Dysfunctional DC subsets in RCC patients: ex vivo correction to yield an effective anti-cancer vaccine.

Dendritic cells (DCs) are potent antigen-presenting cells responsible for the activation and functional polarization of specific T cells. In patients with renal cell carcinoma (RCC) and other cancers, coordinate DC and T cell defects have been reported. In particular, DC and T cell functional subsets that are not conducive to tumor clearance are hypothesized to predominate in patients with advanced-stage disease. Two major peripheral blood DC subsets have been identified in humans: myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) that are believed to mediate contrasting effects on cancer immunity. Given the lack of information regarding DC subsets in patients with RCC, in the present study we have investigated the comparative frequencies and activation states of mDC and pDC in peripheral blood, cancer tissues and lymph nodes of patients with RCC using flow cytometry and immunohistochemistry. Three monoclonal antibodies (mAbs) reactive against specific DC subsets (BDCA-2 or BDCA-4 for pDC and BDCA-1 and BDCA-3 which represent two distinct subsets of mDC, mDC1 and mDC2, respectively) were employed. We observed a significant reduction of both DC subsets in the peripheral blood of patients as compared to normal donors. Similarly, both mDC and pDC were recruited in large numbers into RCC tumor tissues, where they displayed an immature phenotype (DC-LAMP(-)) and appeared unable to differentiate into mature DC (CD83(+)) that were competent to migrate to draining lymph nodes. However, we were readily able to generate ex vivo mDC from RCC patients. These DC stimulated robust anti-tumor CTL in vitro and would be envisioned for use in DC-based vaccines applied in patients with RCC whose existing immune system is judged dysfunctional, anergic or prone to undergo apoptosis.

"Deviceless" hand-assisted laparoscopic donor nephrectomy.

Hand-assisted laparoscopic nephrectomy (HLN) in living donors is a minimally invasive surgical modality that uses classic laparoscopic techniques combined with the surgeon's hand as a support tool during renal dissection. We describe our experience with 14 donors undergoing HLN with a novel "deviceless" technique (DL-HLN). We used a midline or a paramedian incision. The first 10-mm trocar (camera) was inserted near the umbilicus and another 10-mm trocar placed under laparoscopic vision at the level of the anterior axillary line above the iliac crest. DL-HLN was performed in 14 patients (11 women and 3 men) of overall mean age of 40 years (range=33-60). Left nephrectomy was performed in all cases. Mean surgical time was 105 minutes (range=60-150). Estimated blood loss was 50 to 800 mL (mean=200 mL). Mean warm ischemia time was 3.5 minutes (range=2-11). Mean hospital stay was 4 days (range=3-6). In one case, uncontrollable hemorrhage developed due to a renal vein lesion at the level of the adrenal vein outlet, requiring conversion to open surgery. As to graft function, recipient serum creatinine on day 7 ranged from 0.9 to 2.6 mg/dL (mean=1.6). We used no device in our technique. The pneumoperitoneum was maintained by the sealing effect of the muscular fascia around the surgeon's wrist. Moreover, the kidney was removed through the hand port without an Endobag. Our modified HLN technique avoids the use of costly disposables and offers the advantages of a smaller incision.

Incidentally discovered yellowish lesions in a renal graft from a deceased donor.

The opening of Gerota's fascia, soon after harvesting the kidney, is a standard kidney donor procedure in Italy to exclude a renal cell carcinoma (RCC), a frequent finding in older donors. Herein we have reported our experience with the diagnosis and management of subcapsular yellow areas suggestive of RCC on the kidney surface during back-table procedures. From 2001 to 2006, 12/445 grafts showed a single yellowish subcapsular nodule during the back-table procedure which was excised for frozen section (FS) to rule out RCC. The affected donors were 7 males and 5 females of overall mean age of 60 years (range, 25-77 years). The mean nodule diameter was 0.75 cm (range, 0.3-1.2 cm), and all lesions were located in the upper renal pole. In 5 cases, a diagnosis of RCC could not be excluded by FS, and both kidneys were discarded. The final histology confirmed RCC in only 3 cases, and adrenal heterotopia (AH) in the other 2. In the remaining 7 cases, FS showed AH in 4, 1 angiomyolipoma, and 2 areas of infarction confirmed by histology. The adrenal foci consisted of clear cells and scattered cells with eosinophilic, granular cytoplasm and small round nuclei, some with small nucleoli. Immunostains for cytokeratins, CD10, and epithelial membrane antigen were negative, confirming the adrenal origin. AH is the most common pathological yellowish lesion in the upper kidney pole found incidentally during back-table preparation. A histological differential diagnosis with RCC at FS is difficult, relying on the distinction of normal corticoadrenal spongiocytes from Fuhrman grade 1 clear cancer cells. In Italy, for any renal mass suggestive of RCC, a graft discard is mandatory, even if several reports have described cases of renal transplantation performed after back-table excision of small unifocal tumors.

