Zohar A. Dotan

Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis

Cellular senescence has been theorized to oppose neoplastic transformation triggered by activation of oncogenic pathways in vitro, but the relevance of senescence in vivo has not been established. The PTEN and p53 tumour suppressors are among the most commonly inactivated or mutated genes in human cancer including prostate cancer. Although they are functionally distinct, reciprocal cooperation has been proposed, as PTEN is thought to regulate p53 stability, and p53 to enhance PTEN transcription. Here we show that conditional inactivation of Trp53 in the mouse prostate fails to produce a tumour phenotype, whereas complete Pten inactivation in the prostate triggers non-lethal invasive prostate cancer after long latency. Strikingly, combined inactivation of Pten and Trp53 elicits invasive prostate cancer as early as 2 weeks after puberty and is invariably lethal by 7 months of age. Importantly, acute Pten inactivation induces growth arrest through the p53-dependent cellular senescence pathway both in vitro and in vivo, which can be fully rescued by combined loss of Trp53. Furthermore, we detected evidence of cellular senescence in specimens from early-stage human prostate cancer. Our results demonstrate the relevance of cellular senescence in restricting tumorigenesis in vivo and support a model for cooperative tumour suppression in which p53 is an essential failsafe protein of Pten-deficient tumours.

Pten Dose Dictates Cancer Progression in the Prostate

Complete inactivation of the PTEN tumor suppressor gene is extremely common in advanced cancer, including prostate cancer (CaP). However, one PTEN allele is already lost in the vast majority of CaPs at presentation. To determine the consequence of PTEN dose variations on cancer progression, we have generated by homologous recombination a hypomorphic Pten mouse mutant series with decreasing Pten activity: Ptenhy/+ > Pten+/− > Ptenhy/− (mutants in which we have rescued the embryonic lethality due to complete Pten inactivation) > Pten prostate conditional knockout (Ptenpc) mutants. In addition, we have generated and comparatively analyzed two distinct Ptenpc mutants in which Pten is inactivated focally or throughout the entire prostatic epithelium. We find that the extent of Pten inactivation dictate in an exquisite dose-dependent fashion CaP progression, its incidence, latency, and biology. The dose of Pten affects key downstream targets such as Akt, p27Kip1, mTOR, and FOXO3. Our results provide conclusive genetic support for the notion that PTEN is haploinsufficient in tumor suppression and that its dose is a key determinant in cancer progression.

Pattern of Prostate-Specific Antigen (PSA) Failure Dictates the Probability of a Positive Bone Scan in Patients With an Increasing PSA After Radical Prostatectomy

PURPOSE Physicians often order periodic bone scans (BS) to check for metastases in patients with an increasing prostate-specific antigen (PSA; biochemical recurrence [BCR]) after radical prostatectomy (RP), but most scans are negative. We studied patient characteristics to build a predictive model for a positive scan. PATIENTS AND METHODS From our prostate cancer database we identified all patients with detectable PSA after RP. We analyzed the following features at the time of each bone scan for association with a positive BS: preoperative PSA, time to BCR, pathologic findings of the RP, PSA before the BS (trigger PSA), PSA kinetics (PSA doubling time, PSA slope, and PSA velocity), and time from BCR to BS. The results were incorporated into a predictive model. RESULTS There were 414 BS performed in 239 patients with BCR and no history of androgen deprivation therapy. Only 60 (14.5%) were positive for metastases. In univariate analysis, preoperative PSA (P = .04), seminal vesicle invasion (P = .02), PSA velocity (P < .001), and trigger PSA (P < .001) predicted a positive BS. In multivariate analysis, only PSA slope (odds ratio [OR], 2.71; P = .03), PSA velocity (OR, 0.93; P = .003), and trigger PSA (OR, 1.022; P < .001) predicted a positive BS. A nomogram for predicting the bone scan result was constructed with an overfit-corrected concordance index of 0.93. CONCLUSION Trigger PSA, PSA velocity, and slope were associated with a positive BS. A highly discriminating nomogram can be used to select patients according to their risk for a positive scan. Omitting scans in low-risk patients could reduce substantially the number of scans ordered.

The role of indirect radionuclide cystography during the acute phase of pyelonephritis in young women

Authors from Israel have investigated the use of dynamic renal scans in young female patients with acute pyelonephritis, combined with indirect radionuclide cystography. They found that using these techniques may avoid up to half of the delayed voiding cysto‐urethrograms, preventing the related inconvenience and cost.

