The impact of age on intravesical instillation of Bacille Calmette-Guerin treatment in patients with high-grade T1 bladder cancer.

Intravesical instillation of Bacille Calmette-Guèrin (BCG) is the standard adjuvant treatment for high-risk non muscle invasive bladder cancer (NMIBC). Since its mechanism of action is supposed to be linked to the immune system efficiency and senescence could negatively affect this efficiency, BCG efficacy in the elderly has been questioned. This study aimed to assess the impact of age on BCG efficacy and safety in patients with high-grade T1 bladder cancer (BC).Among 123 patients with high-grade T1 BCG scheduled for BCG treatment, 82 were <75 year-old (group A) and 41 were ≥75 year-old (group B). Follow-up: urine cytology and cystoscopy every 3 months for the first 2 years, every 6 months for the third year, and then yearly. Tumor recurrence was defined as pathological evidence of disease at the bladder biopsy; tumor progression was defined as pathological shift to muscle invasive disease at the bladder biopsy or the imaging techniques showing recurrent BC and distant metastasis likely related to it.The median follow-up was 65 months (range 11-152). Recurrence occurred in 35 patients, 19 (23.2%) in the group A and 16 (39%) in the group B. Progression occurred in 18 patients, 12 (14.6%) in the group A and 6 (14.6%) in the group B. Recurrence free rate was similar in both groups up to 2 years. The 5 years progression rate was almost the same in both groups A and B (85.9% vs 84.7%), whereas the 5 years cancer-specific survival (CSS) was 92.6% in the group A and 85.4% in the group B. Of the 18 patients with progression, 11 underwent cystectomy; 12 patients died because of their BC. Kaplan-Meier plots pointed out no difference in recurrence-free, progression-free, and CSS between the 2 groups. Adverse events were similar in the 2 groups. Only 4 (3.3%) patients, 2 (2.4%) in the group A and 2 (4.8%) in the group B, experienced mild adverse reactions compatible with treatment.Elderly patients with high-grade T1 BC are not poorer candidates to BCG treatment, as they had similar benefit and adverse reactions than those aging ≥75 years.

Chemical characterization of exhaled breath to differentiate between patients with malignant plueral mesothelioma from subjects with similar professional asbestos exposure.

Malignant pleural mesothelioma (MPM) is an aggressive tumour whose main aetiology is the long-term exposure to asbestos fibres. The diagnostic procedure of MPM is difficult and often requires invasive approaches; therefore, it is clinically important to find accurate markers for MPM by new noninvasive methods that may facilitate the diagnostic process and identify patients at an earlier stage. In the present study, the exhaled breath of 13 patients with histology-established diagnosis of MPM, 13 subjects with long-term certified professional exposure to asbestos (EXP) and 13 healthy subjects without exposure to asbestos (healthy controls, HC) were analysed. An analytical procedure to determine volatile organic compounds by sampling of air on a bed of solid sorbent and thermal desorption GC-MS analysis was developed in order to identify the compounds capable of discriminating among the three groups. The application of univariate (ANOVA) and multivariate statistical treatments (PCA, DFA and CP-ANN) showed that cyclopentane and cyclohexane were the dominant variables able to discriminate among the three groups. In particular, it was found that cyclohexane is the only compound able to differentiate the MPM group from the other two; therefore, it can be a possible marker of MPM. Cyclopentane is the dominant compound in the discrimination between EXP and the other groups (MPM and HC); then, it can be considered a good indicator for long-term asbestos exposure. This result suggests the need to perform frequent and thorough investigations on people exposed to asbestos in order to constantly monitor their state of health or possibly to study the evolution of disease over time.

ID2-VEGF-related pathways in the pathogenesis of Kaposi's sarcoma: a link disrupted by rapamycin.

