Early embryo loss is associated with local production of nitric oxide by decidual mononuclear cells.

In early embryo loss, the fetus may be considered to be an allograft and, therefore, may be rejected by maternal immunocytes. However, the cytotoxic mechanisms involved are still poorly understood. We have previously shown the involvement of natural killer (NK) cells and mononuclear cells expressing Mac-1 (CD11b) and F4/80 in resorbing compared to nonresorbing embryos. In this study, the role of nitric oxide (NO) in the mechanism of early embryo loss was studied. Pregnant CBA/J females mated with DBA/2 males (20-30% early embryo loss) and CD1 females mated with CD1 males (5-10% early embryo loss) were studied on days 8, 10, and 12 of gestation. Cells from the implantation sites of individual embryos were tested for the production of nitrite and nitrate with or without in vitro challenge with lipopolysaccharide (LPS) to determine whether decidual macrophages were primed in situ. On day 12 of gestation, when resorption was clearly visible, resorbing embryos showed more than a fivefold increase in both basal- and LPS-induced nitrite and nitrate production compared to nonresorbing embryos in both mouse strains tested, indicating that the decidual mononuclear cells were primed. Furthermore, more than 20% of CBA/J embryos showed a significant nitrate release on days 8 and 10 of gestation before any signs of embryo cytopathology. This percentage corresponded to the spontaneous resorption rate seen in CBA/J female X DBA/2 male matings. Similarly, 4% of the embryos from pregnant CD1 mice on days 8 and 12 of gestation produced a significant amount of nitrate, which again correlated with the low incidence of resorption observed in these mice. Using immunohistochemistry, the presence of inducible nitric oxide synthase (iNOS) was detected at implantation sites. Furthermore, decidual cells positive for both iNOS and the macrophage marker Mac-1 were demonstrated in implantation sites by double immunostaining. This strongly suggests that decidual macrophages could be the cellular source of NO production. Aminoguanidine, a selective inhibitor of the iNOS, inhibited the in vitro production of nitric oxide by cells isolated from individual implantation sites, and more strikingly, significantly reduced early embryo losses in CBA/J females mated by DBA/2 males when given orally or parenterally to the gravid females starting on day 6 of gestation. In addition, aminoguanidine-treated pregnant mice showed a significant increase in average litter size when the pregnancies were allowed to proceed to term.(ABSTRACT TRUNCATED AT 400 WORDS)

Prevalence and clinical course of BK virus nephropathy in pancreas after kidney transplant patients.

The influence of BK virus nephropathy (BKVN) in pancreas after kidney (PAK) transplantation is unclear. A retrospective analysis of PAK transplants performed at our center was conducted to determine the impact of BKVN. Among 40 PAK transplants performed using sequential immunosuppression, four patients developed BKVN, as defined by a >20% rise in serum creatinine and BK viremia (BK plasma load >4 log copies/mL), at a median of 19 months following PAK. In all four patients, treatment of BKVN consisted of reduction in tacrolimus, cessation of mycophenolate mofetil, and introduction of leflunomide. With this approach, two patients experienced improvement or stabilization of renal function. The remaining two patients progressed to dialysis dependence despite treatment. Plasma BK load < or =5 log copies/mL was associated with graft preservation. Gender, age, delay between transplants, cumulative Thymoglobulin dose, and type of kidney donor were not associated with BK virus infection. Pancreas graft rejection or dysfunction was not observed with the above immunosuppression modification. Mean amylase and lipase > or =6 months following BKVN treatment remained normal. BKVN is an important cause of kidney allograft loss in PAK patients. Screening and early treatment of BKVN may enable preservation of kidney and pancreas grafts.

Evaluation of the role of exogenous pathogens on the incidence of embryo loss during early pregnancy in mice.

