Michael Kolinsky

Prostate-specific Antigen Decline After 4 Weeks of Treatment with Abiraterone Acetate and Overall Survival in Patients with Metastatic Castration-resistant Prostate Cancer.

BACKGROUND The availability of multiple new treatments for metastatic castration-resistant prostate cancer (mCRPC) mandates earlier treatment switches in the absence of a response. A decline in prostate-specific antigen (PSA) is widely used to monitor treatment response, but is not validated as an intermediate endpoint for overall survival (OS). OBJECTIVE To evaluate the association between early PSA decline and OS following abiraterone acetate (AA) treatment. DESIGN, SETTING, AND PARTICIPANTS We identified mCRPC patients treated with AA before or after docetaxel at the Royal Marsden NHS Foundation Trust between 2006 and 2014. Early PSA decline was defined as a 30% decrease in PSA at 4 wk relative to baseline, and early PSA rise as a 25% increase. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Association with OS was analyzed using multivariate Cox regression and log-rank analyses. Spearmans rho correlation coefficient (r) was calculated to evaluate the association between PSA changes at 4 wk and 12 wk. RESULTS AND LIMITATIONS There were 274 patients eligible for this analysis. A 30% PSA decline at 4 wk was associated with longer OS (25.8 vs 15.1 mo; hazard ratio [HR] 0.47, p<0.001), and a 25% PSA rise at 4 wk with shorter OS (15.1 vs 23.8 mo; HR 1.7, p=0.001) in both univariate and multivariable models. The percentage PSA decline at 4 wk was significantly correlated with the percentage PSA change at 12 wk (r=0.82; p<0.001). Patients achieving a 30% PSA decline at 4 wk were 11.7 times more likely to achieve a 50% PSA decrease at 12 wk (sensitivity 90.9%, specificity 79.4%). Limitations include the retrospective design of this analysis. CONCLUSIONS Patients not achieving 30% PSA decline after 4 wk of AA have a lower likelihood of achieving PSA response at 12 wk and significantly inferior OS. Prospective multicentre validation studies are needed to confirm these findings. PATIENT SUMMARY Prostate-specific antigen (PSA) is commonly used to evaluate response to treatment in metastatic castration-resistant prostate cancer. Expert recommendations discourage reliance on PSA changes earlier than 12 wk after treatment initiation. Our data suggest that early PSA changes are associated with survival in patients receiving abiraterone acetate.

Prognostic risk stratification derived from individual patient level data for men with advanced penile squamous cell carcinoma receiving first-line systemic therapy

BACKGROUND Prognostic factors in men with penile squamous cell carcinoma (PSCC) receiving systemic therapy are unknown. A prognostic classification system in this disease may facilitate interpretation of outcomes and guide rational drug development. We performed a retrospective analysis to identify prognostic factors in men with PSCC receiving first-line systemic therapy for advanced disease. PATIENTS AND METHODS Individual patient level data were obtained from 13 institutions to study prognostic factors in the context of first-line systemic therapy for advanced PSCC. Cox proportional hazards regression analysis was conducted to examine the prognostic effect of these candidate factors on progression-free survival (PFS) and overall survival (OS): age, stage, hemoglobin, neutrophil count, lymphocyte count, albumin, site of metastasis (visceral or nonvisceral), smoking, circumcision, regimen, ECOG performance status (PS), lymphovascular invasion, precancerous lesion, and surgery following chemotherapy. The effect of different treatments was then evaluated adjusting for factors in the prognostic model. RESULTS The study included 140 eligible men. Mean age across all men was 57.0 years. Among them, 8.6%, 21.4%, and 70.0% of patients had stage 2, 3, and 4 diseases, respectively; 40.7% had ECOG PS ≥ 1, 47.4% had visceral metastases, and 73.6% received cisplatin-based chemotherapy. The multivariate model of poor prognostic factors included visceral metastases (P<0.001) and ECOG PS ≥ 1 (P<0.001) for both PFS and OS. A risk stratification model constructed with 0, 1, and both poor prognostic factors was internally validated and demonstrated moderate discriminatory ability (c-statistic of 0.657 and 0.677 for OS and PFS, respectively). The median OS for the entire population was 9 months. Median OS was not reached, 8, and 7 months for those with 0, 1, and both risk factors, respectively. Cisplatin-based regimens were associated with better OS (P = 0.017) but not PFS (P = 0.37) compared with noncisplatin-based regimens after adjusting for the 2 prognostic factors. CONCLUSIONS In men with advanced PSCC receiving first-line systemic therapy, visceral metastases and ECOG PS ≥ 1 were poor prognostic factors. A prognostic model including these factors exhibited moderate discriminatory ability for outcomes and warrants external validation. Patients receiving cisplatin-based regimens exhibited better outcomes compared with noncisplatin-based regimens after adjusting for prognostic factors.

