Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers

Immunotherapy may provide valid alternative therapy for patients with hormone-refractory metastatic prostate cancer. However, if the tumor environment exerts a suppressive action on antigen-specific tumor-infiltrating lymphocytes (TIL), immunotherapy will achieve little, if any, success. In this study, we analyzed the modulation of TIL responses by the tumor environment using collagen gel matrix–supported organ cultures of human prostate carcinomas. Our results indicate that human prostatic adenocarcinomas are infiltrated by terminally differentiated cytotoxic T lymphocytes that are, however, in an unresponsive status. We demonstrate the presence of high levels of nitrotyrosines in prostatic TIL, suggesting a local production of peroxynitrites. By inhibiting the activity of arginase and nitric oxide synthase, key enzymes of L-arginine metabolism that are highly expressed in malignant but not in normal prostates, reduced tyrosine nitration and restoration of TIL responsiveness to tumor were achieved. The metabolic control exerted by the tumor on TIL function was confirmed in a transgenic mouse prostate model, which exhibits similarities with human prostate cancer. These results identify a novel and dominant mechanism by which cancers induce immunosuppression in situ and suggest novel strategies for tumor immunotherapy

Collecting duct carcinoma of the kidney: an immunohistochemical study of 11 cases

BACKGROUND: Collecting duct carcinoma (CDC) is a rare but very aggressive variant of kidney carcinoma that arises from the epithelium of Bellini's ducts, in the distal portion of the nephron. In order to gain an insight into the biology of this tumor we evaluated the expression of five genes involved in the development of renal cancer (FEZ1/LZTS1, FHIT, TP53, P27(kip1), and BCL2). METHODS: We studied eleven patients who underwent radical nephrectomy for primary CDC. All patients had an adequate clinical follow-up and none of them received any systemic therapy before surgery. The expression of the five markers for tumor initiation and/or progression were assessed by immunohistochemistry and correlated to the clinicopathological parameters, and survival by univariate analysis. RESULTS: Results showed that Fez1 protein expression was undetectable or substantially reduced in 7 of the 11 (64%) cases. Fhit protein was absent in three cases (27%). The overexpression of p53 protein was predominantly nuclear and detected in 4 of 11 cases (36%). Immunostaining for p27 was absent in 5 of 11 cases (45.5%). Five of the six remaining cases (90%) showed exclusively cytoplasmic protein expression, where, in the last case, p27 protein was detected in both nucleus and cytoplasm. Bcl2 expression with 100% of the tumor cells positive was observed in 4 of 11 (36%) cases. Statistical analysis showed a statistical trend (P = 0.06) between loss and reduction of Fez1 and presence of lymph node metastases. CONCLUSIONS: These findings suggest that Fez1 may represent not only a molecular diagnostic marker but also a prognostic marker in CDC

[Positive surgical margins after radical prostatectomy]

Positive surgical margins (PSMs) in radical prostatectomy specimens are usually considered a negative prognostic parameter. However, their definition and the management of patients with PSMs remain unclear. The aim of the present review is to define pathological features of PSMs,to report their incidence and risk factors and to update PSMs prognostic meaning and possible treatment modalities.The average incidence of PSMs in contemporary series ranges from 6.5% to 32%. The likelihood of PSMs is influenced by pre-operative PSA (total-PSA and PSA-density), tumor features (volume,grade and stage), previous prostatic surgery (open or TURP), patients\u2019 characteristics (BMI andpelvis shape) and surgeons' skill. Although PSMs are a predictor of biochemical recurrence, their impact on cause specific survival is highly variable and largely influenced by the tumor Gleason Score. Adjuvant radiotherapy is an effective treatment in PSMs patients but early salvage radiotherapy may be an alternative option that guarantees equivalent survival benefits with less side effects. Further studies are required to define the best candidates to adjuvant or early salvage radiation therapy

Metabolic Plasticity in Chemotherapy Resistance

Resistance of cancer cells to chemotherapy is the first cause of cancer-associated death. Thus, new strategies to deal with the evasion of drug response and to improve clinical outcomes are needed. Genetic and epigenetic mechanisms associated with uncontrolled cell growth result in metabolism reprogramming. Cancer cells enhance anabolic pathways and acquire the ability to use different carbon sources besides glucose. An oxygen and nutrient-poor tumor microenvironment determines metabolic interactions among normal cells, cancer cells and the immune system giving rise to metabolically heterogeneous tumors which will partially respond to metabolic therapy. Here we go into the best-known cancer metabolic profiles and discuss several studies that reported tumors sensitization to chemotherapy by modulating metabolic pathways. Uncovering metabolic dependencies across different chemotherapy treatments could help to rationalize the use of metabolic modulators to overcome therapy resistance