The mating of CBA/j female mice (H2k) by DBA/2j male mice (H2d) typically results in an elevated incidence of spontaneous embryo loss thus providing an ideal genetically controlled laboratory model for the study of the factors causing early embryo loss during pregnancy. There is now considerable data on the cells and factors involved in fetal resorption but little is known about the events which activate this process. While the activation of the maternal response to the fetal implant could have endogenous or genetic origins, a role for exogenous factors including microbial pathogens could also be involved. In order to investigate these possibilities, the reproductive success of CBA/j female x DBA/2j male matings in a conventional animal care facility were compared with matings in a specific pathogen free (SPF) animal facility. All animals housed under these conditions were routinely screened by immunoassay and culture, for the presence of a number of viral and bacterial pathogens of mice. The incidence of spontaneous embryo loss in specific pathogen free CBA female mice mated by DBA and other male strains was found to be virtually identical to that of CBA female mice infected with multiple viral pathogens and housed under otherwise identical conditions (non-SPF). However, the numbers of implantation per pregnancy was significantly greater in an SPF facility. Therefore, exposure of mating mice to exogenous viral and bacterial pathogens did not appear to alter the overall incidence of spontaneous embryo resorption. It was concluded that the immunomodulatory effects of infection by common murine pathogens neither augmented nor reduced post-implantation embryo losses.

DNA index and S phase fraction in uveal malignant melanomas.

AIMS: To predict 5 year survival in patients with uveal malignant melanomas DNA indices were studied. METHODS: Using 45 paraffin embedded uveal malignant melanomas, the DNA index and S phase fraction of each tumour were the predictor variables recorded. RESULTS: Using the Cox proportional hazards model, aneuploid tumours and tumours which had an S phase fraction greater than 4% were significant predictors of early death. In order to demonstrate a biological gradient between a larger DNA index and shorter survival time, linear regression and transformed linear regression models were used. However, no such gradient could be demonstrated. CONCLUSION: Although this study shows promise for the use of DNA studies in the prognosis of uveal malignant melanoma, the exact role of these techniques remains to be determined.

FPSUND: a new clinical classification of urinary incontinence.

Urinary incontinence is a frequent condition that is usually clinically classified into three main subgroups: urge, stress and mixed. The latter, which can account for up to 50% of the patients, is notoriously heterogeneous. It is one of the reasons why the reports of therapeutic approaches to treat incontinence vary in the medical literature and it also explains the difficulty to compare results between studies. In an attempt to address this problem and to clarify the field of urinary incontinence, we have developed new clinical classification of urinary incontinence (FPSUND) where each symptom related to incontinence is rated from 0 (no symptoms) to 3 (severe symptoms). In this acronym, "F" stands for frequency of micturition, "P" for the use of protection, "S" for the stress component of incontinence, "U" for urgency, "N" for the number of nocturnal micturition and "D" for the number of diurnal micturition. Urologists from nine different centers across Canada were asked to evaluate female patients suffering from urinary incontinence using the FPSUND classification. A total of 148 women, aged 18 to 70, suffering from urinary incontinence were thus enrolled in the study. A second, independent evaluation of the same patients was performed by registered nurses or by urodynamic technicians. The reproducibility of the classification between two observers, as measured by the Weighted Kappa score was excellent, with kappa scores between 0.47 and 0.74 (p<0.05). Overall, the users of the classification found it very easy to use in a clinical setting. We would like to propose the FPSUND classification of urinary incontinence as a useful mean to evaluate patients suffering from incontinence and as a way to assess treatment outcome.

Long term follow-up of intravesical Bacillus Calmette-Guerin for the treatment of bladder transitional cell carcinoma.

