bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced orotate phosphoribosyltransferase activity in renal cell carcinoma and its prognostic significance
Authors: Mizutani Y. , Toiyama D. , Shiraishi T. , Nakamura T. , Mikami K. , Takaha N. , Okihara K. , Ukimura O. , Kawauchi A. , Miki T. 
Published: March 2020

15590 Background: 5-Fluorouracil ( 5-FU ) is an anticancer agent clinically used against various cancers including renal cell carcinoma ( RCC ). 5-FU is a prodrug and orotate phosphoribosyltransferase ( OPRT ) is the principal enzyme which directly converts 5-FU to an active anticancer metabolite, 5-fluoro-2’-deoxyuridine 5’-monophosphate. Furthermore, OPRT is the key enzyme in the de novo DNA and RNA synthetic process, which converts orotic acid to orotidine 5’-phosphate. Little is known about the significance of OPRT in a variety of cancers including RCC. We investigated OPRT activity in 83 RCC and evaluated the association between OPRT activity and the stage/grade of RCC. The relationship between OPRT activity in RCC cells and their sensitivity to 5-FU was also examined. Methods: OPRT activity in non-fixed fresh frozen RCC and normal kidney were determined enzymatically by the 5-FU phosphorylation assay. The sensitivity of RCC cells to 5-FU was assessed by the microculture tetrazolium dye assay. Results: OPRT activity was approximately 8.5-fold higher in RCC compared to normal kidney. OPRT activity in T3/4 RCC was 3-fold higher than that in T1/2 RCC. OPRT activity in M1 RCC was 2.5-fold higher than that in M0 RCC. In addition, OPRT activity in Stage III/IV RCC was 3-fold higher than that in Stage I/II RCC. The level of OPRT activity in Grade 3 RCC was 3-fold higher than that in Grade 1/2 cancer. Patients with RCC with low OPRT activity had a longer postoperative disease-specific survival than those with high activity in the 5-year follow-up. OPRT activity in RCC cells positively correlated with their sensitivity to 5-FU. Conclusions: The present study has demonstrated that OPRT activity in RCC was higher than that in normal kidney, and that OPRT activity positively correlated with the stage/grade of RCC. Moreover, higher OPRT activity in RCC predicted worse prognosis and higher sensitivity to 5-FU. These results suggest that OPRT activity may be used as both a prognostic parameter and a predictive indicator for 5-FU efficacy in RCC. No significant financial relationships to disclose.
A phase II study of the c-Met RTK inhibitor XL880 in patients (pts) with papillary renal-cell carcinoma (PRC)
Authors: Ross R. W. , Stein M. , Sarantopoulos J. , Eisenberg P. , Logan T. , Srinivas S. , Rosenberg J. , Vaishampayan U. 
Published: March 2020

15601 Background: XL880 is a novel inhibitor of receptor tyrosine kinases targeting MET and VEGFR2/KDR. (IC 50 for MET 0.4nM and KDR 0.8 nM). PRC is a rare (10–15%) subtype of kidney cancer which is notoriously resistant to systemic treatment. The familial form of PRC is associated with germline activating mutations of MET, while amplification and overexpression of MET is seen in the sporadic form. In an ongoing phase I dose escalation study of XL880 in forty patients with advanced solid tumors, five partial responses (PRs) were noted in 3 of 4 treated patients with PRC, and in two pts with thyroid cancer. The MTD in this study was 3.6 mg/kg of XL880 administered orally daily for 5 consecutive days every 2 weeks. Methods: In this phase 2 study, XL880 is administered orally as a single agent at a dose of 240 mg on days 1–5 of each 14 day cycle. Previously untreated pts with a histologic diagnosis of metastatic PRC are eligible and are stratified based on the presence or absence of MET germline mutations. Planned enrollment is 15 evaluable pts in each stratum. Inclusion criteria also include ECOG performance status < 3 and absence of brain metastases. Tumor response is assessed every 8 weeks by RECIST criteria. Archival primary tumor and lymph node metastasis were collected for pharmacodynamic assessments. Results: To date, 6 pts have been enrolled and received XL880. Five pts have tested negative for MET germline mutations; results for one pt are pending. Of 3 pts with at least one post baseline tumor assessment, 1 pt has demonstrated a PR and two pts have demonstrated stable disease > 3 months, one of whom has improvement in bone scan and bone pain. Hypertension has been reported in 2 pts who responded to anti- hypertensive treatment. Two SAEs have been reported as unrelated; pulmonary embolism and intratumoral hemorrhage. MET expression was detected in untreated primary and metastatic tumor. Reduction in Ki67, and an increase in TUNEL labeling were observed in the post treatment sample. Conclusions: XL880 is the 1st orally available small molecule inhibitor of MET to enter the clinic and appears to be generally well tolerated. Anti-tumor activity has been observed and XL880 may represent an active treatment option for pts with PRC. Enrollment continues and updated results will be presented. No significant financial relationships to disclose.
Serum prostate-specific antigen screening for prostate cancer: Analysis of the costs and benefits
Authors: Mermershtain W. , Bone D. , Shteiman T. , Ariad S. 
Published: March 2020