The Id-proteins are a family of four related proteins implicated in the control of differentiation and cell-cycle progression. Down-regulation of Id-gene expression is essential for the differentiation of several cell types. In addition, deregulated Id2 activity inhibits the Rb tumor suppressor pathway and promotes the expression of vascular endothelial growth factor (VEGF). Several members of VEGF family could be involved in Kaposi's sarcoma (KS) development and progression. Lymphatic vascular endothelial hyaluronan receptor-1 (LYVE-1) is the first marker of lymphatic endothelial competence during development in the mature vasculature, and is also expressed on KS spindle cells. Rapamycin (RAPA), an immunosuppressive drug, has been shown to reverse KS growth and to reduce tumor angiogenesis. We evaluate, in transplantation-associated KS and in cultured KS-cells the RAPA effect on Id2 and on de novo lymphangiogenesis. Markers of lymphatic-endothelial-cells (VEGFR-3, LYVE-1) and Id2, expressed at low levels within the normal skin, were up-regulated in KS and returned to normal levels after RAPA introduction. The association between Id2 and lymphangiogenesis is suggested by co-localization of Id2, VEGFR-3 and LYVE-1. RAPA inhibition on Id2 expression was confirmed in vitro in KS-cells, both in basal conditions and upon stimulation with VEGF. In conclusion, our data would suggest a novel molecular mechanism for the antineoplastic effects of RAPA in posttransplant KS.

[Pro and anti-neoplastic effects of immunosuppressive drug in renal transplantation]. / Effetti pro ed anti-neoplastici dei principali farmaci immunosoppressori usati nella pratica clinica trapiantologica.

The increased efficiency of immunosuppressive drugs obtained in the last few years has significantly reduced the incidence of acute rejection, prolonging transplant survival rates. The inevitable trade-off was however an increased rate of post-transplant infections and malignancies. Furthermore, this problem might get more and more serious in the next future due to the increasing incidence of cancer in immunosuppressed transplant recipients; the introduction of new immunosuppressive strategies is expected to extend significantly allograft survival. The inclusion of older recipients in transplant programs will also likely increase this problem. Thus, cancer may represent a serious cause of morbidity and mortality in patients otherwise successfully treated by organ transplantation. Nevertheless, effective approaches to deal with malignancies in immunosuppressed patients are still far from the clinical arena. Therefore, once cancer occurs in a transplant recipient, clinicians only have two options: to reduce or withdraw the immunosuppression eventually causing acute or chronic allograft rejection, or to continue the standard immunosuppressive therapy while beginning specific therapy for the malignancy. Several clinical studies suggest that the use of immunosuppressive drugs may result in increased cancer incidence, in transplant as well as autoimmune disease patients. This clinical observation is supported by experimental data showing that these drugs enhance cancer cell growth characteristics and inhibit DNA repair mechanisms, clearly suggesting that the increased incidence of neoplastic disease in patients treated with several immunosuppressive drugs is at least partially independent of their immunosuppressive action. In this scenario it is of particular interest the fact that some immunosuppressive drugs have both an anti-rejection and anti-neoplastic activity. In this review we focus our attention on this potential dual role of immunosuppressive therapy in the development of neoplasia in transplanted patients.

[Renal neoplasms and renal transplantation: current problems and future perspectives]. / Neoplasie renali e trapianto di rene: problematiche attuali e prospettive future.

Primary carcinomas of the kidney can develop in renal transplantation in four sets of circumstances: (1) detected in the donor, (2) detected as a pre-existing neoplasm in the recipient prior to transplantation, (3) as de novo malignancies arising post-transplantation in the native kidneys of the recipient, (4) or in the graft. In Italy, any renal mass detected during harvesting does not allow the use of any organs for transplantation; however, several reports from other countries have already shown the safety and efficacy of transplanting kidneys with small (<4 cm), unifocal, subcapsular tumors, after resecting the lesion at the back table and verifying the negativity of the surgical margins; this strategy could also be evaluated in Italy to expand the donor pool. Acquired cystic kidney disease (ACKD) is commonly observed in uremic patients undergoing chronic hemodialysis (HD); numerous studies have reported an increased prevalence of renal cell carcinoma (RCC) in association with this nephropathy. The use of ultrasound, computerized axial tomography (CAT) and magnetic resonance imaging (MRI) has greatly improved the ability to detect renal tumors at earlier stages associated with ACKD and the morbidity and mortality rate, in either uremic or transplant patients. RCC in the transplanted kidney is rare and, when recognized, requires nephrectomy. However, a conservative approach with nephron sparing surgery has been reported for selected cases as a useful strategy to treat renal carcinoma in the allograft.

[HCV+ patients on the waiting list for kidney transplantation. Retrospective analysis of data on the patient population with hepatitis C on the waiting list for kidney transplantation in the setting of the AIRT]. / Pazienti HCV+ in lista d'attesa per trapianto renale. Analisi retrospettiva dei dati relativi alla popolazione dei pazienti affetti da epatite C in lista d'attesa per trapianto di rene in ambito AIRT.

