bluuebunny/crossref_metadata_2025 huggingface dataset:
The usefulness of serum X-linked inhibitor of apoptosis protein (XIAP) for predicting recurrence of renal cell carcinoma.
Authors: Hongo Fumiya , Toiyama Daisuke , Ueda Takashi , Kimura Yasunori , Nakamura Terukazu , Mikami Kazuya , Takaha Natsuki , Miki Tsuneharu
Published: March 2020

e15055

Background: The X-linked Inhibitor of Apoptosis protein (XIAP) is associated with cell survival by blocking caspase-mediated apoptosis. We have reported the expression and prognostic value of XIAP in human prostate cancer using prostate tissue microarrays (Clin Cancer Res 2007). The expression and prognostic significance of XIAP in renal cell cancer (RCC) has been rarely studied. To our knowledge, no report on the serum XIAP levels from RCC patients has been published. In this study, we examined serum XIAP levels of RCC patients and normal individuals and evaluated its utility as biomarker. Methods: Peripheral blood samples were obtained from 99 patients (68 men and 31 women, median age; 60.7 years [36-85]) with RCC before surgery. All the patients underwent radical or partial nephrectomy. Blood samples were also collected from 52 healthy controls. The histological grade was as follows: grade 1; n= 5, grade 2; n=72, grade 3; n= 22. The serum XIAP levels were measured by a sandwich enzyme-linked immunosorbent assay. Cut off value was calculated by ROC analysis. Results: The serum XIAP levels in patients with RCC were higher than those of normal control individuals (328.3 pg/ml vs 156.2 pg/ml, p<0.001). At a median follow up of 33 months (1-105M), tumor with low serum XIAP showed significantly longer progression free survival (PFS) than those with high serum XIAP in grade 1-2 group (p<0.001). Conclusions: Serum XIAP level is associated with recurrence and prognosis. These results suggest that it may be used as a novel prognosticator and a potential target for renal cell cancer diagnosis and therapy.
Prognostic factors for metastatic renal cell carcinoma patients with removed metastases: A multicenter study of 559 patients.
Authors: Naito Sei , Kinoshita Hidefumi , Kondo Tsunenori , Shinohara Nobuo , Kasahara Takashi , Saito Kazutaka , Takayama Tatsuya , Masumori Naoya , Terachi Toshiro , Ozono Seiichiro , Naito Seiji , Tomita Yoshihiko
Published: March 2020

e15071

Background: Metastasectomy considered to prolong survival in patients with metastatic renal cell carcinoma (mRCC). However, data on the indications for metastasectomy are limited. We aimed to examine the prognosis and the prognostic factors of mRCC patients who underwent metastasectomy. Methods: We sent questionnaires to Japanese hospitals and collected the data of patients who were diagnosed with mRCC between January 1988 and December 2009 and who had their metastatic lesions removed. We calculated the overall survival between metastasectomy and death or until the last follow-up. We also analyzed the relationship between survival and clinical features and identified adverse prognostic factors by multivariate analysis. Furthermore, we identified the group with a poor prognosis on the basis of the number of prognostic factors for which the patients were positive. These findings were internally validated using bootstrap procedures and the c-index. Results: We collected the data of 559 patients from 48 institutions. The median overall survival period was 80 months (95% CI, 69.7-90.6 months). We detected 5 adverse prognostic factors: incomplete resection by metastasectomy (hazard ratio, 1.75; p = 0.0169); brain metastasis (hazard ratio, 3.26; p = 0.0002); C-reactive protein levels of >1.0 mg/dl (hazard ratio, 2.84; p < 0.0001); Eastern Cooperative Oncology Group performance status of >1 (hazard ratio, 1.65; p = 0.0274); and the worst nuclear grade, i.e., the nuclei of tumor cells are larger than those of normal tubular cells (hazard ratio, 1.59; p = 0.0348). Patients positive for 3 or more of theseadverse prognostic factors had a worse prognosis (median overall survival, 24 months) than those positive for less than 3 factors (median overall survival, 105 months). The c-index for this model was 0.65 at 2 years. Conclusions: We identified 5 adverse prognostic factors for predicting the survival of patients who underwent metastasectomy.
Sunitinb in advanced renal cell carcinoma (RCC): Is effectiveness good enough in real life practice?
Authors: Trojniak Marta Paulina , Imbevaro Silvia , Palozzo Angelo Claudio , Jirillo Antonio
Published: March 2020