Clinical Outcome of Prostate Cancer Patients with Germline DNA Repair Mutations: Retrospective Analysis from an International Study

Background: Germline DNA damage repair gene mutation (gDDRm) is found in >10% of metastatic prostate cancer (mPC). Their prognostic and predictive impact relating to standard therapies is unclear. Objective: To determine whether gDDRm status impacts benefit from established therapies in mPC. Design, setting, and participants: This is a retrospective, international, observational study. Medical records were reviewed for 390 mPC patients with known gDDRm status. All 372 patients from Royal Marsden (UK), Weill-Cornell (NY), and University of Washington (WA) were previously included in a prevalence study (Pritchard, NEJM 2016); the remaining 18 were gBRCA1/2m carriers, from the kConFab consortium, Australia. Outcome measurements and statistical analysis: Response rate (RR), progression-free survival (PFS), and overall survival (OS) data were collected. To account for potential differences between cohorts, a mixed-effect model (Weibull distribution) with random intercept per cohort was used. Results and limitations: The gDDRm status was known for all 390 patients (60 carriers of gDDRm [gDDRm +], including 37 gBRCA2m, and 330 cases not found to carry gDDRm [gDDRm–]); 74% and 69% were treated with docetaxel and abiraterone/enzalutamide, respectively, and 36% received PARP inhibitors (PARPi) and/or platinum. Median OS from castration resistance was similar among groups (3.2vs 3.0 yr, p = 0.73). Median docetaxel PFS for gDDRm+ (6.8 mo) was not significantly different from that for gDDRm- (5.1 mo), and RRs were similar (gDDRm+ = 61%; gDDRm- = 54%). There were no significant differences in median PFS and RR on first-line abiraterone/enzalutamide (gDDRm+ = 8.3 mo, gDDRm- = 8.3 mo; gDDRm+ = 46%, gDDRm- = 56%). Interaction test for PARPi/platinum and gDDRm+ resulted in an OS adjusted hazard ratio of 0.59 (95% confidence interval 0.28–1.25; p = 0.17). Results are limited by the retrospective nature of the analysis. Conclusions: mPC patients with gDDRm appeared to benefit from standard therapies similarly to the overall population; prospective studies are ongoing to investigate the impact of PARPi/platinum. Patient summary: Patients with inherited DNA repair mutations benefit from standard therapies similarly to other metastatic prostate cancer patients.

Effect on Overall Survival of Locoregional Treatment in a Cohort of De Novo Metastatic Prostate Cancer Patients: A Single Institution Retrospective Analysis From the Royal Marsden Hospital