Is Postoperative Arteriovenous Fistula Still a Concern After En Bloc Stapling of the Renal Hilum During Laparoscopic Nephrectomy

PURPOSE To report our experience with en bloc stapling of the renal hilum during laparoscopic nephrectomy (LN) and nephroureterectomy and to compare it with separate stapling performed during the same period at the same institution. PATIENTS AND METHODS We conducted a retrospective review of 125 laparoscopic nephrectomies and nephroureterectomies performed between November 2003 and September 2006 for benign and malignant conditions. The main outcome was assessment of complications, with special emphasis on postoperative arteriovenous fistula. Secondary outcomes included operative blood loss and operative time. Statistical analysis was performed using two-sided parametric, nonparametric, or categorical tests as appropriate. Statistical significance was set at P < or = 0.05. RESULTS The transperitoneal approach and 2.5 mM vascular titanium clips were used in all cases. En bloc stapling (group 1) was performed in 65 patients and individual stapling (group 2) in 60. There was a significantly higher proportion of right-side surgeries in group 1 than in group 2 (51 vs 25%, P = 0.05). Overall complications were 31% vs 32%, P = 0.91; mean operative time (confidence interval [CI]) 130 (95% 119, 141) vs 125 min (95% 115, 136), P = 0.3; and mean operative blood loss (CI) 100 (95% 39, 160) vs 135 mL (95% 76, 193), P = 0.33 did not differ for groups 1 and 2, respectively. After a median follow-up (interquartile range) of 25 (24.7) vs 30 (30.0) months, P = 0.14, no cases of arteriovenous fistula were detected. CONCLUSIONS En bloc stapling of the renal hilum is as safe and effective as individual stapling. Arteriovenous fistula after LN does not seem to be a concern with the use of modern inorganic titanium staplers.

The use of Haemostatic Agents does not impact the rate of hemorrhagic complications in patients undergoing partial nephrectomy for renal masses.

Hemostatic agents(HAs) have gained increasing popularity as interventions to improve perioperative haemostasis and diminish the need for allogeneic red cell transfusion(PBT) despite a paucity of data supporting the practice. The aim of the current study is to examine the efficacy of HAs in reducing the rate of hemorrhagic complications during partial nephrectomy(PN). Data on 657 patients, who underwent elective PN between 2004–2013, were analyzed. The impact of HAs and SURGICEL was evaluated by comparing four sequential groups of patients: Group1 = Sutures alone, Group2 = sutures and HA, Group3 = sutures and SURGICEL, Group4 = both HA and SURGICEL. Complications included post-operative urinary leak(UL), PBT rate, delayed bleeding and post-operative renal failure. Results showed that the use of HAs did not engender a statistically significant difference in overall complications rate. Specifically, the addition of HAs did not reduce the rate of PBT, delayed bleeding or UL. Further analysis revealed that patients who received SURGICEL had significantly higher PBT rate and higher prevalence of UL cases. Addition of HAs to SURGICEL had no effect on the rate of these complications. In the current study, the use of HAs during open and laparoscopic PN did not reduce the rate of negative outcomes. Adequate suture renorrhaphy may be sufficient to prevent hemorrhagic complications.

A Retrospective Feasibility Study of Salvage Pelvic Nodal Radiation in 6 Patients With Biochemical Failure Following Prostate Fossa Radiation: An Alternative to Androgen Deprivation Therapy (ADT).

Purpose:To evaluate salvage pelvic nodal radiation as an alternative to androgen deprivation therapy (ADT) in patients with biochemical failure and lymph node recurrence following salvage prostate fossa radiation. Methods:Six patients with biochemical failure and lymph node recurrence following prostate fossa radiation were treated with salvage pelvic nodal radiation therapy. A gross target volume was contoured using Choline PET/CT, CT, or MRI imaging. The clinical target volume included pelvic nodes. Avoidance structures were created using isodose lines from previous prostate fossa radiation plans. Radiation was delivered using IMRT or VMAT techniques. Failure was defined as a confirmed rise of prostate-specific antigen (PSA) over 0.2 ng/mL. Results:Four patients had presalvage PSA values <1 and 2 patients had PSAs >1. Dose to the clinical target volume was 54 to 60 Gy. The gross target volume dose was 60 to 73.6 Gy. One of the 2 patients with a high PSA received 6 months of concomitant ADT. Mean follow-up after RT for all patients was 24.9 months (range, 18.1 to 33.0 mo). All 5 patients with no ADT had significant PSA responses. PSA reduction was 80% (62% to 100%) of pre-RT PSA. At last follow-up, 2 patients with initial PSA<1 ng/mL remain free of biochemical progression at 33 and 20 months. Four patients have had PSA rise and meet criteria for failure. This included both patients with initial PSA values > 1. Duration of response before failure was 18.1 to 30.7 months. ADT for failure has been started in 1 patient. There was no grade ≥2 GI or GU toxicity. Conclusions:Salvage lymph node irradiation for patients with early biochemical recurrence and radiologic evidence of pelvic nodal metastases is well tolerated and associated with a durable biochemical response and may be an alternative to or may delay the need for ADT in some patients.