OBJECTIVE: To review the long-term follow-up, in terms of recurrence and progression, of transitional cell carcinoma of the bladder treated with intravesical BCG with the following indications: CIS, Ta and T1. MATERIALS AND METHODS: Ninety-two patients who had received complete course of BCG between 1987 and 1993 were included in the study and followed for an average of 59 months (range 12 to 102). RESULTS: The recurrence and progression were looked at. Patients treated with BCG for Carcinoma in situ, 11 of 19 (53%) remained tumor-free after 1 or 2 courses of BCG for the duration of the follow-up (mean 4.9 years, range 1.5 to 8.5 years). For patients treated for recurring tumors, 17 of 50 (34%) had no recurrences after 1 or 2 courses of BCG with the same follow-up. When facing multiple tumors, 10 of 23 (43%) patients did not experience recurrences. Therefore, in the 92 patients treated, 38 presented no recurrences after 1 or 2 courses of BCG, for a success rate of 41%. In terms of progression, of the 19 patients treated with BCG for CIS, 4 (21%) went on to develop muscle invasive disease. Of the 50 patients treated for recurrent tumors, 2 (4%) eventually developed lamina propria invasion (initial lesion was a Ta tumor), 4 (8%) carcinoma in situ and 7 (14%) muscle invasive disease, for an overall progression rate of 26% in this group. Of the 25 patients treated for multiple tumors, 1 (4%) developed CIS and 3 (12%) presented with muscle invasive disease, for an overall progression rate of 16% for the duration of the follow-up. Therefore, 21 of 92 (23%) patients had progression of their disease following BCG therapy. No prognostic factors for recurrence or progression could be identified in these tumors. CONCLUSION: When indications warrant its use, BCG is effective in reducing recurrences and limiting progression in TCC of the bladder. Recurrence within 2 years of treatment is, however, a sign of poor prognosis and other therapeutic options should be sought.

Transforming growth factor-ß levels in aqueous humor during experimentally induced uveitis.

The anterior chamber of the eye is known to be a site of immune privilege. Particularly, the aqueous humor (AqH) appears to possess unique immunoregulatory properties. The authors have previously shown that human AqH (HAqH) may increase or decrease the proliferation of different cell types. Although no single factor has been established as solely responsible for these effects, much attention has been given to the 24-30 kD fraction of AqH, where transforming growth factor-beta (TGF-ß) is found. The purpose of this study was to determine the changes occurring in the rabbit AqH (RAqH) in relation to intraocular inflammation. Heterologous lens or human serum albumin (HSA) immunization-induced uveitis models were used in two groups of New Zealand albino rabbits to study the relationship between uveitis and TGF-ß. AqH and serum samples were obtained serially before, during and after the induction of ocular inflammation. Systemic humoral immunity to HSA or lens antigens was monitored using enzyme-linked immunosorbent assay (ELISA). A mink lung epithelial cell (CCL-64) bioassay for TGF-ß was used to quantify the amount of this cytokine in RAqH. TGF-ß levels in RAqH increased fourfold after the first immunization. A sharp decrease in RAqH TGF-ß levels was found in association with the development of acute intraocular inflammation. The implications of this finding to the etiology of uveitis are discussed.

[FPSUND: a pan-Canadian evaluation of a clinical classification of urinary incontinence]. / FPSUND: évaluation pan-canadienne d'une classification clinique de l'incontinence urinaire.

Historically, urinary incontinence is divided into 3 subtypes: stress, urge and mixed. This latter group, which according to many studies can account for up to 50% of the patients, is very heterogenous. For this same reason, the reports of treatments of urinary incontinence are very difficult to analyse using this simple classification. In a attempt to clarify this situation and to help the acquisition of useful clinical information relating to urinary incontinence, were have developed a clinical classification of urinary incontinence (FPSUND) in which 6 symptoms are graded in severity from 0 to 3. In this acronym, the F stands for frequency, the P for the use of protection, the S for stress-related complaints, the U for urge-related complaints, the N for nocturia and the D for the number of daily micturitions. Urologists across Canada were sent the French or English version of the classification and used it to evaluate 148 female patients aged from 18 to 70, suffering from urinary incontinence. A second, independent evaluation, was also performed on the same patients by registered nurses or urodynamic technicians. Reproducibility between observers, as assessed by the weighted Kappa score ranged from 0.47 and 0.74 (p < 0.05), was very good. Generally, the users of the classification found it very easy to use. In summary, we propose the FPSUND clinical classification of urinary incontinence as a useful and accurate tool to classify urinary incontinence and as a means to assess treatment outcome.