e15072

Background: The sunitnib approval trials have established this multi-targeted TKI as a standard treatment in patients with metastatic RCC. However, even RCTs may fail to show relevant clinical benefit in wider population, as certain patient subtypes are under-represented, notably those with poorer prognostic factors and pretreated. The purpose of the study was to evaluate effectiveness of sunitinb in unselected RCC patients in real life practice in Italy. Methods: The data were collected through national registry on oncology drugs as part of mandatory surveillance program, which allows prospective investigations of effectiveness. RCC patients receiving sunitinb once daily, on schedule 4/2, between 2007 and 2011, had been included. All patients were checked prospectively for toxicity, clinical outcomes and length of treatment using registry inputs. Retrospective analysis of previous and following treatments and mortality data was performed based on clinical records and hospital databases. Results: A total of 106 patients (median age 64 years, M 70/F 36) were reviewed, 77% had prior nephrectomy and 74% were treatment-naïve. At first evaluation we found 28% partial responses, 25% stable diseases, 46% progressions and one discontinuation due to toxicity. The median TTP and OS were 7 and 11.3 months, respectively. Among 102 RCC patients (pts) with metastases (mets) at first diagnosis, 65% had lung mets, 19% pts had liver mets, 25% had bone mets and 8% had brain mets. The Cox regression model showed in subgroups analysis significantly worse survival prognosis in males, brain and liver mets, ECOG PS>1, non-clear cell histology and non prior nephrectomy. Sorafenib treatment after progression on sunitinib (33% pts) did not improved OS. Grade 3 thrombocytopenia, neutropenia, mucositis and HFS caused dosage reductions. Conclusions: The results on examined RCC study population show that sunitinib clinical benefit was gained in selected responders, but in overall the effectiveness was nearly half of that reported in the approval RCTs. Post-marketing studies in real life practice are required in order to verify both effectiveness and safety in general population, testing for external validity of randomized trials.
Expression of Notch family members in stage IV renal cell carcinoma tumors: Notch1 as medium-risk prognosis factor.
Authors: Antón Aparicio Luis M. , Medina Villaamil Vanessa , Aparicio Gallego Guadalupe , Quindós Varela Maria , Vazquez-Estevez Sergio , Leon Mateos Luis , Afonso Afonso Francisco J. , Firvida Perez Jose Luis , Ramos Vazquez Manuel , Calvo Ovidio Fernández , Santomé Lucía , Lázaro Quintela Martin , Santamarina Cainzos Isabel , Anido Urbano
Published: March 2020

e15076

Background: The characterization of factors involved in the etiology of renal cell carcinoma (RCC) may lead to the identification of new targets for therapy and prognostic markers. Recent data indicate that Notch family members can be expressed by malignant RCC cells and this expression may have potential use as a strong prognostic factor. The aim of this study was to investigate the potential of Notch family members as prognostic markers for stage IV patients. Methods: We analyzed, by means of immunohistochemistry and quantitative polymerase chain reaction, protein and mRNA levels of 4 Notch family members in tumor specimens obtained from 48 patients with stage IV RCC. Clinicopathological data for these patients were evaluated. A 34% of the population had hypertension, 7.3% had hypothyroidism, 19.5% were diabetic, 7.7% prediabetic, and 22% showed hyperlipidemia. RCC specimens included clear cell RCC: 34; papillary: 3; mixed: 1; undifferentiated: 1; hypernephroma: 1.The association among biomarkers and clinicopathological factors were explored using One-Way ANOVA test and non-parametric statistics, Mann-Whitney U and Kruskal-Wallis tests. Results: Relative expression of Nocth3 and Notch4 transcript levels were elevated 25-fold in clear cell RCC tumors when compared with normal kidney tissues. Notch1 and Notch2 were overexpressed at protein level in clear cell RCC (p>0.05). Those renal tumors with right localization showed highest levels of Notch4 protein (p=0.096). Notch2 overexpression was associated with patients who had undergone nefrectomy (p=0.038). Finally, Bonferroni post-hoc statistic test showed us a statistically significant association (p = 0.020) between Nocth1 protein expression levels and patients with medium risk prognosis. Conclusions: These results show a deregulated expression of Notch receptors in RCC and suggest a role for this pathway in the progression of this tumoral pathology.
Analysis of the expression of Wnt signaling ligands in metastatic renal cell carcinomas tissue samples.
Authors: Anido Urbano , Medina Villaamil Vanessa , Aparicio Gallego Guadalupe , Quindós Varela Maria , Vazquez-Estevez Sergio , Leon Mateos Luis , Afonso Afonso Francisco J. , Ramos Vazquez Manuel , Firvida Perez Jose Luis , Santomé Lucía , Calvo Ovidio Fernández , Lázaro Quintela Martin , Santamarina Cainzos Isabel , Antón Aparicio Luis M.
Published: March 2020

e15077

Background: Renal cell carcinomas (RCC) constitute a morphologically and genetically heterogeneous tumor.Wnt proteins are a large family of secreted glycoproteins that activate intracellular signal transduction pathways to control a wide variety of cellular processes such as determination of cell fate, proliferation, migration, and polarity.Wnt signalling may be playing a central role during RCC development. Methods: To characterize Wnt signalling activity in RCC, we gathered 48 tumor samples from patients diagnosed with metastatic RCC between years 2006 and 2011. Expression levels of Wnt family members (Wnt1, Wnt2, Wnt3a, Wnt4, Wnt5a, Wnt7a, and Wnt9a) were examined by real-time PCR and immunohistochemistry in tumor and normal tissue from removed kidneys. Results: Wnt1 and Wnt5a were up-regulated in clear cell RCC being their relative expression 2.4.103 (Wnt1) and 4.102 (Wnt5a) times higher in renal tumor tissue than in normal tissue. One-way ANOVA test showed Wnt3a and Wnt4 as the best protein markers to distinguish clear cell RCC (F=3.95, p=0.010 and F=3.05, p=0.029, respectively). Wnt1 and Wnt7a were over-expressed in those cases which had undergone nefrectomy (Mann-Whitney U test p=0.065 and p=0.056 respectively). Finally, Wnt2 protein level was associated with those patients with high risk prognosis (Kruskal-Wallis test p=0.001). Conclusions: Our results indicate that Wnt3a and Wnt4 are potentially useful immunohistochemical markers for the differential diagnosis between clear cell RCC and other subtypes of RCC and also suggest a role for Wnt2 as a high risk prognosis marker.
Molecular expression profiling and pathway analysis in human renal cell carcinoma.
Authors: Medina Villaamil Vanessa , Anido Urbano , Aparicio Gallego Guadalupe , Quindós Varela Maria , Santamarina Cainzos Isabel , Valladares Ayerbes Manuel , Antón Aparicio Luis M.
Published: March 2020

