Effects of transurethral resection under general anesthesia on tumor recurrence in non-muscle invasive bladder cancer

International Journal of Clinical Oncology - The effects of the type of anesthesia (spinal (SA) vs. general (GA)) used for transurethral resection of bladder tumor (TURBT) on non-muscle invasive...     

The clinicopathological characteristics of muscle-invasive bladder recurrence in upper tract urothelial carcinoma

This study aimed to clarify the clinical characteristics and oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) who developed muscle-invasive bladder cancer (MIBC) after radical nephroureterectomy (RNU). We identified 966 pTa-4N0-2M0 patients with UTUC who underwent RNU and clarified the risk factors for MIBC progression after initial intravesical recurrence (IVR). We also identified 318 patients with primary pT2-4N0-2M0 MIBC to compare the oncological outcomes with those of patients with UTUC who developed or progressed to MIBC. Furthermore, immunohistochemical examination of p53 and FGFR3 expression in tumor specimens was performed to compare UTUC of MIBC origin with primary MIBC. In total, 392 (40.6%) patients developed IVR after RNU and 46 (4.8%) developed MIBC at initial IVR or thereafter. As a result, pT1 stage on the initial IVR specimen, concomitant carcinoma in situ on the initial IVR specimen, and no intravesical adjuvant therapy after IVR were independent factors for MIBC progression. After propensity score matching adjustment, primary UTUC was a favorable indicator for cancer-specific death compared with primary MIBC. Subgroup molecular analysis revealed high FGFR3 expression in non-MIBC and MIBC specimens from primary UTUC, whereas low FGFR3 but high p53 expression was observed in specimens from primary MIBC tissue. In conclusion, our study demonstrated that patients with UTUC who develop MIBC recurrence after RNU exhibited the clinical characteristics of subsequent IVR more than those of primary UTUC. Of note, MIBC subsequent to UTUC may have favorable outcomes, probably due to the different molecular biological background compared with primary MIBC.     

Expression of the retinoblastoma protein RbAp48 in exocrine glands leads to Sj?gren's syndrome–like autoimmune exocrinopathy

Although several autoimmune diseases are known to develop in postmenopausal women, the mechanisms by which estrogen deficiency influences autoimmunity remain unclear. Recently, we found that retinoblastoma-associated protein 48 (RbAp48) induces tissue-specific apoptosis in the exocrine glands depending on the level of estrogen deficiency. In this study, we report that transgenic (Tg) expression of RbAp48 resulted in the development of autoimmune exocrinopathy resembling Sjögren''s syndrome. CD4⁺ T cell–mediated autoimmune lesions were aggravated with age, in association with autoantibody productions. Surprisingly, we obtained evidence that salivary and lacrimal epithelial cells can produce interferon-γ (IFN-γ) in addition to interleukin-18, which activates IFN regulatory factor-1 and class II transactivator. Indeed, autoimmune lesions in Rag2^−/− mice were induced by the adoptive transfer of lymph node T cells from RbAp48-Tg mice. These results indicate a novel immunocompetent role of epithelial cells that can produce IFN-γ, resulting in loss of local tolerance before developing gender-based autoimmunity.Autoimmune disease is controlled by environments that include gene variants or various cytokines (1, 2). It can increase susceptibility to autoimmunity by affecting the overall reactivity and quality of the cells of the immune system. There is an autoimmune disease specific for certain organs in the body, involving a response to an antigen expressed only in those organs. Antigen/organ specificity is affected by antigen presentation and recognition, antigen expression, and the state and response of the target organs (3, 4), which are maintained by a local immune system termed here “local tolerance.”Many mechanisms protect tissues from autoimmune damage. These include relative isolation from the immune system and inhibition of the function of invading lymphocytes. For example, the eye has barriers to T cell infiltration and produces immunosuppressive cytokines, such as TGF-β (5). Constitutive expression of Fas ligand within the privileged site might also prevent immune-mediated damage by eliminating Fas-expressing T cells (6). Although they have yet to be well demonstrated in spontaneous animal models or human disease, genetic effects at the level of tissue protection are therefore to be expected. Autoimmune organ damage can be mediated by CD4⁺ T cells, which play a crucial role in the development of autoimmunity (7–9). MHC class II alleles are probably involved in autoimmune disease because different alleles have different abilities to present peptides from target cells to autoreactive CD4⁺ T cells (10, 11). Certain class II alleles might predispose to autoimmunity by increasing positive selection or decreasing negative selection of autoreactive T cells in the thymus. They might also act by inhibiting selection in the thymus of the regulatory CD4⁺ T cells that are thought to prevent autoantigen-specific responses. Evidence for the local tolerance hypothesis is provided by the observation that autoimmune diseases are often tissue specific and sometimes involve antibodies against a restricted set of antigens, thereby prompting us to accept this most simple explanation for the initiation of autoimmunity. The loss of local tolerance is considered to result from the combined effect of different environmental factors. MHC class II genes are constitutively expressed only on hematopoietic cells involved in antigen presentation (dendritic cells, macrophages, B cells, and cortical thymic epithelial cells), but can be aberrantly induced by inflammatory stimuli on many other cell types (such as endothelial cells, hepatocytes, β cells of the pancreas, and thyrocytes) (12, 13). Although it has been implicated in allograft rejection (14), and subsequently in autoimmunity, it is still unknown whether to initiate autoimmunity class II molecules have to be expressed on professional APCs within secondary lymphoid organs or on nonhematopoietic cells of the target organ itself.It has been suggested that estrogenic action is responsible for the strong female preponderance of many autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren''s syndrome (SS) (15, 16). Recent evidence suggests that apoptosis plays a key role in the physiology and pathogenesis of various autoimmune diseases, including SS (17–21). We have demonstrated that estrogenic action influences target epithelial cells through Fas-mediated apoptosis in a murine model for SS (21). Recently, we found that tissue-specific apoptosis in the exocrine glands spontaneously occurring in estrogen-deficient mice may contribute to the development of autoimmune exocrinopathy (22). Searching for the role of estrogen deficiency in the development of autoimmunity, we have recently identified retinoblastoma-associated protein 48 (RbAp48) gene specific for estrogen deficiency–dependent apoptosis in the exocrine glands, and transgenic expression of RbAp48 gene induced tissue-specific apoptosis in the exocrine glands (23). In this transgenic mouse model, we propose a possible clear and defined ab initio relationship between aberrant exposure of MHC class II molecules on IFN-γ–producing epithelial cells and disease development (i.e., autoimmune exocrinopathy).     