Relationship between decidual leukocyte infiltration and spontaneous abortion in a murine model of early fetal resorption.

The relationship between the early cellular response to embryo implantation and subsequent embryo survival was explored. Immunohistochemistry using the anti-CD11b antibody (Mac-1) was used to localize and quantify maternal inflammatory cells present at the fetoplacental interface. CD 11b is expressed mostly on macrophages, but is also present on natural killer (NK) cells, neutrophils, and B cells. The occurrence of CD11b-positive cells at the fetoplacental interface was quantified in CBA/J females mated by DBA/2 males (20-30% embryo loss) and CBA/J females mated by BALB/c males (5-10% embryo loss) in order to investigate the relationship between infiltration by these types of cells and subsequent embryo loss. CD11b-positive cells were found to infiltrate decidua of each embryo starting at Day 6 of gestation. Their numbers sharply increased on Days 7 and 8, to a plateau on Days 8 to 10, well before any damage to the embryo is macroscopically visible on Days 10 to 12 of gestation. The resorption-prone mating of CBA/J female by DBA/2 male showed a significantly elevated number of CD11b-positive cells in 26% of the embryos on the eighth day of gestation compared to CBA/J female by BALB/c male matings which were taken as the reference mating. Moreover, experimental conditions modulating fetal survival in CBA/J mothers such as poly (I:C) treatment of DBA/2-mated females (lower survival) or mating with BALB/c males (higher survival than with the mating with DBA/2 males), were found to be associated with high or low numbers numbers of CD11b-positive cells at the fetoplacental interface. Furthermore, injection of anti-CD 11b into pregnant mice at Day 6 of gestation significantly reduced the subsequent incidence of resorption in the resorption prone CBA/J x DBA/2 mating. These results suggest that CD11b-positive cells are associated with the etiology of spontaneous abortion in this system.

Presence of activated macrophages in a murine model of early embryo loss.

PROBLEM: Even though our knowledge of the phenomenon at play at the fetoplacental interface has greatly advanced during the past years, a complete understanding of the reasons why the developing embryo is not rejected by maternal immune effector cells remains largely unknown. METHODS: We have used immunohistochemistry with the macrophage-specific markers F4/80 and MHC II to study the relationship between decidual infiltration and resorption in murine models of embryo loss between days 6 and 10 of gestation. RESULTS: Analysis of day 8 CBA/J x DBA/2 pregnancies has revealed 2 distinct populations of embryos. The majority (69.4%) expressed low levels of F4/80+ cells, but a minority (30.6%) expressed much higher level of the macrophage marker. In FBA/J x BALB/c, most embryos (91.7%) expressed low numbers of F4/80+ cells. As earlier experiments established that products of activated macrophages (TNF-alpha and nitric oxide) were implicated in embryo loss in this model, the activation status of the F4/80+ macrophages was assessed through the cell surface expression of MHC II. Again, a similar association was established: 30.6% of the CBA/J x DBA/2 embryos were infiltrated by significantly more MHC II+ cells than the control CBA/J x BALB/c mating. Finally, when coordinate expression of F4/80, MHC II and CD11b was assessed, it was found that an embryo significantly infiltrated by cells bearing one of the 3 markers was also heavily infiltrated by cells bearing the 2 other markers. CONCLUSIONS: This study has shown that the augmented infiltration of the deciduum with maternal macrophages is an early event which precedes spontaneous abortion of the early embryo.

Effects of sensory stimuli on the incidence of fetal resorption in a murine model of spontaneous abortion: the presence of an alien male and postimplantation embryo survival.