e15079

Background: Many studies have demonstrated genetic and environmental factors lead to renal cell carcinoma (RCC) occurring during a protracted period of tumorigenesis. It seemed suitable identify and characterize potential molecular markers appearing during of tumorigenesis which might provide rapid and effective possibilities for early detection of RCC. Methods: We assessed using quantitative real-time PCR (qPCR) the profile of 32 markers involved in the cascade of events leading to the formation and progression of RCC: invasiveness, angiogenesis and antiapoptotic mechanisms. RNA of quality was obtained in 90% of samples (N=80, 64/80 clear RCC, 8/80 papillary RCC and 8/80 chromophobe RCC) to carry out the study of gene expression. Nonparametric tests (Pearson's correlation coefficient test and Spearman's rho test, Kruskal — Wallis and Mann — Whitney) and Bonferroni post-hoc test were applied for statistical data analysis. Additionally, a knowledgebase of biological pathways, Reactome, was used to superimpose our quantitative expression data. Results: Statistical analysis comparing medians and means showed the following candidates as the best gene predictors related to different pathological variables (histological type, number of involved nodes, renal pelvis invasion, lymphatic vessels invasion and rupture of the renal capsule): Hif1-α (p<.001), Hif1-β (p=.035), DLL1 (p=0.012), DLL3 (p<.001), c-Kit (p=.002), PDGFR-β (p=.002), PDGFR-α (p=0.026), Bax-β (p=.005), Survivin (p=.028), Notch1 (p=.006), Notch2 (p=.007), Notch3 (p=.016), Notch4 (p=.005), EGFR (p=.029), Glut3 (p=.026), Glut5 (p=.036) and FH (p=.018). Analysis of these genes expression profiles in Reactome tool revealed those cellular pathways over-represented in our RCC cohort, among others, Extrinsic Pathway for Apoptosis and Double-Strand Break Repair (100 and 95% matching in our data, respectively). Conclusions: Our study highlights the reasons to deepen in the knowledge of pathways components and their associations with the underlying pathology characteristics in order to understand the molecular pathology of a tumor and how that influences its biologic behavior. More detailed studies of these pathways are in progress.
Effect of combination of systemic therapy and local therapy with cryoablation on outcome in metastatic renal cell cancer (mRCC): An extended follow-up report.
Authors: Vankayala Hema M. , Litrup Peter , Heilbrun Lance K. , Dickow Brenda , Bang Hyun J , Smith Daryn W. , Adam Barbara , Vaishampayan Ulka N.
Published: March 2020

e15081

Background: Resection of metastasis in renal cancer (mRCC) yields 5-year survival rates of 20% to 30%. Yet most patients (pts) poor surgical candidates or have unresectable disease. Percutaneous cryoablation is a minimally invasive procedure employed for local therapy of metastatic foci, but its role in inducing long term remissions in combination with systemic therapy is unknown. Methods: Following IRB approval and HIPAA compliance, a retrospective review of records for pts receiving cryotherapy and systemic targeted therapy from 2004-2007 at Karmanos Cancer Institute was performed to enable a minimum follow up of 3 years. OS was estimated using the Kaplan-Meier methodology. Results: Of the 27 patients identified 85% were male, 88% Caucasian, and 77% had clear cell histology. 2 pts had sarcomatoid mRCC. All patients had prior nephrectomy. 24 patients had multiple metastatic sites: 9 with 2 sites, 8 with 3 sites and 7 with ≥ 4 sites. 15%, 52%, 11%, and 22% had favorable, intermediate, poor, and indeterminate MSKCC risk score, respectively. Systemic therapy was interrupted for at least 1 week prior to and after cryotherapy and resumed after complete healing. One major complication of nerve paresis was noted from lumbar paravertebral mass cryotherapy. Median number of ablations was 2 (range 1-4). Of the 60 total ablations 13%, 28%, 27%, 17%, and 15% were renal bed, visceral, soft tissue, bone, and lymph nodes respectively. The median OS from diagnosis of metastatic disease was 49.6 months (95% confidence interval: 21.2- 54.9 months).The 2 yr OS rate is 90% (95% CI: 78-100%) and 5 yr OS rate is 68% (49-87%). 8 patients (30%) are alive to date. Conclusions: The strategy of combining systemic therapy and local control of metastasis with cryoablation had favorable impact on OS in mRCC even after longer follow up. Cryoabalation is a minimally invasive, well tolerated technique, applicable to the majority of mRCC patients. Prospective investigation or case-control studies to evaluate the incorporation of cryoabalation with targeted systemic therapy in advanced RCC is warranted.
The association between the treatment-induced hypertension (Htn) and response to neoadjuvant sunitinib in renal cell carcinoma (RCC).
Authors: Maiti Baidehi , Wood Laura S. , Elson Paul , Garcia Jorge A. , Dreicer Robert , Campbell Steven C. , Rini Brian I.
Published: March 2020

