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Purpose To assess the diagnostic accuracy of iXip, a novel biomarker for prostate cancer detection at initial biopsy based on an algorithm including patient age, prostate volume, PSA and PSA-IgM levels,. Materials and methods This was a prospective multicenter study involving 426 consecutive men undergoing initial prostate biopsy with at least 12 cores in a real-life clinical setting. Diagnostic accuracy of iXip for prostate cancer detection was calculated with AUC and compared to that of prostate volume, PSA and PSA-IgM levels. The correlation of iXip with tumor aggressiveness, defined as any cancer with Gleason score ≥7, was evaluated by Spearman ρ coefficient analysis. Results Prostate cancer was diagnosed in 193/426 patients (45%), of which 65 (35%) had Gleason score ≥7. iXip values were significantly higher in patients with cancer than in those without cancer (median value 55% vs. 39%, p Conclusions Our prospective multicenter study suggests that the novel biomarker iXip may be used with a 20% cut-off value in order to reduce the proportion of prostate biopsies by approximately 5%, without missing a single case of cancer. Moreover, higher iXip values are significantly correlated with tumor aggressiveness.

An increased risk of renal cell cancer (RCC) has been reported in overweight persons. The authors aimed to clarify which anthropometric measures are associated with risk of RCC and whether risk may vary according to selected variables. Between 1992 and 2004, they carried out an Italian multicenter case-control study including 767 (494 men, 273 women) incident cases of RCC and 1,534 hospital controls, frequency-matched to cases. To estimate odds ratios and 95% confidence intervals, they used conditional logistic regression matched on study center, sex, and age and adjusted for period of interview, years of education, smoking habits, and family history of kidney cancer. Using body-size measurements taken 1 year prior to diagnosis/interview, the authors found an odds ratio of 1.3 (95% confidence interval (CI): 1.0, 1.7) among obese persons (body mass index (BMI; weight (kg)/height (m) 2 ) � 30) versus normal-weight persons (BMI

We investigated the influence of anthropometric measures at diagnosis and at different ages on prostate cancer risk using an Italian multicentre case-control study conducted between 1991 and 2002 of 1294 histologically confirmed cases and 1451 controls admitted to the same network of hospitals for acute non-neoplastic conditions. Height, weight, body mass index (BMI), waist-to-hip ratio, lean body mass 1 year before diagnosis/interview were not significantly associated with risk. However, a positive association with high BMI at age 30 years was found (odds ratio = 1.2 for BMI greater than or equal to 24.7 vs

Background: An increased risk of renal cell cancer (RCC) has been reported in subjects with hypertension. Whether this association may vary according to sex, smoking, obesity, or RCC clinical presentation is unclear. Results on the link between diabetes mellitus and RCC are inconclusive. Patients and methods: We conducted an Italian multicenter case–control study, including 767 (494 men, 273 women) incident cases of RCC, under 80 years of age, and 1534 hospital controls, frequency-matched to cases. Multiple logistic regression models, conditioned to center, sex, and age, and adjusted for period of interview, education, smoking, and body mass were used to estimate odds ratios (OR). Results: Compared with subjects never treated, patients with a history of treated hypertension [OR = 1.7, 95% confidence interval (CI) 1.4–2.1] reported an excess risk of RCC. This pattern was confirmed in different strata of sex, education, smoking habits, body mass, tumor histological type, stage, or grade. The attributable risk of RCC for treated hypertension in this population was 16%. A slight, nonsignificant increased risk was found for history of diabetes mellitus (OR = 1.3, 95% CI 0.9–1.7). Conclusion: A possible causal role of hypertension in renal cell carcinogenesis is supported by the consistency of the direct association.