Pregnancy outcome may be altered by both genetic and environmental factors. The mating of CBA/J female mice with DBA/2 males normally results in pregnancies characterized by a relatively high incidence of early embryo compared with most other syngeneic or allogeneic matings. This study addressed the role of normal laboratory stress in the induction of early embryo loss. The previously studied 'Bruce effect' describes the total loss of preimplantation embryos (pregnancy block) that is apparently caused by the stress induced by the presence of an alien male and mediated by neuroimmunological effects on prolactin activity. To determine whether this effect could be responsible for the high incidence of postimplantation embryo losses in the CBA/J x DBA/2 model, the original DBA/2 male was replaced on day 6 of gestation by another DBA/2 male, a CBA/J, a C57Bl/6 or a BALB/c male. The relatively high incidence of embryo loss was not affected by removing the original DBA/2 male or introducing another DBA/2 or a CBA/J male, indicating that stress induced by an alien male did not increase the postimplantation losses in this model. Furthermore, the introduction of a DBA/2 male to a CBA/J female that had been mated with a BALB/c male did not elicit early embryo loss. However, the replacement of the original DBA/2 male by a BALB/c male dramatically reduced the incidence of early embryo loss in pregnant CBA/J female mice. The introduction of a C57Bl/6 male also reduced embryo loss but to a lesser extent.(ABSTRACT TRUNCATED AT 250 WORDS)

Decidual infiltration and activation of macrophages leads to early embryo loss.

PROBLEM: There is considerable controversy concerning the root cause and mechanisms of early embryo loss. It has been suggested that most pregnancy losses occur due to morphogenetic anomalies of the embryo. It has also been suggested that the maternal specific immune system rejects the embryo. METHODS: Existing data on the cell and molecular biology of early embryo loss in murine experimental models is reviewed. RESULTS: Using the CBA(female) x DBA/2(male) model of early embryo loss, it has been established that maternal inflammatory cells infiltrate the decidua basalis of all implantation sites within 48 hr after implantation. For most embryos, the relatively low numbers of macrophages (Mphi) and natural killer-like (NK-like) cells of maternal origin remain relatively constant after day 8, whereas 20-30% of the embryos show a significant increase in inflammatory cells in the maternal decidua, corresponding to the incidence of early embryo resorption visible at day 12. Evidence will be reviewed to suggest that decidual NK-like cells are not cytolytic but may be producing the Mphi-activating cytokine interferon gamma (IFN-gamma), which activates decidual Mphi and other cells. Furthermore, embryo loss is ameliorated by in vivo treatment with anti-IFNgamma or anti-NK antisera, indicating that NK-like cells and/or IFNgamma are required for embryo loss, but not for embryo survival. In resorbing embryos, the inflammatory Mphi show evidence of having been primed during early pregnancy, in that in vitro incubation with lipopolysaccharide induced the production of tumor necrosis factor alpha and nitric oxide. CONCLUSION: These findings support the concept that early embryo loss is a nonspecific event mediated by the triggering of cytotoxin production by primed decidual macrophages.

Immunological prevention of spontaneous early embryo resorption is mediated by non-specific immunosimulation.

