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.

Novel biomarkers and genomic tests in prostate cancer: a critical analysis.

The aim of this review is to critically analyze the current state of research in selected biomarkers and genomic-based tests for prostate cancer (PCa) diagnosis, staging, prognostication, and monitoring. Although in Western societies, PCa is the most common solid malignancy and the second leading cause of cancer death in men, the vast majority of men with PCa are diagnosed with clinically localized disease. The widespread use of prostate-specific antigen (PSA) testing, on one hand, has resulted in earlier PCa detection at a potentially more curable stage, but on the other hand has led to an increase in the rate of negative biopsies, as well as overdetection and overtreatment of potentially indolent tumors that would not have become life-threatening to a patient. A multitude of molecular tests and algorithms has been developed to enhance diagnostic accuracy, improve pretreatment and post-treatment patient risk stratification, and identify aggressive versus indolent disease to facilitate therapeutic decision-making. PSA and derivatives (PSA kinetics, PSA density, percentage of free PSA) as well as algorithms based on PSA and PSA isoforms measurements (prostate health index, four-kallikrein score), urinary molecular biomarkers-based tests (Prostate Cancer Antigen 3, and the Michigan Health System Prostate Score) and selected genomic/proteomic tests now commercially available for disease prognostication (such as Confirm MDx, Prostate Core Mitomic Test, Oncotype DX, Prolaris, ProMark, and Decipher) are herein discussed to inform the readers about current and future clinical applications and their limitations. Finally, we briefly touch upon potential biomarkers predictive of response to therapy, such as androgen receptor splice variant AR-V7, and detection and quantification of circulating tumor cells in the blood stream.

Suprapubic-assisted Transurethral Excision of a Vaginal Mesh Eroded Into the Bladder.

A 56-year-old woman with irritative voiding symptoms and recurrent urinary infections was found to have erosion into the bladder of a tension-free vaginal tape placed 61 months before. To achieve radical excision, a 26Fr Amplatz sheath was placed suprapubically under endoscopic vision. A rigid nephroscope with grasping forceps was used to pull the eroded mesh out of the bladder wall while excising it transurethrally with a resectoscope. Postoperative course was uneventful; 12 months after surgery the patient remains asymptomatic. This novel technique provides an effective means of radically removing a mesh eroded into the bladder either transurethrally or suprapubically.

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.

[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.

Paradoxes in longevity: sequence analysis of mtDNA haplogroup J in centenarians.

Previous studies have shown that mitochondrial DNA (mtDNA) haplogroup J is significantly over-represented in healthy centenarians with respect to younger controls, thus suggesting that this haplogroup predisposes to successful aging and longevity. On the other hand, the same haplogroup is reported to have elevated frequency in some complex diseases. To verify if centenarians clustered in a particular lineage within J we have sequenced the D-loop region from 18 centenarians and 18 younger controls, previously characterized to be J. Then the entire mtDNA molecule was sequenced in a sub-sample of nine centenarians to find possible functional mutations associated with haplogroup J in successful aging. No clustering of the J haplogroup mtDNA from centenarians was observed. In addition, most of the mutations found are known as disease-associated mutations. The general picture that emerges from the study is that the J haplogroup of centenarians is surprisingly similar to that found in complex diseases, as well as in Leber Hereditary Optic Neuropathy. This finding implies that the same mutations could predispose to disease or longevity, probably according to individual-specific genetic backgrounds and stochastic events. This data reveals another paradox of centenarians and confirms the complexity of the longevity trait.

Mitochondrial DNA haplogroups and APOE4 allele are non-independent variables in sporadic Alzheimer's disease.

Allele epsilon4 of the nuclear APOE gene is a leading genetic risk factor for sporadic Alzheimer's disease (AD). Moreover, an allele-specific effect of APOE isoforms on neuronal cell oxidative death is known. Because of the role of the mitochondrial genome (mtDNA) in oxidative phosphorylation and oxidative stress, an interaction between APOE polymorphism and mtDNA inherited variability in the genetic susceptibility to sporadic AD can be hypothesized. We have explored this hypothesis by analyzing mtDNA germline variants (mtDNA haplogroups) in a sample of AD patients (213 subjects) genotyped for APOE and classified as APOE epsilon4 carriers and non-carriers. We found that the frequency distribution of mtDNA haplogroups is different between epsilon4 carriers and non-carriers (P=0.018), thus showing non-random association between APOE and mtDNA polymorphisms. The same analysis, carried out in two samples of healthy subjects (179 age-matched and 210 individuals aged more than 100 years), showed independence between epsilon4 allele and mtDNA haplogroups. Therefore, the APOE/mtDNA interaction is restricted to AD and may affect susceptibility to the disease. In particular, some mtDNA haplogroups (K and U) seem to neutralize the harmful effect of the APOE epsilon4 allele, lowering the epsilon4 odds ratio from statistically significant to non-significant values.

Does a retrograde response in human aging and longevity exist?