Micro‐Abstract We retrospectively evaluated the effect of locoregional treatment (LRT) on overall survival (OS) in 300 metastatic at diagnosis (M1) prostate cancer patients. LRT was associated in univariate and multivariate analysis with longer OS, which remained significant for radiotherapy but not for transurethral prostatectomy. These data support further prospective evaluation of the benefit of local control in this patient population. Background: The optimal management of the primary tumor in metastatic at diagnosis (M1) prostate cancer (PCa) patients is not yet established. We retrospectively evaluated the effect of locoregional treatment (LRT) on overall survival (OS) hypothesizing that this could improve outcome through better local disease control and the induction of an antitumor immune response (abscopal effect). Patients and Methods: M1 at diagnosis PCa patients referred to the Prostate Targeted Therapy Group at the Royal Marsden between June 2003 and December 2013 were identified. LRT was defined as either surgery, radiotherapy (RT) or transurethral prostatectomy (TURP) administered to the primary tumor at any time point from diagnosis to death. Kaplan–Meier analyses generated OS data. The association between LRT and OS was evaluated in univariate (UV) and multivariate (MV) Cox regression models. Results: Overall 300 patients were identified; 192 patients (64%) experienced local symptoms at some point during their disease course; 72 patients received LRT (56.9% TURP, 52.7% RT). None of the patients were treated with prostatectomy. LRT was more frequently performed in patients with low volume disease (35.4% vs. 16.2%; P < .001), lower prostate‐specific antigen (PSA) level at diagnosis (median PSA: 75 vs. 184 ng/mL; P = .005) and local symptoms (34.2% vs. 4.8%; P < .001). LRT was associated in UV and MV analysis with longer OS (62.1 vs. 55.8 months; hazard ratio [HR], 0.74; P = .044), which remained significant for RT (69.4 vs. 55.1 months; HR, 0.54; P = .002) but not for TURP. RT was associated with better OS independent of disease volume at diagnosis. Conclusion: These data support the conduct of randomized phase III trials to evaluate the benefit of local control in patients with M1 disease at diagnosis.

Interrogating Metastatic Prostate Cancer Treatment Switch Decisions: A Multi-institutional Survey

BACKGROUND Evaluation of responses to treatment for metastatic castration-resistant prostate cancer (mCRPC) remains challenging. Consensus criteria based on prostate-specific antigen (PSA) and clinical and radiologic biomarkers are inconsistently utilized. Circulating tumor cell (CTC) counts can inform prognosis and response, but are not routinely used. OBJECTIVE To evaluate the use of biomarkers and trends in clinical decision-making in current mCRPC treatment. DESIGN, SETTING, AND PARTICIPANTS A 23-part online questionnaire was completed by physicians treating mCRPC. OUTCOME MEASURES AND STATISTICAL ANALYSIS Results are presented as the proportion (%) of physicians responding to each of the options. We used χ2 and Fishers tests to compare differences. RESULTS AND LIMITATIONS A total of 118 physicians (22.1%) responded. Of these, 69.4% treated ≥50 mCRPC patients/year. More physicians administered four or fewer courses of cabazitaxel (27.9%) than for docetaxel (10.4%), with no significant difference in the number of courses between bone-only disease and Response Evaluation Criteria in Solid Tumours (RECIST)-evaluable disease. Some 74.5% of respondents considered current biomarkers useful for monitoring disease, but only 39.6% used the Prostate Cancer Working Group (PCWG2) criteria in clinical practice. PSA was considered an important biomarker by 55.7%, but only 41.4% discarded changes in PSA before 12 wk, and only 39.4% were able to identify bone-scan progression according to PCWG2. The vast majority of physicians (90.5%) considered clinical progression to be important for switching treatment. The proportion considering biomarkers important was 71.6% for RECIST, 47.4% for bone scans, 23.2% for CTCs, and 21.1% for PSA. Although 53.1% acknowledged that baseline CTC counts are prognostic, only 33.7% would use CTC changes alone to switch treatment in patients with bone-only disease. The main challenges in using CTC counts were access to CTC technology (84.7%), cost (74.5%), and uncertainty over utility as a response indicator (58.2%). CONCLUSIONS A significant proportion of physicians discontinue treatment for mCRPC before 12 wk, raising concerns about inadequate response assessment. Many physicians find current biomarkers useful, but most rely on symptoms to drive treatment switch decisions, suggesting there is a need for more precise biomarkers. PATIENT SUMMARY In this report we analyse the results of a questionnaire evaluating tools for clinical decision-making completed by 118 prostate cancer specialists. We found that most physicians favour clinical progression over prostate-specific antigen or imaging, and that criteria established by the Prostate Cancer Working Group are not widely used.