e15095

Background: Prior studies have shown that development of htn, which is an on-target side effect of VEGF inhibition, is a potential biomarker for response to sunitinib in patients with metastatic RCC. The association of htn with response to neoadjuvant sunitinib was evaluated from a completed phase II trial. Methods: Patients with initially unresectable RCC were treated with sunitinib 50 mg daily until surgical eligibility or disease progression / toxicity. Htn was defined as SBP >=140mm and/or DBP >= 90mm while on sunitinib. Fisher’s exact test was used to assess associations between htn and clinical outcome. Results: Twenty-nine patients with unresectable RCC (72% male; 76% clear cell histology; median age 61 years (range 37-80)) were enrolled. One patient withdrew consent and was excluded from subsequent analysis. Overall, 78% of patients had primary tumor shrinkage, 57% became eligible for surgery based on primary tumor change in the opinion of the treating urologic surgeon, 50% underwent surgery and 57% developed htn. Patients who had primary tumor shrinkage had a non-significantly higher incidence of htn compared to patients who did not have primary tumor shrinkage (77% vs. 50%; p=0.31). Patients who became surgically resectable after sunitinib, however, had significantly more htn than patients who did not attain eligibility for surgery (88% vs. 45% p=0.03). Similar results were seen when the analysis was restricted to patients with clear cell histology tumors (n=20, p=1.0 and 0.06 respectively). Conclusions: There is a significant positive association between the incidence of htn and the ability of neoadjuvant sunitinib to affect surgical eligibility in patients with unresectable RCC.
Real-world treatment profile for patients with tuberous sclerosis complex related angiomyolipoma: A U.S. Healthcare Claims Database study.
Authors: Sun Peter , Liu Zhimei , Kohrman Michael , Bissler John
Published: March 2020

e15096

Background: Angiomyolipoma (AML) is a common benign neoplasm associated with tuberous sclerosis complex (TSC). The objective of this study is to examine the treatment profile for patients with TSC related AML in a real world setting. Methods: A retrospective cohort study was performed using a large US commercial healthcare claims database. Patients with a TSC claim (ICD-9CM: 759.5X) and an AML claim (ICD-9CM: 223.0X) between 2000 and 2009 and with continuous 12-month health plan enrollment after their first AML claim were included into the study. The utilization rates of thirty two medication groups, eight procedure categories, five service places and fifteen provider types were assessed and ranked respectively for the year before first AML claim and the year after the first AML claim. Repeated measures analysis was used to compare these utilization rates between the last pre-AML year and the first post-AML year. Results: The study included 180 patients with a mean age of 28.2 years on their first AML claims, and 67.8% were females. During the first post-AML year, the top five medication groups were central nervous system medications (59.4%), anti-infective agents (50.6%), hormones & synthetic substance (22.8%), cardiovascular agents (18.9%), and autonomic drugs (17.8%); the most commonly used outpatient procedures were evaluation & management procedures (99.4%), anesthesia procedures (99.4%), surgical procedures (72.8%), radiology procedures (96.1%), and medicine procedures (100.0%). More patients consume the following care in the first post-AML year than in the last pre-AML year: anti-infective agents (50.6% vs. 35.0%, p<0.05), surgical procedures (72.8% vs. 60.6%, p<0.05), emergency rooms care (31.1% vs. 18.3%, p<0.05), urologists’ care (38.9% vs. 16.1%, p<0.05), nephrologists’ care (22.3% vs. 11.7%, p<0.05). Conclusions: In a real world setting and among TSC patients with AML, treatment profile changed after the first observed AML diagnosis. Further research is needed to examine the impact of these changes on economic and clinical outcomes of healthcare for patients with TSC related AML.
Post-prostatectomy PSA slope (ProsVue) in Gleason score ≥7 disease
Authors: Moul Judd W. , Lilja Hans , Semmes Oliver John , Vessella Robert , McDermed Jonathan E. , Sarno Mark J. , Klem Robert E.
Published: March 2020

e15113

Background: A case-cohort designed multicenter clinical study addressed the prognostic value of the linear slope of PSA in 304 men after radical prostatectomy (RP) – 64 with clinical recurrence and 240 with stable disease. PSA was measured with Nucleic Acid Detection Immunoassay (NADiA) technology having a limit of quantification of 0.00065 ng (0.65 pg) per mL. Least-squares linear PSA slope (ProsVue) was calculated using 3 serum samples drawn 1.5-20 months (mo) post-RP. Multivariate Cox proportional hazards regression analysis showed that a ProsVue cutpoint of ≤2.0 pg/mL/mo was an independent prognostic factor for identifying men at reduced risk for recurrence along with clinical evaluation (HR=9.824). Of traditional risk factors – pre-RP PSA, Gleason score (GS) and pathologic stage, only GS was an independent prognostic factor (HR=5.3). This study tested the prognostic performance of ProsVue in a 164-man subset with pathologic GS ≥7. Methods: Recurrence was documented by positive imaging, positive biopsy or prostate cancer death. The same ProsVue cutpoint dichotomized men “at reduced” or “not at reduced” recurrence risk compared to clinically recurrent or stable disease status. Uni- and multivariate Cox proportional hazards regression were employed. Results: Median age, pre-RP PSA and percent tumor volume in the subset were 62.6, 7.2 ng/mL, and 20%. Distributions of GS 7, 8, 9 were 76.8%, 14.6% and 8.5%, respectively. Pathologic stages were T0-T2, T3a, T3b and T4 in 41%, 57%, 29% and 7% of men, respectively. Median follow-up in stable and recurrent groups was 10.8 and 4.8 yr. The table compares results in the full cohort and the GS ≥7 subgroup. Conclusions: ProsVue prognostic performance is maintained with GS ≥7. Performance parameters, especially the multivariate hazard ratio (HR) are minimally attenuated vs. the full case-cohort. [Table: see text]
Cabazitaxel plus cisplatin coadministration and drug-interaction study in patients with advanced solid tumors.
Authors: Mita Alain C. , Sundaram Shankar , Sarantopoulos John , Mita Monica M. , Lane Alex R. , Moseley Jennifer L. , Mahalingam Devalingam , Tan Benjamin R. , Dedieu Jean-Francois , Stash Diane , Zhi Xin , Mazuir Florent , Lockhart Albert C.
Published: March 2020