The retrograde response (RR) is a compensatory mechanism by which mutant strains of yeast are able to cope with mitochondrial DNA (mtDNA) impairments by up-regulating the expression of the stress-responder nuclear genes and significantly increasing lifespan. Starting from the observation that both mtDNA variability and Tyrosine hydroxylase (THO, stress-responder gene) variability are correlated with human longevity, we asked ourselves whether mechanisms similar to RR may exist in humans. As a first investigative step we have analyzed the distribution of the mtDNA inherited variants (haplogroups) according to THO genotypes in three sample groups of increasing ages (20-49 years; 50-80 years; centenarians). We found that the mtDNA haplogroups and the THO genotypes are associated randomly in the first group, while in the second group, and particularly in the centenarians, a non-random association is observed between the mtDNA and nuclear DNA variability. Moreover, in centenarians the U haplogroup is over-represented (p=0.012) in subjects carrying the THO genotype unfavorable to longevity. On the whole these findings are in line with the hypothesis that longevity requires particular interactions between mtDNA and nuclear DNA and do not exclude the possibility that an RR has been maintained throughout evolution and it is present in higher organisms.

Inherited variability of the mitochondrial genome and successful aging in humans.

Increasing data indicate that polymorphic variants of nuclear loci can affect rate and quality of aging in humans. However, the mitochondrial genome is another good candidate, because of the central role played by mitochondrial genes in oxidative phosphorylation (OXPHOS) and cell metabolism. A characteristic of the mitochondrial genome (mtDNA) is the high level of interindividual variability that ensues from high mutation rate and unilinear inheritance. Related groups of germline/inherited mtDNA polymorphisms (haplogroups) have been identified as continent-specific sets of stable/ancient/associated restriction fragment length polymorphisms in the mtDNA coding region, representing markers capable of exactly depicting the mtDNA pool of a specific population. The hypothesis can be put forward that mtDNA variants included in a haplogroup may have similar OXPHOS efficiency and therefore act as genetic factors predisposing to individual successful or unsuccessful aging. This idea can be explored by sampling groups of individuals of different ages from a well-defined population and comparing the pools of mtDNA haplogroups between samples. The results obtained by screening mtDNA haplogroups in about 800 Italians of different ages, including more than 200 centenarians, agree with the hypothesis that the inherited variability of the mitochondrial genome is associated with the chance of successful aging and longevity in humans.

Mitochondrial DNA inherited variants are associated with successful aging and longevity in humans.

Mitochondrial DNA (mtDNA) is characterized by high variability, maternal inheritance, and absence of recombination. Studies of human populations have revealed ancestral associated polymorphisms whose combination defines groups of mtDNA types (haplogroups) that are currently used to reconstruct human evolution lineages. We used such inherited mtDNA markers to compare mtDNA population pools between a sample of individuals selected for successful aging and longevity (212 subjects older than 100 years and in good clinical condition) and a sample of 275 younger individuals (median age 38 years) carefully matched as to sex and geographic origin (northern and southern Italy). All nine haplogroups that are typical of Europeans were found in both samples, but male centenarians emerged in northern Italy as a particular sample: 1) mtDNA haplogroup frequency distribution was different between centenarians and younger individuals (P=0.017 by permutation tests); and 2) the frequency of the J haplogroup was notably higher in centenarians than in younger individuals (P=0.0052 by Fisher exact test). Since haplogroups are defined on the basis of inherited variants, these data show that mtDNA inherited variability could play a role in successful aging and longevity.

Age-related changes of the 3'APOB-VNTR genotype pool in ageing cohorts.

The analysis of seven different age cohorts (697 individuals from 10 to 109 years old) revealed age-related changes in the 3'APOB-VNTR genotype pool. By recoding the 3'APOB-VNTR alleles into three size-classes (small, S, 26-34 repeats; medium, M, 35-39 repeats; large, L, 41-55 repeats), an age-related convex trajectory of the frequency of SS homozygotes was found. The frequency of SS in the genotype pool increased from the group aged 10-19 years (3.06 +/- 1.74%) to that aged 40-49 years (8.51 +/- 4.07%). Then it declined reaching the minimum value in centenarians (1.58 +/- 0.90%). The observed trajectory is in agreement with that expected by assuming crossing of mortality curves relevant to subgroups of individuals having different genotypes.

Gene/longevity association studies at four autosomal loci (REN, THO, PARP, SOD2).

The possibility that four loci (REN, THO, PARP, SOD2) are associated with longevity was explored by comparing the genotypic pools of subjects older than 100 years with those of younger subjects matched for sex and geographic area (northern and southern Italy). The markers (all located within the respective gene) were HUMREN4; HUMTHO1; HUMPARP (gt)845nt; SOD2(C/T)401nt. In order to reduce the number of genotypes, multiallelic polymorphisms were recoded as diallelic according to allele size and frequency patterns (small: S, and large: L, alleles). A significant loss of LL homozygous genotypes was found at the THO locus in male but not in female centenarians with respect to matched controls. On the other hand no significant difference was found between case/control genotypic frequencies at REN, PARP, SOD2 loci. The latter loci therefore do not affect inter-individual variability in life expectancy (at least in terms of qualitative variants associated with the tested markers). However, the data is consistent with an association between the THO locus and longevity.