To evaluate the impact of tobacco smoking on specific histological subtypes of transitional cell carcinoma of the bladder (TCC). Between 2003 and 2009, we conducted a hospital-based case-control study in Italy, enrolling 531 incident TCC cases and 524 cancer-free matched patients. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were estimated through multiple logistic regression models. Compared to never smokers, TCC risk was threefold higher in former smokers (95% CI 2.07–4.18) and more than sixfold higher in current smokers (95% CI 4.54–9.85). TCC risk steadily increased with increasing intensity (OR for ≥25 cigarettes/day 8.75; 95% CI 3.40–22.55) and duration of smoking (OR for ≥50 years 5.46; 95% CI 2.60–11.49). No heterogeneity emerged between papillary and non-papillary TCCs for smoking intensity and duration, but the risk for those who had smoked for ≥50 years was twice for non-papillary TCC (OR 10.88) compared with papillary one (OR 4.76). Among current smokers, the risk for a 10-year increase in duration grew across strata of intensity (p-trend = 0.046). Conversely, the risk for a 5-cigarette/day increase in smoking intensity was quite steady across strata of duration (p-trend = 0.18). Study results suggested that duration of smoking outweighs intensity in determining TCC risk, with limited differences across histological subtypes. Elimination of tobacco smoking may prevent about 65 % of TCCs.

BACKGROUND The optimal management of high-risk prostate cancer remains uncertain. In this study we assessed the safety and efficacy of a novel multimodal treatment paradigm for high-risk prostate cancer. METHODS This was a prospective phase II trial including 35 patients with newly diagnosed high-risk localized or locally advanced prostate cancer treated with high-dose intensity-modulated radiation therapy preceded or not by radical prostatectomy, concurrent intensified-dose docetaxel-based chemotherapy and long-term androgen deprivation therapy. Primary endpoint was acute and late toxicity evaluated with the Common Terminology Criteria for Adverse Events version 3.0. Secondary endpoint was biochemical and clinical recurrence-free survival explored with the Kaplan-Meier method. RESULTS Acute gastro-intestinal and genito-urinary toxicity was grade 2 in 23% and 20% of patients, and grade 3 in 9% and 3% of patients, respectively. Acute blood/bone marrow toxicity was grade 2 in 20% of patients. No acute grade ≥ 4 toxicity was observed. Late gastro-intestinal and genito-urinary toxicity was grade 2 in 9% of patients each. No late grade ≥ 3 toxicity was observed. Median follow-up was 63 months (interquartile range 31-79). Actuarial 5-year biochemical and clinical recurrence-free survival rate was 55% (95% confidence interval, 35-75%) and 70% (95% confidence interval, 52-88%), respectively. CONCLUSIONS In our phase II trial testing a novel multimodal treatment paradigm for high-risk prostate cancer, toxicity was acceptably low and mid-term oncological outcome was good. This treatment paradigm, thus, may warrant further evaluation in phase III randomized trials.

Purpose: We evaluated the potential of PET/CT and [F-18] fluoromethylcholine (FCH) in the assessment of suspected recurrence of prostate cancer after treatment. Methods: One hundred consecutive prostate cancer patients with a persistent increase in serum PSA (> 0.1 ng/ml) after radical prostatectomy ( 58 cases), radiotherapy ( 21 cases) or hormonal therapy alone ( 21 cases) were investigated. After injection of 3.7 - 4.07 MBq/kg of FCH, both early ( at < 15 min) and delayed ( at > 60 min) PET/CT scans were performed in 43 patients, delayed PET/CT scans in 53 patients and early PET/CT scans in four patients. Results: Of the 100 patients, 54 ( PSA 0.22 - 511.79 ng/ml) showed positive FCH PET/CT scans. Thirty-seven patients had bone and/or abdominal lymph node uptake, while 17 showed pelvic activity. Malignant disease was confirmed in all but one. Delayed SUVmax of bone metastases was significantly higher (p< 0.0001 by paired t test) than that measured at < 15 min, whereas no differences were observed between early and delayed SUVs of malignant lymph nodes or pelvic disease. Forty-six patients ( PSA 0.12 - 14.3 ng/ml) showed negative FCH PET/CT scans. Of the negative PET/CT scans, 89% were obtained in patients with serum PSA < 4 ng/ml and 87% in patients with a Gleason score < 8. In none of these cases could recurrent tumour be proven clinically during a follow-up of 6 months. Conclusion: FCH PET/CT is not likely to have a significant impact on the care of prostate cancer patients with biochemical recurrence until PSA increases to above 4 ng/ml. However, in selected patients, FCH PET/CT helps to exclude distant metastases when salvage local treatment is intended.