15602 Background: PSA (prostate specific antigen) blood test used as a diagnosing aid for prostate cancer. Physicians disagree on the test performance policy and its necessity, and as a result the referring practices vary from physician to another. We examine whether the use of PSA test in General Health Services, was performed rationally, and cost effectively. Methods: Phase 1: Collection of data on all the prostate cancer patients registered at the Soroka University Medical Center until 2004 and people insured by the Clalit Health Services, that underwent PSA tests in 2002–2004. Phase 2: Cross examination of the patients’ data with data on patients undergoing the test. Phase 3: Determining the number of excessive tests (over 4 tests per person a year). Phase 4: A random study of 90 medical files of patients that underwent a PSA test. The number of references made not according to the instructions (in the files) was multiplied by the number of conducted tests (except those in phase 3), thus reaching the number of irrational tests. Phase 5: Multiplying the number of tests in phases 3–4 by the public rates of the Health Ministry for PSA tests (62 NIS). In addition, a questionnaire was distributed among primary care physicians to learn about their attitudes regarding defensive medicine. Results: In years 2002–2004, 19,418 patients underwent 25,674 PSA tests. 88.6% of the tests turned out as irrational - accumulating to a cost of 1,410,438 NIS. In the course of the recent years there is a trend of increase in the number of tests provided not according to the custom instructions, and this state of affairs suggests lack of awareness to such a high rate of irrational tests, or alternatively, awareness and failure to assign appropriate importance to the problem. Likewise, it was found that there are doctors referring patients to PSA tests as a result of defensive medicine. Conclusions: High percentage of the referrals to PSA test was provided not according to the customary instructions, and some of these referrals stems from defensive medicine. We suggest, guiding rules must be set for referring patients to PSA tests. It is necessary to update primary care doctors on the use and miss use of the tests. No significant financial relationships to disclose.
Oncologic significance of pathologic T2 positive surgical margin in robotic-assisted laparoscopic prostatectomy
Authors: Levinson A. , Berkman D. S. , Goluboff E. T. , Samadi D. B. 
Published: March 2020

15607 Background: A positive margin (PM) after radical prostatectomy (RP) in organ confined (pT2) prostate cancer (CaP) is considered a surgical error. In addition, capsular incision may occur at a higher frequency with robotic and laparoscopic techniques than with traditional open RP. However, the mechanism and significance of capsular violation may be different between open RP and Robotic Assisted Laparoscopic Prostatectomy (RALP). We sought to determine biochemical disease free survival (BDFS) for patients (pts) who underwent RALP at our institution who had a pT2 PM and compared them to those who did not. Methods: We reviewed our prospective IRB approved database for RALPs performed by a single surgeon. To permit adequate follow-up only cases prior to March 2006 were included. Biochemical failure (BF) strictly defined as any PSA >0.1ng/ml. No pt received adjuvant therapy without a BF. Results: Since Jan 2003, 435 consecutive pts underwent RALP for clinically localized CaP. 211 of these cases were before March 2006, of which 194/211 (92%) had sufficient data for analysis. Mean follow-up was 9.8 mos (range 0.7–41.6). Mean age, preoperative PSA, and path Gleason Score were 60 yrs, 6.6 ng/ml, and 6.9, respectively. Pathologic stages: pT2 77%; pT3a 13%; pT3b 7%, pT4 3%. Overall, 7.2% (14/194) experienced BF at a median of 2.5mos (0.7–15.3). BDFS rates by pathologic stage were pT2 95.3% (142/149), pT3a 91.7% (22/24), pT3b 76.9% (10/13), and pT4 71% (5/7). pT2 pts with a PM had the same rate of BF, (4.4% 1/23), as pT2 pts with negative margins (NM) (4.8% 6/126, p=0.932) and pT3 NM (0% 0/19, p=0.36), but was statistically less than pT3 PM (27.8% 5/18, p=0.035). In multiple linear regression analysis, preoperative PSA >10ng/ml was the most predictive variable of BF even after adjusting for Gleason sum, pathologic stage, and surgical margin status. Conclusions: There may be a different mechanism between a PM in organ confined open RP pts and RALP pts. In our series of RALPs, only one of 23 pT2 PM pts suffered a biochemical recurrence. BDFS for these pts was 95.7%, and did not vary significantly from pT2 NM nor pT3 NM pts. A larger series with longer follow-up will determine whether the oncologic significance of a PM in pT2 RALP pts is different than that of open RP pts. No significant financial relationships to disclose.
Prostate weight as an independent predictor for both extracapsular extension and positive surgical margins during robotic- assisted laparoscopic radical prostatectomy
Authors: Msezane L. , Zorn K. C. , Gofrit O. N. , Steinberg G. D. , Zagaja G. P. , Lin S. , Shalhav A. L. 
Published: March 2020