[Echo-guided percutaneous treatment of renal cysts: aspiration vs continuous 24-hour drainage]. / Trattamento percutaneo ecoguidato delle cisti renali: aspirazione vs drenaggio continuo di 24 ore.

The results of 2 treatment options, percutaneous aspiration vs percutaneous aspiration and continuous drainage over 24 hours, in the management of simple renal cyst were compared. Thirteen patients were managed with aspiration alone (group 1) while 19 with aspiration and continuous drainage (group 2). Recurrence rate was 100% in group 1 and 73% in group 2 (p: n.s.). Therefore, we believe that the higher cost of continuous drainage are not justified.

[Renal peripelvic multicystic lymphangiectasia: is echographic diagnosis possible?]. / La linfangiectasia multicistica peripielica renale (LMPR): è possibile una diagnosi ecografica?

We describe the role of US, in the diagnosis of LMPR and in differentiating LMPR from other renal disease, such as hydronephrosis and parapelvic cysts. In 10 patients mild to moderate hydronephrosis showed at the US, bilateral in 8 cases, was not confirmed at IVP and CT scan evaluation. Instead, compression of the collecting system by multiple cysts arising from the renal sinus was revealed by CT scan in 8 cases and by IVP in 2. At the U.S. the profile of the calices appeared irregular, differing from the features of hydronephrosis; furthermore calices were adjacent each other, separated only by a thin membrane. All patients were asymptomatic. The examination of the cystic liquor and wall, obtained percutaneously or during surgical procedures, showed the lymphatic origin of them. We cannot provide definitive data regarding how to differentiate LMPR from hydronephrosis at U.S.. In asymptomatic patients the U.S. evidence of dilated calices with irregular profile and thin membrane separating each other, can strongly suggest the diagnosis of LMPR.

[Role of color Doppler echography (ECD) in the diagnosis and follow-up of post-biopsy arteriovenous fistula in the transplanted kidney]. / Ruolo dell'ecocolor Doppler (ECD) nella diagnosi e nel follow-up delle fistole artero-venose post-bioptiche del rene trapiantato.

CCD is an helpful imaging technique during biopsy of transplanted kidney, since it has reduced the incidence rate of complications associated to this procedure. Among possible complications one of the most frequent is the arteriovenous fistula. We report our experience with CCD in diagnosis and monitoring of this complication and we underline its role in case of conservative management.

Effect of preoperative thoracic duct drainage on canine kidney transplantation.

Chronic drainage of the thoracic duct to the esophagus was developed in dogs, and its efficacy in immunomodulation was tested using kidney transplantation. Compared to 9.7 days in the control, the mean animal survival was prolonged to 9.9 days, 17.8 days, and 18.5 days when TDD was applied preoperatively for 3 weeks, 6 weeks, and 9 weeks, respectively. Prolongation was significant after 6 weeks. Patency of the fistula was 93.5, 80.4, and 76.1% at respective weeks. Number of peripheral T-lymphocytes determined by a new monoclonal antibody diminished after 3 weeks. All animals were in normal health, requiring no special care for fluid, electrolyte, or protein replacement.

Allele frequency distributions at seven DNA hypervariable loci in a population sample from Calabria (southern Italy).

Genotype and allele frequencies at seven Variable Number of Tandem Repeats (VNTR) loci currently used for forensic purposes have been estimated in a population sample from Calabria (south Italy). DNA target regions relevant to four microsatellites (THO.1; REN.4; D12S67; DYS19) and three minisatellites (D1S80; 3'APOB; TPO.10) were amplified by Polymerase Chain Reaction (PCR) and analysed by electrophoresis and ethidium bromide or silver staining. For all loci, the observed genotypes were found to be in agreement with those expected by the Hardy-Weinberg equilibrium. Data on allele frequencies were in line with those found in sample groups from northern or central Italy, tested for some of the above polymorphisms.

Dermatological toxicity from chemotherapy containing 5-fluorouracil.

5-Fluorouracil (5-FU) is an antimetabolite frequently used in the treatment of cancer. The most common adverse reactions are acute gastrointestinal effects and bone marrow suppression while neurological, ocular and dermatological toxicities are unusual. Several cutaneous manifestations can be found. They are hyperpigmentation, maculo-papular eruption and palmar-plantar erythrodysesthesia (PPES) promptly reversed with discontinuation of 5-FU. The etiopathogenesis of such manifestations is still unknown particularly as regards PPES, but it has been postulated that the local drug accumulation secondary to different scheduling (continuous infusion instead of bolus infusion), the total amount of drug, alcoholism, local trauma, increased blood flow could be responsible for them. In this study we have reported 10 cases of dermatological toxicity (1 of these had PPES) observed from January '91 to December '93 in 81 patients treated with bolus injection of 5-FU containing combination chemotherapy.