCG treatment in superficial bladder cancer is suggested by the development of a peripheral immune response induced by BCG]. / La nécessité d'un traitement prolongé par BCG dans les cancers superficiels de la vessie est suggérée par l'évolution de la réponse immunitaire périphérique induite par le BCG.

Optimal duration of immunotherapy treatment by BCG for the prevention of recurrences of superficial bladder cancer is still unknown. We have studied the evolution and duration of the cellular immunity response at the peripheral level after BCG intravesical instillations. Our results show that immunity activation after BCG is of short duration and don't take more than 6 months. Our results support, strengthen and partially allow to explain the utility of maintenance treatment by BCG following 6-weekly instillations.

Evolution and clinical significance of the T cell proliferative and cytokine response directed against the fibronectin binding antigen 85 complex of bacillus Calmette-Guerin during intravesical treatment of superficial bladder cancer.

PURPOSE: The antitumorigenic effect of intravesical bacillus Calmette-Guerin (BCG) in superficial bladder cancer was reported to be initiated by the attachment of BCG to the bladder wall via fibronectin. The antigen 85 complex secreted in BCG culture filtrate binds specifically to fibronectin and is a powerful T cell stimulus. Therefore, we investigated the evolution and clinical significance of the cellular proliferative response and cytokine production during intravesical BCG therapy against this purified antigen 85 complex. MATERIALS AND METHODS: Evolution of the lymphoproliferation, interleukin-2 and interferon-gamma production of peripheral blood lymphocytes against tuberculin (purified protein derivative), purified antigen 85, BCG culture filtrate, whole BCG bacilli and pokeweed mitogen was tested before and after 6 weekly intravesical BCG instillations in 29 patients with superficial bladder cancer at intermediate or high risk for recurrence. RESULTS: A major increase in the lymphoproliferative response against purified protein derivative, antigen 85, BCG culture filtrate, whole BCG and pokeweed mitogen was observed in 69.0, 65.5, 79.3, 48.3 and 65.3% of the patients, respectively, analyzed after BCG therapy. Reactivity returned to baseline values at 6 months of followup. Of the patients who received a second BCG course because of tumor recurrence 66% had a novel increase in lymphoproliferation against antigen 85. An increase in the production of interleukin-2 and interferon-gamma by peripheral lymphocytes against antigen 85 was noted in 42.1 and 50% of the treated patients, respectively, after a single BCG course. During a mean followup of 23.11 months 48.5% of the patients remained tumor-free. No correlation could be found between the immunological response against any of the BCG antigens and the clinical evolution of the response. CONCLUSIONS: Intravesical BCG instillations induce a transient (less than 6 months) peripheral immune activation against several purified BCG antigens and among them the fibronectin binding antigen 85 complex. Reactivation is observed in most cases after additional BCG courses. The absence of long lasting immune activation after a single 6-week course of BCG could be related to the increased clinical efficacy observed with BCG maintenance instillations.