PROBLEM: Spontaneous early embryo resorption following implantation occurs in many species, but little is known regarding the causes or the prevention of early pregnancy failure. Embryo and fetal loss have widely been assumed to be due to maternal allospecific immune rejection. Alloimmunization therapy with paternal tissues has been successfully used in human and murine pregnancies to prevent early embryo demise. The mechanisms of this treatment have been assumed to be the induction of antigen specific, fetal "graft" enhancing antibodies and suppressor cells. The purpose of this study was to investigate the validity of this assumption. METHOD: To investigate these general assumptions, female CBA/J mice were immunized with either specific or nonspecific antigens prior to mating with DBA/2 or Balb/c males. Further, a model system for the study of bacterial lipopolysaccharide (LPS) induced abortion was used to demonstrate the nature of antigen specific immune protection against abortion. RESULTS: Whereas the administration of 1 microgram of LPS to CFW female x CFW male pregnant mice on day 7 of gestation induced complete fetal resorption, prior immunization with 20 micrograms of LPS completely prevented LPS induced abortion as long as the anti-LPS antibody titers remained above a threshold value of about 1/500. Therefore, early embryo loss could be induced by a bacterial infection and could be prevented by appropriate immunity to abortogenic factors. However, due to the short half-life of IgM antibodies, immunity to LPS was short-lived and the protective effect of LPS immunization against LPS induced abortion waned after 5 wk. Through the use of the CBA/J female x DBA/2 male model system to study spontaneous early embryo loss, previous vaccination of CBA/J female mice with Balb/c spleen cells expressing paternal MHC antigens, complete Freund's adjuvant (CFA) or LPS, all decreased the incidence of spontaneous resorption in subsequent pregnancies. Similarly, a previous mating with a Balb/c male prevented spontaneous embryo loss for a period of up to 6 wk. However, none of the immunotherapeutic vaccinations or matings had a permanent effect on CBA/J female x DBA/2 male embryo survival, which one would have expected if specific immune mediators were involved. CONCLUSION: The results of this study indicated that the decrease in the incidence of spontaneous embryo resorption following alloimmunization was more likely to be due to nonspecific immunomodulatory effects on the immune system of the female mice, as opposed to specific antipaternal immunity. This may, in part, explain the placebo effects observed for alloimmunization therapy for human habitual pregnancy loss. The relevance of these results to the development of immunotherapy strategies for the prevention of habitual abortion is discussed.

Role of interferon-gamma in the priming of decidual macrophages for nitric oxide production and early pregnancy loss.

We have previously shown that both priming and triggering signals were needed for nitric oxide production by decidual macrophages and that nitric oxide was responsible for embryo wastage. In this study, we investigated the role of IFN-gamma as the primary signal for macrophage activation in early embryo loss. IFN-gamma-deficient (GKO) and heterozygous F1 control mice were injected with lipopolysaccharide (LPS) at day 7 of gestation. The results showed that the GKO mice were more resistant to LPS-induced embryo loss than the wild type. This suggested that IFN-gamma was needed for LPS-induced embryo resorption and that decidual macrophages from pregnant GKO mice were not primed and could not be activated when given LPS. Further, the results showed that IFN-gamma mRNA was simultaneously expressed in the same embryos that also expressed mRNA markers for macrophage activation (TNF-alpha and iNOS), indicating that macrophage activation could be a consequence of IFN-gamma production. Similarly, we investigated the role of IL-12 as a switch cytokine capable of eliciting TH1-associated cytokine production including IFN-gamma. The results showed that IL-12 mRNA expression was correlated with IFN-gamma expression and macrophage activation. In this in vivo study, we showed for the first time that spontaneously increased decidual IFN-gamma expression is detrimental to embryo survival.

Embryo infiltration by maternal macrophages is associated with selective expression of proto-oncogenes in a murine model of spontaneous abortion.

The causes and precise mechanisms leading to early embryo loss in mammals remain largely unknown, especially from a molecular point of view. Using the CBA/J x DBA/2 murine model of early spontaneous embryo loss (25-30% embryo loss), we have previously demonstrated the involvement of infiltrating activated macrophages and their cytolytic products such as nitric oxide and tumor necrosis factor alpha (TNF alpha) in the etiology of early embryo loss. On the other hand, far fewer of the CBA/J x Balb/c conceptuses (5-10% embryo loss) displayed significant cellular infiltration and nitric oxide and TNF alpha. Having used probes for cellular activation markers, we now present evidence indicating that significantly increased expression of AP-1 family members, Ha-ras, Ki-ras, v-erbA, v-raf, v-abl, and c-myc was present in 24.4% of the CBA/J x DBA/2 embryonic units that also harbored significant Mac-1, F4/80, and class II major histocompatibility complex (MHC) molecule cellular infiltration. In contrast, only 7% of CBA/J x Balb/c conceptuses displayed increased proto-oncogene expression and increased cellular infiltration. Therefore, macrophage infiltration, cellular activation as identified by the increased expression of proto-oncogenes, and the production of cytotoxic macrophage products are closely linked to early embryo loss. These data add to the evidence that activated maternal macrophages may be directly responsible for spontaneous pregnancy failure.