BACKGROUND: HCV infection in hemodialysis is still a matter of debate from an epidemiological and clinical point of view. Evaluation criteria for HCV-infected patients as transplant candidates are still not adequately standardized. Aims of the present study were to investigate: 1. the percentage of HCV positive patients on the waiting list of three Italian regions belonging to the Associazione InterRegionale Trapianti (AIRT); 2. to analyze the clinical approach in the evaluation of these patients in the attempt to define national guidelines for their pre- and post-transplant management. PATIENTS: We evaluated 2045 uremic patients on the waiting lists of four transplant centers (Bari, Bologna, Modena, Novara) belonging to AIRT at 31/12/2002. RESULTS: The overall prevalence of HCV positive patients was 14.2%, with a peak in the Puglia waiting list. The most common screening tests were AST and ALT serum levels and viral load (HCV RNA). Although there is a clear evidence that histological parameters are the main diagnostic and prognostic markers, a liver biopsy was performed in only 9.5% of patients. An even smaller percentage of HCV-infected patients underwent anti-viral therapy. CONCLUSIONS: Our retrospective analysis evidenced the need to improve common clinical strategies in approaching HCV-infected canditates to renal transplantation in the attempt to improve their post-transplant outcome.

[Malignant neoplasia and kidney transplantation. Retrospective analysis of data on the population having kidney transplantation with de novo neoplasia in the setting of the AIRT]. / Trapianto renale e neoplasie. Analisi retrospettiva dei dati relativi alla popolazione dei trapiantati di rene affetti da neoplasie de novo in ambito AIRT.

BACKGROUND: In transplanted patients undergoing immunossuppressive therapy the incidence of malignant neoplasia is 3-4 times higher than in the general population. Aim of the present study was to evaluate the prevalence of different tumours and the links between modulation of immunosuppressive therapy and patient and graft survival. PATIENTS: We evaluated 2029 kidney-transplanted patients from four Transplant Centres (Bari, Bologna, Modena, Novara) belonging to the Associazione InterRegionale Trapianti (AIRT). RESULTS: The incidence of neoplastic disease after transplantation was 3.9% in our population with a median time between transplantation and clinical onset of 23 months. We demonstrated a significant difference in the geographical distribution of different tumours. We did not observe any correlation with specific immunosuppressive drugs. Finally, dramatic reduction of the immunosuppression levels did not modify either the patients' or the graft's survival. CONCLUSIONS: Several factors can influence the post-transplant onset of neoplastic diseases with immunosuppressive therapy playing a pivotal role. The implementation of a National Registry would be the first step in an attempt to optimise immunosuppression in this particular group of patient's.

[Correlation between the onset of early proteinuria and the outcome of renal transplantation. Experience of a single centre]. / Correlazione tra insorgenza di proteinuria precoce e decorso clinico del rene trapiantato. Esperienza di un singolo centro.

BACKGROUND: Proteinuria is associated with an increased risk of renal failure. In chronic kidney transplant failure it is associated with poorer graft outcome. MATERIALS AND METHODS: In our Unit 405 renal transplants were performed between April 1992 and December 2001. We analysed 1) the main causes of post-transplant proteinuria and 2) the prognostic significance for graft outcome in patients with a minimum follow-up of 6 months. RESULTS: Early proteinuria was associated with a higher incidence of chronic allograft nephropathy (CAN) and de novo/recurrent nephropathies. Graft outcome was poorer in patients with early persistent proteinuria. CONCLUSIONS: Proteinuria after renal transplantation increases the risk of graft failure. We can, therefore, hypothesize that a graft biopsy is the best way to reveal the causes of proteinuria so that therapeutic interventions, which have been shown to reduce proteinuria, can be applied immediately.

[Herpetic viruses and renal transplantation]. / Virus erpetici e trapianto renale.

Over the last few years emerging evidence indicate the involvement of herpes viruses in the pathogenesis of several medical complications in transplanted patients. Herpes viruses are transmitted via inter-human contact and cause a primary infection, which commonly fails to give clinical signs and may persist even for years in a latent state in healthy subjects. In transplanted patients, herpes viruses may be transmitted through the transplanted organ or may be reactivated because of the use of powerful immunosuppressive drugs. Moreover, the persistence of immunosuppression greatly favours the clinical expression and severity of virus infection. Thus, herpes viruses seem to be involved in both acute and chronic deterioration of graft function, in the pathogenesis of post-transplant lymphoproliferative disorders and Kaposi sarcoma, and even in vessel atherosclerosis. This review will focus on relevant clinical aspects of herpes-virus infection, namely cytomegalovirus, EBV, herpes simplex 1 and 2, varicella zoster virus, HHV-6, HHV-7 and HHV-8, in kidney transplanted patients.