15608 Background: Pre-operative prediction of pathological stage represents the cornerstone of prostate cancer management. Patient counseling is routinely based on pre-operative PSA, Gleason score and clinical stage. In this study, we evaluated whether prostate weight (PW) is an independent predictor of extracapsular extension (ECE) and positive surgical margin (PSM). Methods: Between February 2003 and November 2006, 709 men underwent robotic-assisted laparoscopic radical prostatectomy (RLRP). Pre-operative parameters (patient age, pre-operative PSA, biopsy Gleason score, clinical stage) as well as pathological data (prostate weight, pathological stage) were prospectively gathered after IRB approval. Evaluation of the influence of these variables on ECE and PSM outcomes were assessed using both univariate and multivariate logistic regression analysis. Results: Mean overall patient age, pre-operative PSA and PW were 59.6 years, 6.5ng/ml and 52.9g (range 5.5–198.7g), respectively. Of the 393, 209 and 107 men with PW <50g, 50-<70g and >70g, ECE was observed in 20.1%, 15.3% and 9.3%, respectively (p=0.015). In the same patient cohorts, PSM was observed in 25.4%, 14.4% and 7.5%, respectively (p<0.001). In a multivariate logistic regression analysis, PW, in addition to pre-operative PSA, biopsy Gleason score and clinical stage, was an independent risk factor for ECE (p<0.001). Similarly, in multi-variate analysis, PW was observed to be a risk factor for PSM (p<0.001). Conclusions: PW is an independent predictor of both ECE and PSM, with an inverse relationship having been demonstrated between both variables. PW should be considered when counseling patients with prostate cancer treatment. No significant financial relationships to disclose.
Phase I/II study of sequential-intermittent docetaxel (D) and imatinib (Im) in hormone refractory prostate cancer (HRPC) (NYU 04–47)
Authors: Lan F. , Ballard H. , Chen A. , Chachoua A. , Taneja S. , Ferrari A. 
Published: March 2020

15613 Background: Platelet-derived growth factor (PDGF) is frequently expressed in advanced prostate cancer (PC) lesions where it supports PC cell growth and neo-angiogenesis. Im. is a PDGF inhibitor that blocks cell cycle progression in G1-S through inhibition of erk1–2 kinase. D. blocks cell cycle progression in G2-M. Anti-tumor responses can increase when the block to cell cycle progression in G2M precede the blocks in G1-S. This study was designed to determine tolerablity and activity of sequential D followed by Im in HRPC patients (pts). Methods: Eligibility: 2 prior hormone manipulations, any prior chemotherapy, PSA= 5 ng/ml, ECOG PS 0–2. Treatment schema: D IV day 1 followed in 24–36 hours by Im PO daily x 14 days, every 21 days until toxicity or progression. Cohorts (C) planned were: #1, D. 60 mg/m2, Im. 400 mg; #2, D 70mg/m2, Im 400 mg; #3, D 70mg/m2, Im 600 mg. Results: 12 pts enrolled: 6 in C#1, 3 each in C#2,3. Median age,73 (range: 61 to 85). Median number cycles (Cy) 3 (range: 2 to 10). Toxicity grade (TG)1–2 observed in 9 (75%) pts (6, 2, 1 in C#1, 2,3 respectively): anemia 9, neutropenia 1, lymphopenia 6, thrombocytopenia 3, hyperglycemia 8, hyponatremia 2, abnormal bicarbonate 7, hypoalbuminemia 3, fatigue 5, neuropathy 3, nausea/vomiting 3, constipation 2, pain 2, fever 2, increased creatinine 2. TG3: afebrile neutropenia, 4 pts. Cy1. TG 4: febrile neutropenia,1 pt C#1,Cy1; GI bleed/intestinal perforation, 1 pt C#3, Cy7. PSA decline =50%: 1 pt C#2; 2 pts C#3. Conclusions: sequential and intermittent dosing of D and Im was well tolerated with high doses of both drugs. The most common toxicity was neutropenia which was prevented with growth factors. The MTD was not reached. PSA responses occurred at the higher doses. An ongoing phase II study of sequential D. 70mg/m2 and Im. 600 mg x 14 days will define activity. No significant financial relationships to disclose.
Phase II trial investigating the effects of zoledronate and dexamethasone in hormone resistant prostate cancer
Authors: Din O. , Horsman J. , James N. , Wood K. , Kirkbride P. 
Published: March 2020