A series of patients with concurrent transitional cell carcinoma involvement of the prostate and bladder is reviewed to define the impact of prostate involvement pathways and the degree of prostate invasion on survival rate.A total of 72 patients who underwent radical cystectomy for pathological stage pT4a (D1) cancer was divided into contiguous--stage pT4a, transitional cell carcinoma of the bladder extended into the prostate through the bladder wall and noncontiguous--stage pT4a simultaneous transitional cell carcinoma of the prostate and bladder carcinoma that did not directly infiltrate into the prostate through the bladder wall. In the latter group the degree of prostate invasion was classified as urethral mucosal involvement, ductal/acinar involvement, stromal invasion and extracapsular extension. The survival rate was estimated by the Kaplan-Meier and Cox proportional hazards methods. Comparisons between curves were performed by univariate log rank and multivariate L-ratio tests.The overall 5-year survival rate for stage pT4a was 21.5% (median followup 64 months). Furthermore, 46% and 7% of patients in noncontiguous and contiguous pT4a groups, respectively, were estimated to be alive (p0.000). Those with positive nodes experienced a poor outcome in both groups. Of patients with noncontiguous pT4a stage 100% with urethral mucosal involvement, 50% with ductal/acinar involvement and 40% with stromal invasion were estimated to be alive. The major prognostic factors were bladder tumor stage, nodal involvement and degree of prostate invasion.The invasion pathways of the prostate in patients with transitional cell bladder carcinoma have a statistically significant prognostic role. Contiguous and noncontiguous involvements are 2 distinct clinicopathological features and they should not be included in the same stage. In the noncontiguous stage pT4a group bladder and prostate transitional cell carcinoma should be separately staged, and prostate involvement also should be staged according to invasion degree.

Radical cystectomy is the most common treatment for deeply invasive bladder cancer; due to reported operative risks, concerns have been expressed regarding the suitability of this operation in elderly patients. We reviewed the morbility and mortality rates in 50 patients aged 70 years and over (elderly group), undergoing radical cystectomy and urinary diversion, to verify if this procedure could be considered as initial treatment in older-age patients. The findings were compared with those observed in 50 patients aged 40 to 69 years (control group). In the elderly group there was no operative mortality; however 2 patients (4%) died post-operatively due to pulmonary embolism and multi-organ-failure syndrome respectively. Four patients (8%) were re-operated due to intestinal obstruction (2 pts), pelvic hematoma (1 pt) and wound dehiscence (1 pt). Wound separation was the more frequent complication (15%); 6% of patients experienced extended intestinal atonia. The length of hospital stay was 17.1 days. In the control group, surgical complications were comparable to those observed in the elderly group: furthermore medical complications were more frequent. In conclusion, these data suggest that radical cystectomy and urinary diversion can be safely performed in the elderly. Radical surgery is an effective treatment modality for elderly individuals who are in reasonably good general health. A higher incidence of medical complications must be expected in elderly patients.

Shortly after Morales' original report, several phase II trials confirmed the effectiveness of intravesical bacillus Calmette-Guérin (BCG) in superficial bladder cancer therapy. Concerns have been expressed about the toxicity related to this new therapeutic modality. These phase II trial data led European urologists to try to answer some questions related to BCG therapy, such as the optimal schedule and dose, the most effective BCG strain and the value of BCG compared with current chemotherapeutic drugs. To date, phase III trials have shown that BCG is more effective than thiotepa and doxorubicin in reducing tumour recurrences and progression and that BCG seems to be as effective as mitomycin C. Toxicity is significantly higher with BCG compared to chemotherapeutic drugs; no strain of BCG seems to be superior in this respect. Further studies are required to identify the optimal schedule and dose, as well as the best therapeutic efficacy/toxicity ratio.