Primary renal lymphoma does exist: case report and review of the literature.

Primary renal lymphoma (PRL) is a controversial and rare disease and there is still no agreement on its existence. Many cases have been reported in the literature, but clear diagnostic criteria have not yet been established. Most of the reported cases are questionable because of incomplete staging or the presence of extrarenal disease. Here we report a new case and a review of the literature based on a critical examination of the diagnostic procedure. Thus, probably only 29 cases, ours included, should be recognized as PRL, because only these cases fulfil the three diagnostic criteria and underwent complete diagnostic screening, including renal biopsy, bone marrow biopsy and thoraco-abdominal computerised tomography (CT).

Interference of angiotensin-converting enzyme inhibitors on erythropoiesis in kidney transplant recipients: role of growth factors and cytokines.

BACKGROUND: Recent data indicate that factors other than erythropoietin (EPO), such as insulin-like growth factor 1 (IGF-1), can promote erythropoiesis in vitro and correct the anemia of chronic renal failure in vivo. IGF-1 is produced by the liver under growth hormone control, as well as by other sources, including the kidney. The erythropoietic role of growth factors and cytokines and their possible modulation by angiotensin-converting enzyme inhibitors (ACEI) has never been explored. METHODS: This study evaluated the serum levels of EPO, IGF-1, interleukin (IL)-2, IL-3, and granulocyte macrophage-colony-stimulating factor in 40 kidney transplanted patients with or without posttransplant erythrocytosis (PTE) and in 10 living kidney donors. Then, the effect of ACEI therapy on the above pattern was examined in patients with PTE. RESULTS: EPO and IGF-1 serum levels were significantly higher in patients with PTE than in patients without PTE and in living kidney donor subjects. ACEI therapy significantly reduced hematocrit (Hct) as well as circulating IGF-1 and EPO levels. Of note, the decrease in IGF-1 was prominent mainly in those patients whose EPO levels were not significantly modified by ACEI therapy. In all of the patients Hct levels displayed a direct relationship with circulating IGF-1 levels, but not with EPO concentration. Growth hormone did not significantly differ among the groups examined, whereas it steeply increased under ACEI. Finally, no significant difference in IL-2, IL-3, and granulocyte macrophage-colony-stimulating factor serum levels was detected. CONCLUSIONS: IGF-1 seems to play a role in the ACEI-related decrease of Hct in patients with PTE, chiefly in patients without any modification of EPO serum levels.

Renal expression and urinary concentration of EGF and IL-6 in acutely dysfunctioning kidney transplanted patients.

BACKGROUND: Despite marked improvements in the success of solid organ transplantation, a significant percentage of transplanted organs is lost due to recurrent episodes of acute cellular rejection. The mechanisms that govern allograft rejection likely include a complex regulatory network of multiple cytokines and growth factors. DESIGN AND METHOD: This study investigated the kidney gene (in situ hybridization) and protein (immunohistochemistry) expression and the urinary excretion rate of IL-6 and EGF in 29 renal transplant recipients: 16 with acute cellular rejection (AR) and 13 with acute tubular damage/cyclosporine toxicity (ATD). RESULTS: AR patients displayed a 4-fold increase of renal IL-6 expression, which localized chiefly to proximal tubular cells and monocytes/macrophages, whereas EGF signal was extremely weak or even absent. In ATD patients, EGF expression was markedly reduced, while IL-6 specific signal was unchanged. In all the patients examined the renal expression of IL-6 and EGF strictly correlated with their urinary excretion rate (r:0.459, P:0.001). Thus, urinary IL-6/EGF ratio was markedly increased in the former group (> 20-fold at day 1), where it paralleled the modifications of plasma creatinine over time (r:0.603, P < 0.0001), and was only slightly increased in the latter group (< 3-fold). CONCLUSION: Kidney transplanted patients with acute cellular rejection or acute tubular damage/CyA nephrotoxicity exhibit a distinctly different pattern of intragraft expression of IL-6 and EGF, which is closely reflected by their rate of urinary excretion.