15629 Background: Response rates to second line therapy in hormone resistant prostate cancer have been shown to be relatively low. Current options of management include dexamethasone, zoledronate or more recently, cytotoxic chemotherapy. Many trials have studied their effects as monotherapy. The aim of this study is to assess the efficacy and safety of the combination of zoledronate and dexamethasone in these patients. Methods: 20 patients were identified in 2004–2005. All had histologically confirmed prostatic adenocarcinoma and biochemically confirmed hormone resistance. All patients had bone metastases as confirmed on radionuclide imaging. Treatment consisted of 6 cycles of zoledronate at a dose of 4 mg, given at 4 weekly intervals, in combination with dexamethasone 2–4 mg once a day. Calcium/vitamin D supplementation was given throughout the zoledronate treatment. Data was collected prospectively on serum PSA, quality of life and pain score. Results: Of the 20 patients in the study, 11 completed the full 24 weeks of treatment. Reasons for not completing the study included disease progression, treatment toxicity, fracture and death. The overall response rate, as defined by an initial fall of serum PSA of more than 50%, was 35% (7 out of 20 patients). In those who responded, the sustained fall in PSA, during the trial period, lasted on average 3.0 months. Conclusion: This study has demonstrated clinically significant effects on tumour response for the combination of zoledronate and dexamethasone in hormone resistant prostate carcinoma. With the emergence of newer chemotherapeutic agents, this combination could be used as an effective, but less toxic alternative. No significant financial relationships to disclose.
Deleted In Cancer 1 (DICE1): Search for a function in prostate carcinoma (PCa)
Authors: Filleur S. , Wieland I. , Nelius T. , Kennedy R. , De Riese W. , Wieacker P. 
Published: March 2020

15634 Background: Recently, DICE1 gene (MIM 604331 ) was identified to colocalize with the microsatellite marker D13S284 in 13q14.3, a region frequently affected by allelic deletion in PCa. We previously showed that DICE1 mRNA expression is down-regulated in PCa cell lines compared to normal prostate tissue, due to DICE1 promoter hypermethylation; suggesting that DICE1 is a tumor suppressor gene. Methods: Human PCa cell lines PC3 and DU145 were lipo-transfected with mammalian expression plasmids encoding for the full length DICE1 gene or for its N- (APAI construct) and C-terminal (DEAD construct) fragments. The constructs expression was determined by semi-quantitative PCR and quantified by Real-time PCR. Clonogenic formation and apoptotic assays were performed. Results: The PCR analysis showed that the expression of DICE1, APAI and DEAD domains in transfected PC3 and DU145 cell lines was increased 30.6, 75.2 and 27.9 fold in PC3 cells and 4.3, 5 and 2.5 fold in DU145 cells, respectively, compared to non-transfected cells. The function analysis showed that the ectopic expression of DICE1 suppressed clonogenic growth of PC3 and DU145 cell lines. Surprisingly, we showed that like DICE1, DEAD and APAI inhibit the PC3 and DU145 clonogenic growth suggesting that both regions are involved in prostate tumor growth inhibition. The apoptosis assay could not show any DNA fragmentation activity for DICE1. Conclusions: We demonstrated that DICE1 is a tumor suppressor in PCa. DICE1 mRNA expression is down-regulated in PCa cell lines compared to normal prostate tissue and its ectopic expression in PCa cell lines inhibits their capacity to form clonogenic colonies in vitro. The functional analysis could not reveal any role of DICE1 in PCa apoptosis, suggesting that other molecular mechanisms are involved. No significant financial relationships to disclose.
Termination of intraperitoneal chemotherapy is driven by treatment toxicity rather than catheter dysfunction
Authors: Edwards R. P. , Richard S. D. , Krivak T. C. , Zorn K. K. , Sukumvanich P. , Kelley J. L. 
Published: March 2020