Evaluation of tamoxifen and anastrozole in the prevention of gynecomastia and breast pain induced by bicalutamide monotherapy of prostate cancer.

PURPOSE: To determine whether tamoxifen or anastrozole prevents gynecomastia and breast pain caused by bicalutamide (150 mg) without compromising efficacy, safety, or sexual functioning. PATIENTS AND METHODS: A double-blind, placebo-controlled trial was performed in patients with localized, locally advanced, or biochemically recurrent prostate cancer. Patients (N = 114) were randomly assigned to either bicalutamide (150 mg/d) plus placebo or in combination with tamoxifen (20 mg/d) or anastrozole (1 mg/d) for 48 weeks. Gynecomastia, breast pain, prostate-specific antigen (PSA), sexual functioning, and serum levels of hormones were assessed. RESULTS: Gynecomastia developed in 73% of patients in the bicalutamide group, 10% of patients in the bicalutamide-tamoxifen group, and 51% of patients in the bicalutamide-anastrozole group (P < .001); breast pain developed in 39%, 6%, and 27% of patients, respectively (P = .006). Baseline PSA level decreased by > or = 50% in 97%, 97%, and 83% of patients in the bicalutamide, bicalutamide-tamoxifen, and bicalutamide-anastrozole groups, respectively (P = .07); and adverse events were reported in 37%, 35%, and 69% of patients, respectively (P = .004). There were no major differences among treatments in sexual functioning parameters from baseline to month 6. Elevated testosterone levels occurred in each group; however, free testosterone levels remained unchanged in the bicalutamide-tamoxifen group because of increased sex hormone-binding globulin levels. CONCLUSION: Anastrozole did not significantly reduce the incidence of bicalutamide-induced gynecomastia and breast pain. In contrast, tamoxifen was effective, without increasing adverse events, at least in the short-term follow-up. These data support the need for a larger study to determine any effect on mortality.

Vasoactive intestinal polypeptide (VIP) is not an androgen-dependent neuromediator of penile erection.

The effects of castration on vasoactive intestinal polypeptide (VIP) immunostaining in human corpus cavernosum (CC) and the relationship between VIP immunostaining and erectile function were studied in patients with localised prostate cancer who had (Group 1 = castrated) or had not (Group 2 = control) undergone 3-month neoadjuvant chemical castration before radical prostatectomy. Evaluation of erectile function included medical and sexual history, physical examination, and measurement of total serum testosterone. CC biopsies were taken at the end of radical prostatectomy and samples immunostained with anti-human VIP antibody. Specific staining was quantified by image analysis and expressed in arbitrary units (AU). Chemical castration induced erectile function deterioration in 70% of patients due to loss of sexual interest and confidence in the ability of having an erection rather than reduced ability of obtaining sexually induced erections. Average VIP content was 34.5 AU in Group 1 and 39 AU in Group 2 and this difference was not statistically significant. Chemical castration does not influence VIP immunostaining of human CC, suggesting that VIP is not an androgen-dependent neuromediator of penile erection and that it can be responsible for sexually induced erections in castrated patients.

Double J stent with antireflux device in the prevention of short-term urological complications after cadaveric kidney transplantation: single-center prospective randomized study.