Bacillus Calmette-Guerin (BCG) intravesical therapy represents a major advance in the treatment of superficial transitional cell carcinoma of the bladder. To date, however, the optimal treatment schedule must be defined and the toxicity related to the treatment is significant. The preliminary results of a randomized ongoing study performed to evaluate the effectiveness and relative toxicity of a low dose (75 mg.) BCG regimen in the treatment of superficial bladder cancer therapy are reported. A total of 126 patients (70 for prophylaxis of recurrent stages Ta and T1 papillary tumors and 56 for treatment of carcinoma in situ or with microinfiltration of the subepithelial connective tissue) underwent a 6-week course of 75 mg. BCG (Pasteur vaccine). An additional course was given in patients who failed to respond to the induction course. Maintenance therapy was administered in complete responders monthly for 1 year and then quarterly for 1 year. The prophylaxis group (transurethral resection plus BCG) was randomized versus transurethral resection alone (63 patients, control group). A complete response in the prophylaxis, control and therapy groups was observed in 74, 17 and 57% of the patients, respectively, while 4, 17 and 12.5%, respectively, experienced tumor progression. The additional course of therapy increased the response rate. On the contrary, previous unsuccessful intravesical chemotherapy did not affect the response rate. In regard to toxicity, irritative disturbances (27%) and fever (17%) appeared to be significantly decreased compared with the rates reported in the literature. No major complications were experienced. In conclusion, a low dose (75 mg.) Pasteur strain BCG regimen was effective as prophylaxis against recurrent superficial papillary tumors and as treatment of carcinoma in situ or with microinfiltration of the subepithelial connective tissue. Toxicity related to the treatment appeared to be low.

Matrix-assisted laser desorption/ionization (MALDI) has been employed for the determination of molecular weights of alpha- and beta-globins obtained from blood samples of healthy and diabetic subjects. Glycated species, originating from the reaction of glucose with the proteins, are easily evident. The MALDI measurements allowed one to distinguish between simple glycation and glyco-oxidation processes of haemoglobin. In fact, together with the products arising from simple glucose condensation on the two proteins, compounds at different oxidation levels were evident. Due to its high specificity, MALDI must be considered a valuable tool for diagnosis in the diabetes field.

Since its introduction in 1992, intracytoplasmic sperm injection (ICSI) has made the treatment of severe male infertility possible, particularly that of azoospermia, both secretory and secretory. Some azoospermic subjects have a pathological development of the seminal pathways, and in particular of the vas deferens and/or ejaculatory ducts. A large part of these subjects show, like patients affected by cystic fibrosis, mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. Some of these azoospermic subjects are indeed paucisymptomatic fibrosis cystic patients who bear the risk of transmitting cystic fibrosis, seminal pathways alterations and, possibly, renal malformations to their offspring. We describe a case of an infertile patient with right CUAVD and azoospermia previously treated by crossed epididimovasostomy in the absence of any genetic and an adequate anatomic evaluation. He was then found to be CFTR mutation positive and without demonstrable spermatozoa in the vesicular fluid despite ultrasound evidence of left ejaculatory duct obstruction. During the second TESA-ICSI cycle an ongoing pregnancy was obtained. An extensive genetic examination for CFTR mutations and a through anatomical study is, therefore, mandatory in these patients to select the most appropriate treatment in CFTR mutation positive and negative CUAVD patients.