e15116

Background: Cabazitaxel (Cbz) is a novel taxane with in vivo efficacy in taxane-sensitive and -resistant tumors. Therapeutic synergism of Cbz/cisplatin (Cis) has been shown in tumor-bearing mice. Since Cbz is primarily metabolized by CYP3A, drug interactions may occur with modulators of CYP3A. Methods: The primary objective of part 1 of this phase I study (NCT00925743) was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Cbz/Cis. Secondary objectives included safety, pharmacokinetics (PK) and efficacy. The objective of part 2 was to assess efficacy at the MTD. The effect of the antiemetic aprepitant (a moderate CYP3A inhibitor) on the PK of Cbz was also examined. Eligible patients (pts) had ECOG PS ≤ 1 and confirmed metastatic or unresectable solid tumors for which Cis therapy was considered appropriate. A 3 + 3 dose escalation at a starting dose (level 0) of 20/75 mg/m2 (Cbz/Cis), administered IV Q3W, was used. The MTD was the highest dose at which 0/3 or ≤ 1/6 pts experienced a DLT in Cycle 1. Results: Pts (n = 25; 10 in part 1; 15 in part 2) with a median age of 56 yrs were enrolled. The most frequent primary tumors were lung (n = 4), prostate, ovary and pancreas (each n = 2). Of 6 evaluable pts, 2 had a DLT at dose level 0 (Grade 3 acute renal failure; febrile neutropenia). The MTD was 15/75 mg/m2 as no DLTs were observed; 18 pts were treated at the MTD and 60 cycles were administered (median = 3; range 1–8). The most frequent non-hematologic treatment-related adverse events (all grades/grade 3–4) were nausea (78%/22%), vomiting (72%/11%), fatigue (61%/17%), anorexia (67%/11%) and diarrhea (44%/0%). Incidence of grade 3–4 neutropenia was 78%; 1 pt had febrile neutropenia. The combined PK profile of Cbz/Cis did not appear to differ vs those of the single agents. The ratio of Cbz clearance with vs without aprepitant co-administration was 0.81 (90% CI 0.36–1.85). Stable disease was seen in 11 pts; 1 pt (prostate carcinoma) had an unconfirmed partial response. Conclusions: The MTD of Cbz/Cis was 15/75 mg/m2. The combination had a manageable safety profile consistent with a platinum/taxane combination. No PK interactions between Cis and Cbz were seen; aprepitant did not appear to alter the PK of Cbz.
Racial differences in prostate cancer incidence and mortality.
Authors: Bjurlin Marc , Guinan Patrick , Christensen Kevin , Rubenstein Marvin
Published: March 2020

e15119

Background: Prostate cancer is the second leading cause of male cancer deaths in the U.S. There are significant racial differences in prostate cancer incidence and mortality. Methods: The SEER Database for 2008 was analysed for designated areas: Connecticut, Detroit, and Hawaii, assuming that these areas are surrogates for whites, blacks, and Asians, respectively. Results: Incidence and mortality (see Table). Conclusions: Assuming that the geographic SEER areas (Conn, Det, Ha) are surrogates for whites, blacks, and Oriental populations, we conclude that the incidence and mortality rates for blacks are higher than those for whites and Orientals. [Table: see text]
Impact of salvage therapy with APC8015F on the overall survival (OS) benefit achieved with sipuleucel-T in three phase III studies of metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Gomella Leonard G. , Nabhan Chadi , DeVries Todd , Whitmore James Boyd , Frohlich Mark Walter , George Daniel J.
Published: March 2020

e15120

Background: Sipuleucel-T is an autologous cellular immunotherapy approved for asymptomatic or minimally symptomatic mCRPC. Three phase III sipuleucel-T trials (D9901, D9902A and D9902B [IMPACT]) allowed control patients (pts) to receive salvage treatment with an autologous product derived from previously frozen cells (APC8015F). We previously reported that salvage therapy with APC8015F demonstrated no deleterious effect and may have improved outcomes in control pts, potentially reducing the observed survival benefit seen with sipuleucel-T. Thus, we performed an exploratory analysis of pooled data from phase III studies to estimate the impact of APC8015F treatment on the OS benefit conferred by sipuleucel-T. Methods: We analyzed the effect of salvage APC8015F therapy on OS, and used a rank-preserving structural failure time (RPSFT) model to estimate control arm OS if treatment with APC8015F had not occurred. This allows estimation of the effect of sipuleucel-T treatment on OS, adjusting for salvage effect. Results: Median OS from randomization in the three pooled trials was 25.4 months with sipuleucel-T (n=488) and 21.5 months with control (n=249). Of the control arm pts, 165 (66.3%) subsequently received APC8015F. Median OS from randomization in the control population was 23.6 months for pts receiving APC8015F and 12.7 months for those who did not. Using the RPSFT model, and assuming APC8015F was as effective as sipuleucel-T, the estimate of median OS for control pts was 17.3 months, representing an 8.1 month median increase in OS with sipuleucel-T. Results from extensions of the RPSFT model, where APC8015F is assumed to have less treatment effect than sipuleucel-T, will be presented. Conclusions: These analyses estimated a median OS benefit for sipuleucel-T between 3.9 and 8.1 months, assuming that APC8015F had either no efficacy or comparable efficacy to sipuleucel-T, respectively. The results suggest a possible greater treatment effect of sipuleucel-T than was reported in the three phase III studies. Future studies should account for potential crossover treatment bias as this may diminish estimates of OS benefit.
Venous thromboembolism in prostate cancer patients treated with robot-assisted radical prostatectomy and pelvic lymph nodes dissection.
Authors: Hamdan Shadi E. , Kozyreva Olga N. , Tuerk Ingolf , Gupta Shachi
Published: March 2020