The placement of a double J stent to protect a uretero-vesical anastomosis in a kidney transplant is a widespread procedure performed to reduce the incidence of fistula and stenosis at the anastomosis. However, the presence of a double J stent may cause vesicoureteral reflux (VUR), predisposing one to urinary tract infections (UTIs), which may be a significant source of morbidity for the graft. We evaluated whether a ureteral stent incorporating an antireflux device can reduce the incidence of ureteral reflux and UTIs. From January to December 2003, 44 kidney transplant recipients were randomized to receive a 14-cm 4.8-F double J stent with (group A) or without an anti-reflux device (group B). Primary end points were the reduction of the incidence of VUR and of UTIs. The secondary end point was the graft function, on the basis of mean serum creatinine level at 3, 6, and 12 months. We failed to observe statistically significant differences in terms of either the incidence of VUR and UTIs, or the short-term outcomes of the grafts. We concluded that the anti-reflux device does not have an impact on the incidence of stent-related side effects.

Effects of complete androgen blockade for 12 and 24 weeks on the pathological stage and resection margin status of prostate cancer.

AIMS: To compare the pathological stage and surgical margin status in patients undergoing either immediate radical prostatectomy or 12 and 24 weeks of neoadjuvant hormonal treatment (NHT) in a prospective, randomised study. METHODS: Whole mount sections of 393 radical prostatectomy specimens were evaluated: 128 patients had immediate surgery, 143 were treated for 12 weeks and 122 for 24 weeks with complete androgen blockade. RESULTS: Histopathology revealed organ confined tumours in 40.4% of patients with clinical stage B disease in the immediate surgery group, whereas 12 and 24 weeks of NHT increased the number of organ confined tumours to 54.6% and 64.8%, respectively. Among patients with clinical stage C tumours, pathological staging found organ confined disease in 10.4%, 31.4%, and 61.2% in the immediate surgery, 12 weeks of NHT, and 24 weeks of NHT groups, respectively. Preoperative NHT caused a significant decrease in positive margins both in patients with clinical stage B and C disease. The extent of margin involvement was not influenced by preoperative treatment. CONCLUSIONS: Neoadjuvant androgenic suppression is effective in reducing both the pathological stage and the positive margin rate in patients with stage B and C prostatic cancer undergoing radical surgery. Some beneficial effects are evident in those patients treated for 24 weeks, and it is reasonable to assume that the optimal duration of NHT is longer than three months.

The effects of androgen depletion on human erectile function: a prospective study in male-to-female transsexuals.

The objective of the study was to determine the effects of androgen depletion on erectile function in a population of male-to-female transsexuals. The erectile function of 25 consecutive male-to-female transsexuals on androgen depletion treatment and scheduled for surgical gender reassignment was prospectively evaluated using medical and sexual history, physical examination, total serum testosterone, International Index of Erectile Function (IIEF-15) questionnaire, penile colour-coded Doppler ultrasonography (CDU) after pharmacological stimulation and nocturnal penile tumescence (NPT) test. All but one had undetectable or low testosterone. Subjective erectile function, according to IIEF-15 scores, and penile CDU findings did not correlate with testosterone levels, whereas NPT test findings correlated well with testosterone levels. These findings would suggest that nocturnal erections are androgen-dependent whereas sexually induced erections are androgen-independent. It can also be assumed that testosterone is important but not essential for male erectile function and that other androgen-independent pathways can be responsible for sexually induced erections.

Standard interleukin-2 (IL-2) and interferon-alpha immunotherapy versus an IL-2 and 4-epirubicin immuno-chemotherapeutic association in metastatic renal cell carcinoma.

BACKGROUND: Recombinant human interleukin-2 (IL-2) has a well-documented anti-tumor activity against RCC and has demonstrated a synergistic anti-tumor activity between doxorubicin and IL-2, thus providing better survival. This study investigated the toxicity and efficacy of the association between doxorubicin and IL-2, and interferon-alpha, and the immuno-chemotherapeutic association with IL-2 and 4-Epirubicin. PATIENTS AND METHODS: Patients with histologic evidence of metastatic or advanced RCC were randomized to receive either IL-2 + IFN-alpha (Arm A) or IL-2 + 4-Epi (Arm B). Arm A patients received IFN-alpha subcutaneously at doses of 3 million UI on days 1, 3 and 5 for 6 weeks. Arm B patients received 4-EPI at doses of 25 mg/m2 on days 1, 8, 15, 22, 29 and 36. Treatment cycles were repeated at 10 week intervals. RESULTS: Of 38 evaluable patients, we observed 2 complete responses, 2 partial responses, 1 minimal response, 1 mixed response, 21 stationary disease and 11 disease progressions. There was no significant difference in overall survival between the two groups. However in arm B, the median overall survival for responding patients was better than that of patients who experienced a disease progression. Performance status was the only predictive prognostic factor. CONCLUSIONS: Our analysis confirms the low response rate associated with IL-2 treatments but seems to indicate a role of anthracycline in improving the survival of responding patients with an acceptable toxicity.