The IgG glycation level of 30 healthy subjects and 60 type 2 diabetic patients with different degrees of metabolic control was evaluated by matrix-assisted laser desorption ionization mass spectrometry, a technique allowing the determination of mass increase of the IgG molecule. When applied to the digested mixture obtained by the action of papain on the plasma protein fraction, the same method established the mass increase of Fab and Fc fragments of IgG; for the former, a higher mass increase was found, possibly explained by its high reactivity to glucose. Experimental results were confirmed by molecular modeling calculations. Results suggest that the immunodeficiency observed in diabetic patients may be due to the inhibition of molecular recognition between antibody and antigen as a result of a change in functionality of the modified Fab fragment of IgG.

The diagnosis of prostate neoplasm is still limited today by the variable power of prediction of the three main surveys used: prostate-specific antigen (PSA), digito rectal exploration (DRE) and ultrasound transrectal (TRUS). The study aimed to estimate the benefits and the diagnostic impact of the color Doppler ultrasonography on the diagnosis of prostate neoplasm through biopsies targeted on areas with abnormal flow. With this purpose, 222 biopsies performed on 71 patients between 1997 and 1999 were considered, which led to a diagnosis of neoplasm in 36 patients. Of the 84 biopsies that revealed prostate adenocarcinoma, 74 (64.3%) were correlated to hypoechoic lesions with abnormal flow signals while 41 (35.6%) showed a benign pathology (prostatitis or benign prostatic hyperplasia) (p0.0011). In five patients (13%) who did not present any evident lesions at a first transrectal ultrasound, the diagnosis of neoplasm was made only through biopsies targeted on areas with abnormal flow. Therefore, the color Doppler exam can be used during prostate ultrasonography either to consolidate the diagnosis or to give a useful target in case of isoechoic lesions.

At the Institute of Urology, University of Padova, 125 patients with multifocal superficial bladder cancer underwent treatment with intravesical Mitomycin C (MMC; 1 weekly instillation of 40 mg for 8 consecutive weeks) between January 1982 and December 1988. Eighty-four patients had multifocal papillary tumors (stages Ta-T1) and 41 patients had carcinoma in situ of the bladder. At 6 and 36 months the tumor free percentage in the group with papillary tumors was 69 and 36%, respectively; for carcinoma in situ the complete response percentage at the same intervals was 80 and 36%. Thirty-one patients previously unsuccessfully treated with adriamycin did not show any difference compared to untreated ones. The authors emphasize the efficacy and low toxicity of intravesical MMC in multiple superficial bladder cancer. The possibility of long-term relapse suggests maintenance therapy.

The glycation-induced functional change of immunoglobulins is of particular interest. The glycation levels of IgG in 10 healthy subjects and 20 diabetic patients with different degrees of metabolic control were studied by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry. It reveals the number of glucose molecules that have condensed on the protein, which range from 1 to 5 for healthy subjects, from 5 to 9 for well controlled diabetic patients, and from 10 to 25 for poorly controlled ones. The identification of the most favored glycation sites has been obtained by MALDI analysis of standard and in vitro glycated IgG and plasma protein fraction of a healthy subject after digestion with papain, releasing Fab and Fc fragments of the molecule. Both experiments, as well as molecular modeling of the whole protein, confirm that the most of glucose molecules have condensed on the Fab fragment of IgG, suggesting that the immune deficiency observed in diabetic patients may be explained at the molecular level by a more effective glycation of the Fab fragment, thus inhibiting the process of molecular recognition between antibody and antigen.