Early embryo loss is associated with the prior expression of macrophage activation markers in the decidua.

In early embryo loss, the activation of maternal immune effector mechanisms play a critical role in determining the success or failure of a pregnancy. We have previously shown that increased nitric oxide production by decidual macrophages is involved in early embryo loss occurring at day 12 of gestation. In this study, using reverse transcription-PCR and Southern blotting, the expression of inducible nitric oxide synthases (iNOS) and TNF-alpha mRNA was determined to quantify macrophage activation in individual murine embryos in a model of spontaneous early embryo loss. At day 8 of gestation, 32 and 29% of embryos with no apparent pathology showed an increase in iNOS and TNF-alpha mRNA expression, respectively. This corresponds to the natural resorption rate seen in the mouse model. In addition, the percentage of embryos with increased iNOS and TNF-alpha mRNA expression was further augmented when pregnant mice were induced to abort at a higher rate. These results showed, for the first time, a correlation between increased iNOS and TNF-alpha expression and embryo resorption. The results provide evidence for the presence of activated macrophages at implantation sites before overt embryo damage occurs.

Characterization of cadherins expressed by murine thymocytes.

Thymocytes develop in close apposition to the stromal cells of the thymus. The ontogeny of thymocytes is dependent on intimate interactions between these cells and the stromal cells. The molecular mechanisms involved in regulating thymocyte-stromal cell interactions remain to be clearly defined. In this study, we utilized a polymerase chain reaction strategy to identify members of the cadherin family of cell adhesion molecules that are expressed by CD4+ CD8+ thymocytes, the major cell type in the thymus. One classical cadherin (E-cadherin), three atypical cadherins (OB-cadherin) K-cadherin, and cadherin-8), and two novel cadherins (T1-cadherin and T2-cadherin) were found to be expressed by the CD4+ CD8+ thymocytes. The discovery that these cells display multiple cadherins opens a new area of investigation concerning the adhesive mechanisms involved in modulating thymocyte-stromal cell interactions. We speculate that cadherins will prove to play an essential role in the ontogeny of thymocytes.

Long-term followup of initial Ta grade 1 transitional cell carcinoma of the bladder.

PURPOSE: We evaluate the long-term outcome of initial Ta grade 1 transitional cell carcinoma. MATERIALS AND METHODS: A total of 152 patients with initial Ta grade 1 bladder tumor were followed for a mean of 76 months (range 6 to 241). Recurrence was defined as positive findings on cystoscopy or biopsy. Progression was defined as an increase in tumor grade or stage. RESULTS: Tumor recurrence in 83 of 152 patients (55%) was noted within 12 months of followup in 38 patients (46%), between 12 and 24 in 11 (13%), and between 24 and 60 in 22 (27%). A significant number of recurrences (12, 14%) were diagnosed more than 60 months after the first tumor. Of 83 patients with recurrence 31 (37%) had progression, including 21 to grade 2 and 2 to grade 3 disease. Carcinoma in situ was diagnosed in 3 patients and 5 had muscle invasive disease. Progression occurred more than 24 months after initial diagnosis in 20 patients and more than 60 months after first tumor event (2 had carcinoma in situ and 2 had muscle invasive disease) in 12. CONCLUSIONS: Ta grade 1 bladder transitional cell carcinomas have a high recurrence rate and progression is not uncommon. These findings warrant close long-term followup, even when in some settings the trend is to discontinue followup after 5 years without any abnormal findings.