Combined adrenal adenoma and myelolipoma in a patient with Conn syndrome. Case report.

Adrenal myelolipoma is an uncommon benign tumor usually discovered by chance in patients with hypertension, obesity, arteriosclerosis or cancer. The association with adrenocortical endocrine dysfunctions is rare. We report herein an unusual case, the second in the literature to the best of our knowledge, of combined adrenal adenoma and myelolipoma in a patient with Conn syndrome.

Effect of total androgen ablation on pathologic stage and resection limit status of prostate cancer. Initial results of the Italian PROSIT study.

The likelihood of finding organ-confined untreated prostate cancer (PCa) by pathological examination at the time of radical prostatectomy (RP) is only 50% in patients with clinically organ-confined disease. In addition, tumour is present at the resection margin in approximately 30% of clinical T2 (clinical stage B) cases. The issue of clinical "understaging" and of resection limit positivity have led to the development of novel management practices, including "neoadjuvant" hormonal therapy (NHT). The optimal duration of NHT is unknown. We undertook the present analysis to evaluate the effect of NHT on pathologic stage of PCa and resection limit status in patients with prostate cancer and treated with total androgen ablation either for three or six months before RP. Between January 1996 and February 1998, 259 men with prostate cancer underwent radical retropubic prostatectomy and bilateral pelvic node dissection in the 26 centres participating in the Italian randomised prospective PROSIT study. Whole mount sectioning of the complete RP specimens was adopted in each centre for accurately evaluating the pathologic stage and resection limit status. By February 1998, haematoxylin and eosin stained sections from 155 RP specimens had been received and evaluated by the reviewing pathologist (RM). 64 cases had not been treated with total androgen ablation (e.g. NHT) before RP was performed, whereas 58 and 33 had been treated for three and six months, respectively. 114 patients were clinical stage B whereas 41 were clinical stage C. After three months of total androgen ablation, pathological stage B was more prevalent among patients with clinical B tumours, compared with untreated patients (57% in treated patients vs. 36% in untreated). The percentage of cancers with negative margins was statistically significantly greater in patients treated with neoadjuvant therapy than those treated with immediate surgery alone (69% vs. 42%, respectively). After six months of NHT therapy the proportion of patients with pathological stage B (67% vs. 36%, respectively) and negative margins was greater than after 3 months (92% vs. 42%, respectively). For clinical C tumours, the prevalence of pathological stage B and negative margins in the patients treated for either 3 or 6 months was not as high as in the clinical B tumours, when compared with the untreated group (pathological stage B: 31% and 33% vs. 6% in the clinical C cases, respectively. Negative margins: 56% and 67% vs. 31%, respectively). The initial results of this study suggest that total androgen ablation before RP is beneficial in men with clinical stage B because of the significant pathological downstaging and decrease in the number of positive margins in the RP specimens. These two effects are more pronounced after six months of NHT than after three months of therapy. The same degree of beneficial effects are not observed in clinical C tumours.

Treatment of advanced urothelial carcinoma with M-VECA (methotrexate, vinblastine, epirubicin and carboplatin).

Transitional cell carcinoma of the urinary tract is actually considered very sensitive to cisplatin-containing regimens. Nevertheless, the generally impaired renal function and poor performance status of these patients are responsible for the severe toxicity usually occurring when cisplatin, either alone or in combination with other agents, is administered to these patients. The aim of this study was to verify the possibility of substituting carboplatin for cisplatin, and epirubicin for doxorubicin in the M-VAC regimen in order to reduce toxicity and improve patient tolerance. Thirty-five patients with advanced urothelial tract carcinoma were treated with a chemotherapeutic regimen composed of methotrexate (30 mg/m2 iv on days 1, 15, 22), vinblastine (3 mg/m2 iv on days 2, 15, 22), epirubicin (35 mg/m2 iv on day 2) and carboplatin (250 mg/m2 iv on day 2) every 4 weeks (M-VECA). All patients had bidimensionally measurable disease. Of the 32 evaluable patients, 5 (16%) obtained a complete response and 10 (31%) a partial response (response rate: 47% C.I. = 30%-64%). Grade III-IV leuko-thrombocytopenia was observed in 25%, and mucositis in 19% of cases. Nevertheless, recovery was prompt and opportune dosage reductions avoided severe toxicity in subsequent cycles in most patients. In conclusion, M-VECA is a safe and effective regimen for the treatment of patients with metastatic urothelial tumors.