e15123

Background: Cancer and cancer treatment increases the risk of venous thromboembolism (VTE). Pelvic lymph nodes dissection (PLND) during radical prostatectomy increases the risk of VTE. Robot-assisted radical prostatectomy (RARP) is becoming increasingly popular, yet VTE data are not well reported. The aim of the study is to assess the rate of VTE in prostate cancer patients who underwent RARP with and without PLND. Methods: The records of 768 patients who underwent RARP by a single surgeon from 2008-2011 were reviewed for postoperative venous thromboembolism. Patient demographics, Gleason score, clinical stage, PSA, surgical approach and other operative variables were collected by prospective prostate cancer database. Information obtained from patient visit 6-8 weeks after the surgery was included in the database. VTE diagnosis was retrieved from inpatient and outpatient medical records. Fisher's exact test was used to determine the association between RARP with PLND and the occurrence of postoperative VTE. Results: Of the 768 patients who underwent RARP (mean age was 59.8 years, range: 40-77 years), 419 (54%) underwent PLND. Compared to patients who underwent RARP alone, patients who underwent RARP with PLND had higher PSA (mean PSA 7.3 vs. 5.3 p=0.0002), rate of Gleason score ≥ 7 (82% vs. 13% p=<0.0001) and more advanced tumor stage pT3 (39% vs. 12% p=<0.0001). Venous thromboembolism occurred in 5 of 419 (1.2%) patients who underwent RARP with PLND, and in 1 of 349 (0.28%) patients who underwent RARP (p=0.22). The lymph node metastasis rate was 7%. Conclusions: The incidence of VTE in prostate cancer patients treated with RARP is low. PLNDis not associated with a significantly increased risk of venous thromboembolism as compared to RARP alone.
Correlation of circulating tumor cells (CTCs) and clinical biomarker endpoints in metastatic prostate cancer patients.
Authors: Amato Robert J. , Melnikova Vladislava O. , Zhang Yujian , Liu Wen , Wang Yuan , Shah Parth K. , Jensen Brett T , Torres Karen E. , Davis Darren W.
Published: March 2020

e15124

Background: Circulating tumor cells (CTCs) are found in human blood when cancers undergo metastatic dissemination, and CTCs have been reported as a surrogate marker for tumor response and linked to shorter survival in metastatic prostate cancer patients. This study assessed the use of CTCs as a continuous factor for clinical monitoring of prostate cancers patient in real time and evaluated the association between baseline CTC number, various clinical characteristics, and survival. Methods: CTCs were enumerated using the CellSearch FDA cleared CTC kit in 206 patients with metastatic prostate cancer. Variables including metastatic site, PSA, Gleason score, level of testosterone and androgen treatment were tested for association with CTC number. The probability of patient survival over time was estimated by the Kaplan-Meier method. Results: Baseline CTC numbers were strongly associated with survival (p<0.0001), with overall survival being significantly poorer in patients with ≥5 CTCs. Significantly higher CTC numbers were observed in patients with bone metastasis (mean=41.1 CTCs) compared to those with lymph node metastasis (mean=2.5 CTC, p=0.026). Analysis of the association between CTC counts and PSA level revealed a weak positive correlation between CTC number and PSA (Correlation coefficient r=0.269, Significance level p<0.001). CTC number further correlated with the Gleason score (p=0.009) and lower testosterone levels (p<0.0001). Patients with no androgen depletion had significantly lower numbers of CTCs (median=3.94) compared to those with androgen depletion (median=406, p<0.001). Conclusions: Baseline CTCs are predictive of patient survival and are significantly correlated with clinical characteristics in prostate cancer patients.Our study confirms previous findings that support the use of CTC levels as a prognostic biomarker for prostate cancer patients.
Effects of 6 months of abiraterone acetate (AA) on muscle and adipose mass in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Brondfield Samuel Craig , Weinberg Vivian K. , Koepfgen Kathryn M. , Molina Arturo , Ryan Charles J. , Small Eric Jay , Harzstark Andrea Lynne
Published: March 2020

e15137

Background: AA, an inhibitor of androgen biosynthesis, has been shown to prolong overall survival in patients with mCRPC who have previously been treated with chemotherapy. ADT has been shown to result in muscle wasting in prostate cancer patients. The effects of AA on progression of muscle and fat wasting have not been characterized. We evaluated whether 6 months of AA therapy altered total skeletal muscle mass or adipose mass. Methods: 10 sequential patients who responded to AA therapy for at least 6 months and had available computed tomography (CT) scans were retrospectively selected from the phase I-II COU-AA-002 study. CT image analysis was used to quantify change from baseline in total skeletal muscle and adipose tissue after 6 months of AA treatment. Skeletal muscle and adipose tissue cross-sectional area were calculated at the L3 level using Slice-O-Matic software V4.3. Previously published regression models were used to estimate fat-free mass, fat mass and skeletal muscle mass. Paired t-tests were performed to determine the change in measurements. Results: At baseline, 7 of 10 patients were overweight or obese (body mass index [BMI] > 25 kg/m2), and none were underweight. Advanced muscle wasting (sarcopenia, previously defined as the ratio of skeletal muscle cross-sectional area at L3 level to height < 52.4 cm2/m2) was present at baseline and 6 months in 9 of 10 pts. Over 6 months of AA treatment, patients lost an average of 1.9 kg ± 3.6 kg (p = 0.13). Mean changes (kg) (±standard deviation) in total skeletal muscle mass (-0.80 ± 1.71, p = 0.18) and total non-adipose mass (-1.44 ± 3.09, p = 0.17) were not significant. A significant decrease in total adipose mass (-0.61 ± 0.84, p = 0.048) was observed. Conclusions: Sarcopenia is prevalent in patients with mCRPC. AA was not related to significantly worsening sarcopenia or overall weight loss during the first 6 months of treatment; however, this may reflect a relatively short duration of therapy and/or small sample size. A significant loss of adipose tissue was observed, which is unexpected given the known effects of ADT, which increases adipose mass. Evaluation of additional AA treated patients is ongoing.
Progression of castrate-resistant (CR) disease in nonmetastatic (M0) prostate cancer (PC) patients: A retrospective cohort study using data from the Henry Ford Health System (HFHS).
Authors: Beebe-Dimmer Jennifer , Cetin Karynsa , Yee Cecilia , Lamerato Lois , Stryker Scott , Liede Alexander , Schwartz Kendra L. , Shahinian Vahakn B.
Published: March 2020