The monitoring of glycemic control in diabetic subjects has been greatly improved by the development of analytical methods for the measurement of glycohemoglobin concentrations, which reflect average serum glucose concentrations 4–8 weeks preceding the analysis. In particular, because HbA1c is considered one of the most powerful markers in such evaluations (1), optimized conditions for its determination still remain one of the major goals of clinical chemistry, as recently emphasized by Miedema (2). The development of methods without the limitations inherent in chromatographic, electrophoretic, and immunological procedures (3) is certainly of great interest. These methods may be used to measure HbA1c directly and/or to determine the extent of glycation of the “universal calibrator”. Choosing between these two different approaches is necessarily related to the feasibility (and to the price/performance ratio) of each method. In this context, Roberts et al. (4) recently showed the potentialities of electrospray ionization mass spectrometry (ESI/MS) for quantifying glycohemoglobin. ESI mass spectra from the analysis of whole blood samples were used to evaluate the percentage of glycohemoglobin directly, and comparison of the ESI data with those from established affinity chromatographic procedures showed a particularly good linear relationship. These evaluations were based on the four ionic species detected in ESI conditions after baseline subtraction, i.e., glycated and nonglycated α- and β-globins. A different, highly specific approach for unequivocal HbA1c evaluation, which was proposed recently by Kobold et al. (5), is based on enzymatic cleavage of hemoglobin by an endoproteinase. This treatment yielded the β-N-terminal peptides of HbA1c and HbA, and their separation and quantification was performed by ESI/MS and capillary electrophoresis. This procedure may be used as a reference method for HbA1c measurement. In previous investigations (6)(7)(8)(9)(10), we demonstrated that matrix-assisted laser …

Matrix-assisted laser desorption ionization (MALDI) mass spectrometry (MS) has been applied to achieve a qualitative and quantitative evaluation of glycated globins on a wide number of healthy and diabetic subjects. The method allowed us to establish that both alpha- and beta-globins are glycated and that, in addition to simply glycated products, other species are detected. Investigations by different sample treatments and by analysis of the glycated beta-globin fraction obtained by preparative chromatography indicated that these species correspond to glyco-oxidized globins. Consequently MALDI-MS can be validly employed to evaluate not only the glycation level, but also the degree of oxidative stress. The percentages of glycated and glycooxidized species were calculated from the related MALDI spectra by the measurement of the related peak areas, without any other treatment of data. A linear relationship between HbA1c values and the total percentage of glycated and glyco-oxidized globins has been found, and its slope (< 1) has been rationalized by the uncorrected evaluation of glycated globins content in the standard samples employed for HbA1c measurements.

Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry has been employed for the evaluation of the glycation level of IgG from healthy subjects and also from well- and badly-controlled diabetic patients. The measurements have been performed on untreated plasma protein fractions. The data obtained have shown that a clear mass increase, originating from non-enzymatic glycation processes, is observed in the case of diabetic patients: for well-controlled ones it is in the range 512-1565 Da, while it becomes 827-4270 Da for badly-controlled diabetic patients. This approach indicates that MALDI mass spectrometry is a highly specific tool that can be employed in the metabolic control of diabetic patients and in studies relating the IgG glycation level to possible immunological impairment.

A new method, based on matrix-assisted laser desorption/ionization (MALDI) measurements, has been developed for the evaluation of the glycation level of globins, a relevant parameter for diabetes control. It shows high levels of reproducibility and specificity, allowing the different glycated and glyco-oxidized products of both α- and β-globins to be distinguished. Such specificity is reflected in its possible diagnostic use not only for the control of diabetes, but also for the occurrence of ‘oxidative stress’. The comparison, for the same samples, of the obtained MALDI data with the related HbA1c values, determined by a high performance liquid chromatographic method, allowed it to be established that HbA1c percentages are not, as usually retained, related to the simply glycated β-globin, but to the whole pool of glycated and glyco-oxidized α- and β-globins. © 1997 John Wiley & Sons, Ltd.

Matrix-assisted laser desorption/ionization (MALDI) has been employed for the determination of molecular weights of alpha- and beta-globins obtained from blood samples of healthy and diabetic subjects. Glycated species, originating from the reaction of glucose with the proteins, are easily evident. The MALDI measurements allowed one to distinguish between simple glycation and glyco-oxidation processes of haemoglobin. In fact, together with the products arising from simple glucose condensation on the two proteins, compounds at different oxidation levels were evident. Due to its high specificity, MALDI must be considered a valuable tool for diagnosis in the diabetes field.