The Ongoing Challenges of Targeting the Androgen Receptor

Perhaps more than any other malignancy, systemic therapy for metastatic prostate cancer has focused on a single oncogenic target: the androgen receptor (AR). Dramatic regressions following castration occur in the vast majority of patients, as first demonstrated in the seminal work of Charles Huggins in 1941 [1]. Even in the castration-resistant setting, however, the cancer remains androgen driven in most patients [2], a concept that has been unequivocally proven by the clinical success of abiraterone acetate and enzalutamide. Even docetaxel, a broad-spectrum antineoplastic, is thought to exert at least part of its effect against prostate cancer by preventing microtubule-dependent movement of the AR from the cytoplasm to the nucleus [3]. Despite successes in targeting the AR, resistance to these agents invariably develops; recent evidence suggests that, at least some cases, this is due to ongoing activity of the AR [4]. The fact that resistance and disease progression are frequently heralded by rising prostate-specific antigen (PSA) indicates the ongoing biological activity of the AR; therefore, interest in targeting AR signalling remains. A number of novel therapies that either directly or indirectly target the AR have been developed recently with purported theoretical advantages over abiraterone or enzalutamide. VT-464 offers more selective inhibition of CYP17 C17,20-lyase with less effect on 17a-hydroxylase compared with abiraterone, potentially decreasing mineralocorticoid toxicity, and is reported not to require steroid coadministration. Galeterone has been reported to act as both a dual inhibitor of C17,20-lyase and as an AR antagonist and may not require steroid coadministration. ARN-509, which is chemically very similar to enzalutamide, is an AR antagonist that shows higher potency and lower central nervous system penetration than enzalutamide. All of these agents are currently undergoing evaluation in clinical trials [5]. In this month’s issue of European Urology, Massard and colleagues reported data on another addition to the field, a compound called ODM-201 [6]. Like enzalutamide and ARN-509, this drug functions as an AR antagonist by interacting with the ligand binding C-terminus domain and prevents nuclear translocation of the full-length AR; however, it is reported to have higher AR binding affinity than either enzalutamide or ARN-509 and biological activity against some forms of mutated AR that enzalutamide and ARN-509 do not inhibit. Moreover, ODM-201 is reported to be unable to cross the blood–brain barrier; therefore, it is less likely to predispose patients to seizures [7,8]. To understand the current study, onemust be familiar with the clinical development of ODM-201. In brief, the phase 1/2 ARADES trial [7] found that doses of ODM-201 up to 1800 mg daily were well tolerated, with no dose-limiting toxicities in patients with metastatic castration-resistant prostate cancer (CRPC) and no maximum tolerated dose identified, with the most common toxicities being fatigue, diarrhoea, arthralgias, back pain, and headache. Patients were randomised to receive 200, 400, or 1400 mg of ODM-201 daily, with three different cohorts of patients represented at each dose level: chemotherapy and CYP17 inhibitor naive; postchemotherapy and CYP17 inhibitor naive; and post–CYP17 inhibitor. PSA and objective response rates were similar across dose levels, with chemotherapyand CYP17 inhibitor–naive patients unsurprisingly showing the highest response rates. Based on these data, the randomised phase 3 ARAMIS trial of ODM-201 versus placebo in high-risk nonmetastatic CRPC (ClinicalTrials.gov identifier NCT02200614) was EU RO P E AN URO LOGY 6 9 ( 2 0 1 6 ) 8 4 1 – 8 4 3

PD57-08 CENTRALIZATION OF RADICAL CYSTECTOMY FOR BLADDER CANCER IN A UNIVERSAL HEALTHCARE SYSTEM: EARLY RESULTS FROM A CANADIAN ACADEMIC CENTER

and diagnosis of bladder cancer controlling for age, smoking history and race. RESULTS: We identified 42,774 patients with BPH. The median follow-up was 87 months. There were 11,864 (27.7%) African Americans (AA), 11,863 (27.7%) Caucasians, and 6,340 (14.8%) Hispanics in this population. 5,698 (13.3%) patients were prescribed Finasteride. Bladder cancer was diagnosed in 84 of 5,698 (1.5%) patients who were prescribed Finasteride compared with 863 of 37,076 (2.3%), who were not prescribed Finasteride (p<0.001). Multivariate logistic regression analysis showed that Finasteride use was protective of bladder cancer (OR: 0.57, CI: 0.45-0.71, p<0.001). When we stratified the data based on race, Finasteride use was protective of bladder cancer in Caucasians (2.1% vs. 3.8%, p1⁄40.001) and Hispanics (0.8% vs. 1.6%, p1⁄40.042), but not in AA (1.7% vs. 1.7%, p1⁄40.854). CONCLUSIONS: Our study confirms previous findings from the PLCO study that men who are on Finasteride have lower incidence of bladder cancer but only in Caucasians and Hispanics. Future research and randomized controlled studies may be needed to confirm these findings.