e15147

Background: Androgen deprivation therapy (ADT) is the cornerstone treatment of advanced PC, but is frequently used in the M0 setting. After a variable period of hormone-sensitivity, most patients develop CR disease (rising prostate-specific antigen [PSA] despite ongoing ADT). These men are at increased risk of developing bone metastases (BMT), particularly in those with higher serum PSA and shorter PSA doubling time (DT). The epidemiology and natural history of M0 CRPC has not been well-studied in a population-based setting. Methods: A retrospective cohort study was conducted using HFHS administrative data and included 691 men diagnosed with M0 PC between 1996 and 2005, who received ADT, with serial PSA measurements to determine CR. Patient records through 12/31/2008 were reviewed for outcomes of interest. CRPC was defined as 2 consecutive PSA rises, with “high risk” defined as PSA ≥8 ng/mL or PSA DT ≤10 months (mos) after the development of CRPC (Smith MR et al. Lancet 379:39-46, 2012). The risk of BMT was estimated for the entire cohort and for the CRPC and high-risk CRPC subsets. Results: Of the 691 patients included in the cohort (median age: 73 years, 48% African American), 98% received only GnRH agonists and 2% had orchiectomy. Median follow-up for the entire cohort after ADT initiation was 49 mos (IQR=45). 101 patients (15%) met criteria for CRPC during follow-up, with a median of 18 mos on active ADT prior to CRPC development (IQR=14). Of CRPC patients, 85% met criteria for high-risk (of those, 16% had PSA ≥8 ng/mL, 12% had PSA DT ≤10 mos, and 72% had both). Among all patients, 12% (n=82) developed BMT during follow-up, with 42% (n=36) of the high-risk CRPC subset developing BMT. Median time from high-risk CRPC to BMT was 9 mos (IQR=17). Conclusions: The HFHS resource allowed for our investigation of PSA characteristics corresponding to disease progression in a racially diverse patient population. A substantial proportion of M0 PC patients on ADT will eventually develop CR disease. Once a patient has CRPC, the risk of BMT is relatively high.
Therapeutic options in metastatic castration-resistant prostate cancer (mCRPC): A cost-effectiveness analysis.
Authors: Zhong Lixian , Srinivas Sandy , Pon Vickie , Nguyen Nicole , Frear Meghan , Kwan Sherry , Gong Cynthia , Malmstrom Robert , Loucks Aimee , Wilson Leslie
Published: March 2020

e15154

Background: Initial therapy for metastatic prostate cancer is androgen deprivation therapy. Uniformly progression of disease occurs despite castration. Docetaxel is then the standard of care. Abiraterone (Abi) and cabazitaxel (Cab) are approved for mCRPC post docetaxel with improvements in survival We seek to evaluate the cost-effectiveness of Abi and Cab compared to mitoxantrone (Mit) and prednisone for mCRPC. Methods: A decision tree model was constructed comparing four treatments for mCRPC patients over an 18 month period: 1) Abi, 2) Cab, 3) Mit, and 4) prednisone only. Chance nodes included baseline pain as a severity indicator, grade III & IV adverse events (AE) (neutropenia and cardiac ) and survival at 18mos. Survival rates and probabilities were from published data. Cost of drug regimens were based on 2010 US dollars and average wholesale price (AWP). Model cost inputs included drug-costs, administration costs, management of AE’s, radiation for pain, and costs associated with death. Health utilities for baseline pain, bone pain, neutropenia, cardiac events, and radiation were obtained from published data. Sensitivity analyses were conducted focused on baseline severity and costs of drug. Results: Base case estimates suggest that Cab and Abi are most effective. The incremental cost effectiveness ratio (ICER) for Mit vs. placebo is $110K/QALY, Abi vs. Mit is $76K/QALY and for Cab vs. Abi, the ICER is $925K/QALY. Model-sensitive parameters include Abi AWP and cost of Mit side effect management; Abi becomes less cost-effective as its AWP increases, or if the cost of Mit side effect management decreases. When baseline severity increases, Mit becomes cost-effective over placebo and Abi remains cost-effective over Mit. Cab remains not cost-effective at tolerable thresholds. Conclusions: Compared to Cab, Mit, and placebo, Abi is the most cost-effective option in docetaxel-refractory mCRPC patients due to its ability to prolong survival and maintain a willingness-to-pay threshold (WTP) of $100K. Despite higher survival with Cab, it is not cost-effective because of costs associated with treatment of neutropenia. In situations where illness is more severe, Abi remains the cost-effective choice.
Histone deacetylase inhibitor (HDACi) LBH589 interference with androgen receptor expression transcriptional activity in prostate cancer cells.
Authors: Thelen Paul , Ringert Rolf-Hermann , Strauß Arne
Published: March 2020