Quando eseguire la biopsia prostatica

none6METODI Il processo metodologico seguito può essere così schematizzato: 1) individuazione delle domande a cui la revisione della letteratura doveva rispondere • un reperto rettale sospetto/positivo è sufficiente per eseguire una biopsia prostatica? • per quale valore di PSA totale è necessario eseguire una biopsia prostatica? • quale parametro risulta essere più affidabile nel porre indicazione alla biopsia prostatica in casi dubbi? (reperto rettale negativo e/o PSA nella zona grigia tra x e 10 ng/ml) • se utilizzi il rapporto libero/totale, per quale valore di cut-off effettui la biopsia? 2) stesura delle strategie di ricerca bibliografica per l’identificazione degli studi MEDLINE (1966-2003) #2 Search PSA OR "prostate specific antigen" OR "prostate-specific antigen" OR "prostate specific-antigen" OR "prostate-specific-antigen" OR "Prostate- Specific Antigen" [MESH] OR "prostatic specific antigen" OR "prostatic-specific antigen" OR "prostatic specific- antigen" OR "prostatic-specific-antigen" OR PSAD OR PSAd OR PSAV OR PSAv OR fPSA OR f/tPSA OR F/TPSA OR cPSA OR c/tPSA OR C/TPSA #3 Search DRE OR digital rectal examination OR digital rectal exam #4 Search prostate biopsy OR prostate biopsies OR prostatic biopsy OR prostatic biopsies #5 Search (#2 OR #3) AND #4 Field: All Fields, Limits: English, Human CL (I issue, 2003) Prostate biopsy OR prostatic biopsy OR prostate cancer OR prostatic cancer Tommaso Prayer-Galetti1, Vincenzo Ficarra2, Roberta Franceschini3, Giovanni Liguori4, Pasquale Martino5, Riccardo Schiavina6 1Clinica Urologica, Università di Padova; 2U.O. Clinicizzata di Urologia, Policlinico Borgo Roma, Verona; 3Centro Indicatori Biochimici di Tumore, Ospedale Civile di Venezia; 4Clinica Urologica, Ospedale di Cattinara, Trieste; 5Cattedra di Urologia, Università di Bari; 6Clinica Urologica, Policlinico S. Orsola-Malpighi, Bologna Quando eseguire la biopsia prostatica. QUESITO N. 1 5458 MEDLINE 5483 individuati Processo di revisione 286 eleggibili (257 recuperati) 25 COCHRANE LIBRARY Archivio Italiano di Urologia e Andrologia 2005; 77, 3 - Suppl. 1 T. Prayer-Galetti, V. Ficarra, R. Franceschini, G. Liguori, P. Martino, R. Schiavina 4 DESCRIZIONE DELLE EVIDENZE In ambito urologico non esistono linee guida sulle indicazioni all'esecuzione di una biopsia prostatica basate su una revisione sistematica della letteratura o che riportano i livelli di evidenza che sono alla base delle raccomandazioni riportate. Al contrario sono disponibili alcune “Guidelines" redatte sulla base dell'esperienza e sul parere di esperti. Dalle linee guida pubblicate non è possibile identificare valori di cut-off per il PSA totale o i suoi derivati definiti univocamente come “normali” o “patologici”. È confermato invece da tutti questi documenti e dagli atti del Prostate Cancer Consensus Conference 2002 che la diagnosi di carcinoma prostatico viene posta solo quando vi è la conferma istologica del tumore. Analizzando i 257 lavori selezionati si evidenzia come le indicazioni alla biopsia prostatica si siano progressivamente modificate nel tempo. Negli anni ’70 la presenza di un nodulo prostatico palpabile al reperto rettale era la principale indicazione alla biopsia. Dalla metà degli anni ’80 la progressiva diffusione dell’utilizzo del PSA e dei suoi derivati (PSA corretto per età, PSA density, PSA libero, rapporto PSA libero/totale, PSA velocity, PSA complessato) ha fatto sì che la più frequente indicazione all’esecuzione di una biopsia sia un PSA “anormale”. Nel corso dei 20 anni presi in esame si sono modificate le modalità di raccolta ed analisi dei campioni sierologici, la tecnologia delle apparecchiature ecografiche, le modalità di esecuzione delle biopsie ecoguidate e le modalità di raccolta e preparazione dei frustoli bioptici. In particolare l’utilizzo di schemi bioptici che, nel corso degli anni, hanno incluso un numero sempre maggiore di prelievi p...noneTommaso Prayer-Galetti ; Vincenzo Ficarra ; Roberta Franceschini ; Giovanni Liguori ; Pasquale Martino ; Riccardo SchiavinaTommaso Prayer-Galetti ; Vincenzo Ficarra ; Roberta Franceschini ; Giovanni Liguori ; Pasquale Martino ; Riccardo Schiavin

Study of diagnostic accuracy of Fagan's two-step nomogram in increasing the value of predictive tools for prostate cancer: application of specific spatial distribution of positive/negative bioptic cores to predict extracapsular extension

BACKGROUND: Prostate cancer (PC) represents the second most frequent cancer in the male population worldwide. It is mandatory to have a very accurate staging to choice the best possible treatment. AIMS: To test the possibility of improving the performance of Partin's tables in predicting the pathological staging of PC by introducing bioptic parameters through an innovative statistic tool (Fagan's two-step nomogram). METHODS: We prospectivelly collected data of all 1048 consecutive patients undergoing saturation 24-core transrectal prostate biopsy. Then, in eligible 94 patients, we compared the prediction of presence/absence of extracapsular extension of neoplasm (EPE+/-), with pathological assessment of invasion through (pseudo)capsule in the prostatectomy specimens. Starting from the probability of EPE- (pre-test probability, calculated with formula "100%-risk of EPE+"), we used Fagan's nomogram to examine the diagnostic sensitivity (DSe) and specificity (DSp) of negative "lateral" bioptic cores. RESULTS: We specifically analyzed the status of "lateral" cores in each side (94 patients\u2009 7\u20092 sides\u2009=\u2009188 sides). "Lateral" cores were negative in 42.5% of sides (80/188) with a DSe and DSp of 91.7 and 45.4%, respectively. In these sides, the mean probability of EPE+ according to Partin's tables was 21.6%. With Fagan's nomogram, the post-test probability of EPE+ when all "lateral" cores were negative was 14.1%, with a substantial gain of 7.5%. DISCUSSION: The spatial distribution of bioptic positive cores allowed us to demonstrate the role Fagan's nomogram in increasing the accuracy of already existing, predictive tools for PC. CONCLUSIONS: This pioneering study may justify the use of the above nomogram in testing "local" predictive parameters in combination with pre-existing nomograms