Kidney transplants from infected donors: our experience.

Organ procurement from infected donors may transmit a disease to the recipient that could cause a graft loss and/or recipient morbidity. Retrospectively, all kidney transplants from infected donors at our center in the last 4 years were reviewed. A donor was considered infected in the presence of at least one positive culture before procurement. From January 1999 to 2003, 23 of 160 donors (14.5%) were infected: in 10 donors a positive blood culture; in 3, a urine culture; and in 13, a bronchial culture. In a further 12 (7%) donors, only the preservation solution was contaminated. Organisms isolated were: Staphylococcus coagulase.neg. (n = 7); Staphylococcus epidermidis (n = 3); Staphylococcus aureus (n = 6); Klebsiella pneumoniae (n = 3); Pseudomonas aeruginosa (n = 4); Acinetobacter (n = 1); Candida albicans (n = 13); Aspergillus (n = 1); and Escherichia coli (n = 1). All except 2 kidneys were transplanted with positivity in all cultures. All recipients received general, nonspecific, antibacterial and antifungal prophylaxis until the antibiotic and antifungal spectrum was ready. Patient and graft survival rates at 6 months were 94% and 93%, respectively. Two deaths occurred due to bacterial arteritis (P aeruginosa), and 2 acute graft losses due to fungal arteritis. Kidneys from infected donors seem suitable for transplants. Only grafts infected by vasculotropic agents (S aureus, P aeruginosa, and C albicans) should be discarded.

Medical and surgical complications after kidney transplantation from "suboptimal donors": one centre's experience.

To overcome the organ shortage, the pool of donors can be expanded to include aged donors (>55 years old) or patients with diabetes and long-standing hypertension, the so-called "suboptimal donors." Our experience on medical and surgical complications in kidney recipients from such donors and their impact on the graft and patient survival rates is reported. From January 1998 to April 2003, 276 kidney transplantation were performed: 107 from suboptimal donors (group A) and 169 from optimal ones (group B). After a mean follow-up of 26.8 months (range, 1-63 months), the 1-year graft survival rate was 89.3% and 97% for groups A and B, respectively. Medical complications were observed in 18.8% of group A and 6% of group B and surgical complications in 34.5% and 20%, respectively. In conclusion, even if the complication rate is higher among the suboptimal donor group, the patient and graft survival rates appear to be only slightly affected, therefore, validating the use of marginal donors.

Adjuvant hormone therapy after radical prostatectomy: indications and results.

Despite recent advances in staging modalities, nearly 30-40% of patients undergoing radical prostatectomy for clinically localized prostate cancer have residual disease. In these cases, one or more of the following conditions may be present: extracapsular disease, positive margins, invasion of the seminal vesicles, lymph node metastases or the postoperative persistence of PSA values above the biological threshold. The optimal management for residual prostate cancer remains controversial and in this setting adjuvant therapy could be appropriate. In the present review we examine the conditions in which hormonal adjuvant therapy can be indicated and the results available from retrospective or non-randomized studies. From the data in the literature and in the absence of randomized prospective studies, prudent conclusions could be drawn on the efficacy of adjuvant hormonal therapy. In cases of small volume, low grade (Gleason score < 7) prostate cancer in stage C or D1, radical surgery coupled with adjuvant hormonal therapy leads to survival rates in stage C similar to those in the intraprostatic stage, and in stage D1 with minimal lymph involvement, seems to delay clinical development of metastases. Finally, the quality of life associated with adjuvant therapy and the drug regimens available for this therapy are reviewed.

[Antibacterial activity of fosfomycin in chronic kidney infections]. / Attività antibatterica della fosfomicina nelle infezioni renali croniche.