e15156

Background: Development of incurable castration resistant prostate cancer (CRPC) is intrinsically tied to androgen receptor (AR) deregulation. Our previous research demonstrated that the estrogen receptor-β regulates AR transcriptional activity when relieved from epigenetic repression by HDACi treatments. Here we investigated the HDACi LBH589 established clinically in cancer treatments for its therapeutic function in CRPC. Methods: LBH589 (obtained from Novartis, Switzerland) was used (1 through 100µM) to treat representative CRPC-cell models i.e. LNCaP with an AR mutation and VCaP featuring AR overexpression. We investigated tumor cell proliferation with a BrdU-test and investigated AR including AR splice variants, PSA, PCA3,TMPRSS2-ERG, IGF-axis genes and ERβ expression by real-time RT-PCR, ELISA and Western blots. Results: LBH589 treatment even at low concentrations of 1µM reduced excessively AR expression in LNCaP and diminished even overexpressed AR to moderate levels in VCaP. Accordingly, tumor cell proliferation and the expression of androgen regulated genes PSA, PCA-3 and TMPRSS2-ERG (in VCaP) decreased. Furthermore, the expression of IGF-1 receptor and IGF-1 was reduced. Whereas, the expression of pro-apoptotic, anti-proliferative IGFBP-3 and the expression of tumor suppressor ERβ were increased, even at highest LBH589 concentrations. Conclusions: The main target in CRPC therapy is the AR equipped with resurgent activity by gain of function and overexpression. HDACi treatments with LBH 589 while restoring ERβ expression directly intervenes with this AR surge resulting in reduced tumor cell proliferation and tumor cells adopt a less malignant phenotype. Such measures in the core of CRPC deregulations alone or in combination with further anti-androgen treatments might reduce the potential of escape mechanisms of CRPC-tumors in future therapy approaches.
Antitumor effects of zoledronic acid in combination with histone deacetylase inhibitor valproic acid.
Authors: Strauß Arne , Loertzer Hagen , Ringert Rolf-Hermann , Thelen Paul
Published: March 2020

e15158

Background: The established utilisation of bisphosphonates is the treatment of metastatic bone disease derived from several tumor types including prostate (PCa) and breast cancer. However, recently preclinical as well as clinical evidence support anti-tumor activities of these drugs in their own right. To probe into the molecular basis of such observations we treated PCa bone metastasis derived cell lines (VCaP, PC-3) and breast cancer cells (MCF-7) with zoledronic acid (ZA) and ZA in combination with valproic acid (VPA). HDAC-Inhibitor VPA according to our previous findings rectifies aberrant androgen receptor signalling and thus, implies an anti-androgen element in these treatments. Methods: PCa cells (VCaP, PC-3) and breast cancer cells (MCF-7) were treated with ZA (Zometa, Novartis) at 0, 5, 25 or 100µM or same ZA concentrations in combination with VPA (5mM). Tumor cell viability and proliferation were analysed by AlamarBlue- and BrdU-tests. Gene expression and PSA secretion was quantitated by real time RT-PCR and was further assessed with ELISA-kits, respectively. Results: In all cell types ZA has no impact on tumor cell viability or proliferation of its own exceeding the effects of VPA alone. Likewise, PSA secretion in VCaP cells is not further diminished in the combined ZA/VPA treatments. However, among a marked impact on cancer relevant gene expression protective elements such as vitamin D- and β-estrogen-receptor are up-regulated by ZA alone and in excess by the combined treatment. Other genes associated with protective features such as IGFBP-3, SOCS-3 and Se-BP-3 are up-regulated only by the ZA/VPA combination. Conclusions: We present molecular evidence for anti-tumor effects of zoledronic acid. Our data suggest the necessity of a concomitant anti-androgen treatment for maximal benefit. The genes addressed by such treatments are more associated with cancer prevention than immediate androgen signalling targets. Therefore, the main anti-tumor potential of ZA may emerge from an early onset of combined therapies to prevent bone metastases.
Testosterone levels as a prognostic factor for survival in patients with castrate-restistant prostate cancer (CRPC).
Authors: Gomez de Liaño Alfonso , Maroto José Pablo , Martin Lorente Cristina , Cillan Elena , Macias Ismael , Stradella Agostina , Sullivan Ivana , Murata Paola , Arqueros Cristina , Anguera Georgia , Condori Dhiossett , Barnadas Agust
Published: March 2020

e15159

Background: To analyze the prognostic value for survival of the absolute levels of serum testosterone in patients under the definition of CRPC (PSA and/or clinical progression with a testosterone level below 50 ng/dL). Methods: 49 patients were included in 4 non-hormonal first line phase II-III trials in our institution since August 2006 until Jan 2012 for metastatic CRPC. Inclusion criteria of those trials uniformly required castrate levels of testosterone. Survival was calculated since the date of entrance in the trial. Results: Median age was 71 years (53-89). 9/49 (18%) of the patients had visceral metastases. Median PSA was 66.7 U/L (0.1-936). Median testosterone level was 11.54 ng/dL (range 0.2-49.9). All patients had metastatic prostate cancer, previous treatment consisted of at least 2 hormonal maneuvers (adding or stopping antiandrogen for a wash-up period of 42 days for bicalutamide). All patients received at least one line of chemotherapy for CRPC as part of the trial or after the completion of the trial. Median survival was 21.85 months. For 26 patients with a serum testosterone level below the median value, median survival was 17 months and 35.45 months for those patients with a testosterone level over 11.51 ng/dL (p value 0.036). Conclusions: Testosterone serum levels even under castration level (below 50 ng/dL) were a prognostic factor for survival in patients with metastatic prostate cancer considered castration resistant.