Radiological findings of primary localized amyloidosis of the ureter

Localized amyloidosis is a rare condition, especially that involving the ureter. Because of its rarity and the difficulty in differentiating this condition from urothelial carcinoma by intravenous urography and computed tomography, nephroureterectomy has often been performed unnecessarily for this disease. The authors encountered two cases of this disease, both of which showed a negative urine cytology, no obvious mass effect, and a hypointensity on T2-weighted imaging. Because these findings are very rare in urothelial carcinoma, ureteroscopy-guided biopsy was performed, which yielded the diagnosis of amyloidosis. The patients were then treated and followed up at our institute. Primary localized amyloidosis of the ureter should be considered when evaluating ureteric lesions visualized as hypointensities on T2-weighted images that do not show an obvious mass effect, which could help in the avoidance of unnecessary surgery.     

Effects of separate application of three growth factors (TGF-beta1, EGF, and PDGF-BB) on mechanical properties of the in situ frozen-thawed anterior cruciate ligament

OBJECTIVE: To clarify effects of a separate application of TGF-beta1, EGF, and PDGF-BB on the material properties of the in situ frozen-thawed anterior cruciate ligament. DESIGN: Twenty-eight rabbits were divided into four groups after undergoing the in situ freeze-thaw treatment in the right anterior cruciate ligament. In 3 of the 4 groups, 4 ng TGF-beta1, 20 ng EGF, and 4 microg PDGF-BB was applied to the frozen anterior cruciate ligament, respectively. In the remaining sham treatment group, only fibrin sealant as a vehicle was applied. Each animal was sacrificed at 12 weeks after surgery. BACKGROUND: If the role of growth factors in ligament healing and remodeling is understood, better therapies can be designed for ligament trauma. METHODS: The freeze-thaw treatment was performed three times using the originally developed cryo-probe. The cross-sectional area of the anterior cruciate ligament was measured by the optical non-contact method. After preconditioning, each specimen was stretched to failure. The ligament strain was determined with a video dimension analyzer. RESULTS: The tensile strength and the tangent modulus of the anterior cruciate ligament in the TGF-beta1 group was significantly higher than in the sham group, but significantly lower than in the normal control group. There were no significant differences in the strength and the modulus between the EGF group, the PDGF-BB group, and the sham group. CONCLUSIONS: In this model, an application of 4 ng TGF-beta1 significantly inhibited some of the material deterioration that occurs in the in situ frozen-thawed anterior cruciate ligament, while an application of 20 ng EGF or 4 microg PDGF-BB did not significantly affect the deterioration. RELEVANCE: This information will be useful in the future to develop a new biological therapy for ligament reconstruction to prevent the graft deterioration after transplantation.