PD73-08 THE IMPACT OF INTRA VS. POST-OPERATIVE BLOOD TRANSFUSION ON CANCER RECURRENCE AND SURVIVAL FOLLOWING NEPHRECTOMY FOR RENAL CELL CARCINOMA

INTRODUCTION AND OBJECTIVES: The effects of perioperative blood transfusion (PBT) on morbidity, mortality following cancer surgery have previously been demonstrated in several malignancies including renal cell carcinoma (RCC). However, the significance of transfusion timing is still unclear. The purpose of this study is to evaluate whether intraoperative BT (InBT) differ from postoperative BT (PoBT) in regards to oncological outcomes in patients treated with nephrectomy for RCC. METHODS: Study included 1159 patients with RCC who underwent radical (RN) or partial nephrectomy (PN) between 1988 and 2013. PBT was defined as receipt of packed red blood cells either during surgery or during the postsurgical hospitalization. Univariate and multivariate models were used to evaluate the association of BT with cancer-specific survival (CSS), disease-free survival (DFS) and overall survival (OS). RESULTS: Of 1159 patients undergoing nephrectomy, 198 patients (17.1%) received a PBT. Patients were next divided into 3 groups; no PBT, InBT alone (n1⁄4117) and PoBT alone (n1⁄460). Twenty one patients of the PBT group (10.6%) received both intra and postoperative transfusion. Given the small number of patients, this subgroup was excluded. On multivariate analyses, receipt of InBT was associated with significantly increased risk of local disease recurrence (HR: 2.3; P1⁄40.025), metastatic progression (HR: 2.2; P1⁄40.006), cancerspecific mortality (HR: 2.95; P1⁄40.009) and all-cause mortality (HR: 2.05; P1⁄40.007); while receipt of a PoBT did not independently bear an increased risk of local recurrence (p 1⁄4 0.1), metastatic progression (P1⁄40.095) or kidney cancer death (P1⁄40.53), yet did significantly increase the risk of overall mortality (HR: 2.6; P1⁄40.002). CONCLUSIONS: In the current cohort, InBT but not PoBT was associated with significantly increased risk of cancer recurrence and cancer-specific mortality. This observation requires further studies to assess the impact and management of more restrictive intraoperative blood management strategies.

Staging of Prostate Cancer

Prostate cancer, with an incidence that is correlated to age, is the most common cancer tumor diagnosed among men older than 50 years, and an even higher incidence is found among patients older than 75. It is estimated that 234,460 men will be diagnosed during 2006 and 27,350 deaths will be attributed to prostate cancer in the United States. Thus, it is the 3rd most common cause of cancer-specific death, following lung cancer, in Western men (Jemal et al. 2006). The lifetime risk for prostate cancer is estimated to be one in six among countries with active screening programs. Since 1990 there has been a decline in prostate cancer death. Of the patients diagnosed from 1995 to 2000, around 90% were diagnosed during local or regional stages. The 5-year survival rate for those patients approached 100%, while the overall survival rate for all stages increased during the past 20 years from 67% to 99%, with a 10-year survival rate of 92%.

What is the probability of a positive bone scan (+BS) in patients with a rising PSA after radical prostatectomy (RP): A new nomogram

4553 Background: Physicians often order bone scans periodically to assess for metastases in patients with a rising PSA after RP (biochemical recurrence, BCR), but most scans are negative. We studied pre- and postoperative characteristics of patients to find factors predictive of a positive scan. METHODS From our SPORE prostate cancer database we identified all patients with BCR (3 subsequent peaks in PSA ≥0.1 ng/ml) after RP. We analyzed the following features at the time of each BS for their association with a positive scan: preoperative PSA, neoadjuvant hormonal therapy (NHT), time to BCR, pathologic findings (surgical margin, extracapsular extension, seminal vesicle invasion, lymph node metastases, and pathologic Gleason score), PSA level before the BS (trigger PSA), PSA doubling time (PSA DT), and time from BCR to BS were incorporated into a predictive model. RESULTS There were 927 scans in 330 patients with BCR. We excluded 318 scans done while the patient was on androgen deprivation therapy. Of the 609 eligible scans, only 84 (13.8%) were positive for metastases. In multivariate analysis trigger PSA (P=0.014), NHT (P=0.03), and time from BCR to bone scan (P=0.05) predicted a +BS. Pathologic variables and PSA DT did not add to the accuracy of the model. A nomogram for predicting the bone scan result was constructed with a concordence index of 0.9. A policy of ordering a BS only when the probability of a +BS is >15% would eliminate 76% of the scans currently ordered in patients with BCR after RP and will lead to a significant savings in the health care expenses. CONCLUSIONS Patients with BCR after RP have a low frequency of +BS (13.8%). Trigger PSA, NHT, and time from BCR to scan were significant predictors of a +BS. A highly accurate nomogram can be used to select patients according to their risk for a positive scan. Omitting scans in low risk patients could substantially reduce costs. No significant financial relationships to disclose.