Cabazitaxel for the Treatment of Prostate Cancer

Prostate cancer is the most common malignancy in Western men, and the third most likely cause of cancer death. Treatments options for metastatic castration resistant prostate cancer (CRPC) have recently expanded, with cabazitaxel being the first in a new wave of agents to show an improvement in overall survival (OS). This taxane derivative shares many properties with docetaxel; however, there are several important differences, most notably the preserved antitumor activity of cabazitaxel in docetaxel-resistant cancers. Cabazitaxel may act through a different mechanism compared to docetaxel, with no apparent cross-resistance between cabazitaxel and other treatments for CRPC, such as abiraterone, enzalutamide, and docetaxel. The pivotal phase III TROPIC trial of cabazitaxel versus mitoxantrone, both in combination with prednisone, in metastatic CRPC demonstrated an improvement in OS of 15.1 versus 12.7 months (p < 0.0001), with secondary endpoints favoring the cabazitaxel arm. Of concern, toxicity was greater in patients treated with cabazitaxel, with higher rates of hematologic and gastrointestinal adverse events, and more treatment related deaths. However, several published reports of expanded access programs have demonstrated a more manageable toxicity profile with appropriate supportive care. While some questions exist regarding the use of this agent, including the identification of the optimal dose, sequencing with other agents, and its use in combinations, cabazitaxel represents an important advance in the field of CRPC and remains a valuable treatment option for men suffering from this disease.

Abstract 3973: Diffusion-weighted imaging of bone metastases as treatment response biomarker in prostate cancer

INTRODUCTION: Response assessment of bone metastases (BM) remains a challenge for drug development in metastatic castration resistant prostate cancer (mCRPC) as standard imaging techniques, computed tomography and bone scintigraphy, fail to characterize BM. Diffusion-weighted imaging (DWI) is a functional MRI technique that studies the motion of water molecules within a tissue informing on cellularity. We hypothesized that changes in whole body (WB) DWI informs on BM response to treatment in mCRPC. METHODS: We conducted a phase II trial of the PARP inhibitor olaparib in mCRPC (TOPARP-A; CRUK/11/029); the primary endpoint was response rate defined using RECIST 1.1, PSA falls of ≥50% and conversion of circulating tumour cell (CTC) counts from ≥5 to RESULTS: Overall, 33/42 pt consented to the WB-DWI substudy of whom 21 had WB-DWI at baseline and at 12w. Of these 29% (6/21) were classified as responders to olaparib as per the primary endpoint definition and had not progressed prior to 12w. At baseline, median CTC count was 46 CTC/7.5ml blood and median PSA was 411 ng/ml for this cohort. When assessing all the areas of DWI signal abnormality, median volume of BM per patient was 445ml and mADC was 782 x10-6 mm2/s. Baseline CTC counts and PSA were significantly associated with volume of BM (ρ = 0.59, p = 0.005; ρ = 0.64, p = 0.002 respectively). All pts who responded to olaparib showed a decrease in volume of BM (median -41.1%, range -58.8%, -6.3%), whilst in non-responders a decrease was not observed in any pt (median 20.7%, range 0.0%, 76.9%); the difference between responders and non-responders was statistically significant (p = 0.001). Increases in mADC after 12 weeks of treatment were associated with increased odds of response (Odds Ratio: 1.08, 95% CI 1.00, 1.15, p = 0.04). Additionally, we detected a significant positive association between changes in volume of BM estimated by DWI and best percentage change in PSA and CTC (ρ = 0.63, p = 0.002 and ρ = 0.77, p CONCLUSION: Decrease in volume and increase in mADC of BM assessed by WB-DWI are indicators of response to olaparib in BM from mCRPC. These data require validation but support the use of WB-DWI for assessing BM during treatment. Citation Format: Raquel Perez-Lopez, Matthew D. Blackledge, Helen Mossop, Joaquin Mateo, David Collins, Veronica A. Morgan, Alison McDonald, Shahneen Sandhu, Aurelius Omlin, Diletta Bianchini, Zafeiris Zafeiriou, Pasquale Rescigno, Michael Kolinsky, Daniel Nava Rodrigues, Penny Flohr, Berni Ebbs, Gemma Fowler, Nuria Porta, Emma Hall, Martin Leach, Johann S. de Bono, Dow-Mu Koh, Nina Tunariu. Diffusion-weighted imaging of bone metastases as treatment response biomarker in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3973.