Authors have carried out a retrospective study in vitro on the bacteria isolated from renal parenchyma and stones in patients with CPN associated to kidney stones. Results show a different inhibitory action of the some antibiotics to Proteus, E. coli and P. aeruginosa. Fosfomycin inhibits the growth of bacteria in a wide range of concentration (50-1000 microgram/ml). A prospective study in vivo shows an excellent therapeutic action of fosfomycin in recurrent urinary infections, and a very good one in CPN and in some forms associated to kidney stones.

Endothoracic nodules in patients who under-went nephrectomy for renal cell carcinoma. Results of surgical resection.

AIM: A review of our experience with surgical resection of endothoracic nodules in patients who underwent nephrectomy for renal cell carcinoma (RCC) is presented, to evaluate the incidence of metastases in our series and the effectiveness and the opportunity of surgical treatment in this sort of patients. METHODS: Between January 1988 and January 2002, 41 consecutive patients (33 men, 8 women) underwent resection for suspected endothoracic metastases from RCC; 1 more male patient for metastases from an occult renal cancer. Mean age was 62 y (range: 43-80 y). Mean time between nephrectomy and 1st pulmonary resection in 41 patients was 29 mo (range: 0-120 mo). Nineteen patients had solitary lesions, 11 multiple unilateral and 12 bilateral. Antero-lateral thoracotomy was performed in 37 patients, median sternotomy in 1, simultaneous bilateral thoracotomy (clam-shell) in 2, sterno-laparotomy in 1, thoracofrenolaparotomy in 1. Wedge excision was performed in 36 patients, lobectomy with lymphadenectomy in 5, mediastinal limphadenectomy in 1. Six patients had repeat resection for recurrent metastases. RESULTS: Only 24 patients (57%) had histologic diagnosis of pulmonary metastases from RCC; 11 (26%) had benign lesions; 7 (17%) primary lung cancer. Mean follow-up was 25 mo (range: 1-91 mo). Overall, 4-y survival was 50%. Patients with solitary metastasis had a lower survival than those with 4 and more lesions. CONCLUSION: The evidence of pulmonary nodules in patients submitted to nephrectomy for RCC is not necessarily indicative of metastatic disease. Pulmonary resection for RCC metastases, even bilateral and recurrent, may help prolong survival in selected patients.

Management of bilateral ureteric injuries after gynaecological and obstetric procedures.

The outcome of 24 patients affected by bilateral injuries of the ureter after gynaecological and obstetric procedures was analyzed. Five patients were not treated because they were asymptomatic, while 19 patients underwent different kinds of surgical procedures. Ureteric stenting was performed in 4 patients, reconstructive procedures in 9, internal diversions in 2 and external diversions in 4. Good results were achieved in 14 (74%) of the 19 treated patients. The success rate, however, was remarkably higher (85%) in the group of patients treated with ureteric stenting or reconstructive procedures than in those treated with diversions (50%). Ureteric stenting and bilateral reconstructive procedures, when feasible, constitute the simplest and safest way to repair short ureteric injuries. In the management of extensive injuries nephrostomy represents a safe and valid alternative to open surgical diversions which do not improve the quality of life and may even be life-threatening.

[Immunological monitoring after renal transplantation from living donors]. / Monitoraggio immunologico dopo trapianto renale da donatore vivente.

Monitoring of immune responses were done in kidney recipients from living donors using the following assays: CH-50, alternative pathway of complement activation, circulating Ag-Ab complexes, cytotoxic antibodies. All patients had survived 3 to 5 years from transplant. While some alternations (fall of CH-50, cytotoxic antibodies, circulating Ag-Ab complexes) occurred after the episodes of chronic rejection in 2 patients, despite a well functioning allograft, the inhibition of alternative pathway of complement activation demonstrated a coincidental capability to predict rejection episodes. The blocking mechanism of the alternative pathway of complement activation during rejection is not fully understood. The enhancing role of B-lymphocyte antibodies and the function of circulating immunecomplexes were also discussed.

[Cross test with B-lymphocytes in transplantation immunology]. / La prova crociata con i B-linfociti nell'immunità da trapianto.

Cross-matching procedure with B-lymphocytes may facilitate the detection of cytotoxic antibodies. This finding suggested a reliable use of the test in immune monitoring after kidney allograft from living donor. The possible enhancing role of B-lymphocyte antibodies was also discussed.