Abstract 4340: DNA repair genes aberrations in germline DNA in metastatic castration-resistant prostate cancer patients

INTRODUCTION: DNA repair defects are found in mCRPC and are therapeutically actionable; germline BRCA mutation-associated (gBRCA) prostate cancer has a poor prognosis. We hypothesized that metastatic castration resistant prostate cancer (mCRPC) is enriched for germline DNA repair mutations and that these may be relevant to patient outcome. METHODS: Targeted-sequencing for DNA repair genes was conducted in germline DNA from patients consenting to 3 clinical trials between 2013-2015. Germline DNA was extracted from saliva or buccal swabs using the Oragene kit; libraries were constructed using a customized Qiagen panel and sequenced using the Illumina MiSeq. Family history and clinical data were prospectively collected. For time to event analyses unadjusted Cox regression models were used and comparisons were made using log-rank tests. RESULTS: Germline samples from 154 mCRPC patients were available. Median age at diagnosis was 61years (y), median time to castration-resistance was 14.5 months (m) and median overall survival (OS) from initial diagnosis of prostate cancer was 106.8m; 69% (91/131; 24 N/A) of patients were initially diagnosed with Gleason≥8 tumors. 130/154 (84.4%) and 131/154 (85.0%) received Docetaxel and Abiraterone respectively. Of 154 patients, 4 were previously known to be gBRCA2 mutation carriers and were removed from the prevalence analysis but included in the clinical analyses; 22/150 (14.7%, 95%CI 9.4-21.4%) harboured a truncating or frameshift mutation in a DNA repair gene (9 BRCA2, 6%; 4 ATM, 2.7%; 2 PALB2, 1.3%, 1 each for CHEK2, FANCI, MRE11A, NBN, RAD51C, RAD51D and MSH6). Overall, patients with any germline DNA repair aberrations had a worse median OS (75.8 vs 106.8 m; log-rank p = 0.04). Time to resistance to primary hormonal ablation was shorter specifically for gBRCA2 mutations carriers (11.0 vs 14.8 m; log-rank p = 0.01) but not for non-BRCA2 repair aberrations. Age at diagnosis was similar in patients with or without DNA repair germline mutations (median 61.3 vs 61.7y, Mann-Whitney p = 0.41) as well as frequency of Gleason≥8 tumors (16/21 [76%] vs 75/109 [68%]; Mann-Whitney p = 0.23) Response rates to Docetaxel (14/18 [77.8%] vs 64/94 [68.1%]; Fisher exact p = 0.67) and Abiraterone (10/21 [47.6%] vs 44/94 [46.8%]; Fisher exact p = 0.73) were similar among individuals with and without mutations. Family cancer history was collected in 125/154 cases (81%). While having cases of ovarian/prostate/breast/pancreas cancers in these patients’ families associated with a higher likelihood of finding a germline mutation (Odds Ratio 3.36, p = 0.03), 5 of 68 (7.4%) men with no cases of ovarian/prostate/breast/pancreas cancers registered in their families carried a germline mutation in a DNA repair gene. CONCLUSIONS: mCRPC is enriched for patients with germline mutations in DNA repair genes (15%), with 6% having gBRCA2 mutation. Germline DNA repair aberrations are associated with a worse prognosis from mCRPC. Citation Format: JOAQUIN MATEO, Suzanne Carreira, Helen Mossop, Pasquale Rescigno, Michael Kolinsky, Elena Castro, Ada Balasopoulou, Jo Hunt, Desamparados Roda, Claudia Bertan, Jane Goodall, Susana Miranda, Penny Flohr, Nuria Porta, Zsofia Kote-Jarai, David Olmos, Christopher J. Lord, Emma Hall, Ros Eeles, Johann S. de Bono. DNA repair genes aberrations in germline DNA in metastatic castration-resistant prostate cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4340.