16054 Background: Three separate studies have shown increased survival for women with epithelial ovarian carcinoma treated with intraperitoneal (IP) chemotherapy. Barriers to its use have included toxicity concerns. We compared the morbidity associated with IP cisplatin- based chemotherapy and IP immunologic therapies. Methods: A retrospective cohort analysis of patients diagnosed with epithelial ovarian carcinoma treated with IP chemotherapy at a single institution from 1996–2006 was performed. Patients were separated into those who received IP Interleukin-2 or Interleukin-12 and those who received cisplatin-based IP chemotherapy. Primary endpoint was completion of the intended treatments. Complications arising from the placement or use of the catheter were deemed catheter-related and included obstruction of flow or catheter site infection. Those felt to be caused by treatment toxicity (e.g. nausea, pain, fever) or progression of disease were deemed treatment-related. Chi square test was used for all univariate analysis. Results: Seventy-five patients were identified. Thirty-five (46.6%) received IL-2 or IL-12, while 40 (53.4%) received cisplatin-based chemotherapy. There were 16 complications that led to treatment termination (21.3%). Immunologic therapy had an increased frequency of early termination (n=13, 37.1%) compared to cisplatin-based therapy (n=3, 7.5%) (p=0.002). There were 3 (8.6%) catheter-related complications in the immunologic group and 2 (5%) in the cisplatin-based group (p=0.54). Reasons for termination of therapy in the immunologic therapy group were progression of disease (n=5), catheter site infection (n=3), grade 3/4 nausea (n=3), and grade 3/4 abdominal pain (n=2). In the cisplatin therapy group, reasons for termination included catheter site infection (n=1), catheter site leak (n=1), and progression of disease (n=1). Conclusion: Local-regional immunotherapy produces significantly more complications and local symptoms than cisplatin-based regimens. Catheter complications were not significantly different between the two groups, and accounted for a small percentage of the treatment terminations in this series. No significant financial relationships to disclose.
The target genes research for diagnosis, therapy and prognosis in cases with ovarian cancer
Authors: Bakhidze E. V. , Malek A. V. , Belyaeva A. V. 
Published: March 2020

16060 Background: Epithelial ovarian cancer has one of the worst prognoses among gynecologic malignancies. Molecular genetic analyses of ovarian cancers have uncovered genetic alterations of several genes. Normal tissues were readily distinguished from tumor tissues. These studies identified several genes, such as High mobility group A2 (HMG A2) proteins. The expression of HMG A2 gene is detected in foetal stage of human development and stopped in normal adult tissues. Elevation of the HMG A2 gene expression was shown for several human malignant tumours. Targeted supression of HMG A2 protein synthesis can be one of important directions for anti-tumour therapy in cases of ovarian cancer Methods: The HMG A2 gene expression was searched in 48 flash-frozen samples of ovarian serous papillary adenocarcinoma and 12 samples of normal ovarian tissue. The HMG A2 gene expression was investigated by RNA in situ hybridisation. Results: High and middle level of HMG A2 gene expression was shown in 37 from 48 (77%) ovarian cancer samples. HMG A2 mRNA was not detected in normal ovarian surface epithelium. Low grade tumour differentiation (G3) was detected in 24 cases from 37 (64,9%), middle differentiation (G2) was detected in 12 cases (32,4%) and high grade differentiation (G1) was detected in 1 case (2,7%). Conclusions: HMG A2 high expression is a typical and important feature of serouse type of ovarian carcinoma. High level of HMG A2 gene expression correlate with low grade tumour differentiation. No significant financial relationships to disclose.
Phase II pilot study of biweekly cisplatin and gemcitabine in multi-refractory ovarian cancer
Authors: Sutton G. , Fisher W. , Rivers S. 
Published: March 2020

16065 Background: Preclinical data suggest the combination of cisplatin and gemcitabine may have synergy in inhibiting ovarian cancer growth in vitro. Clinical trials in breast cancer support the use of biweekly gemcitabine. A pilot trial of biweekly cisplatin and gemcitabine in multi-refractory ovarian cancer was undertaken. Methods: This was a single-stage phase II pilot trial. Eligible patients had platinum-resistant, multidrug-refractory epithelial ovarian cancer with CA125 levels exceeding 90 units/ml and acceptable renal, hepatic, and bone marrow function. Cisplatin 30 mg/m2 IV and gemcitabine 800–1000 mg/m2 IV were given biweekly (d1, 15) and CA125 levles monitored. Toxicity was monitored before each course and graded by NCI-CTC. Responses were measured using Rustin's criteria (JCO 15:172,1997). Treatment was continued until disease progression or prohibitive toxicity supervened. Results: Eleven patients aged 30–71 years (median 58 years) with advanced ovarian cancer received cisplatin and gemcitabine. They had been treated with from 1 to 7 (mean 3.9) previous chemotherapy regimens. A total of 85 course (mean 7.7 courses/patient) were administered, Toxicity included CTC grade 2 anemia in 3 patients and one case each of grade 2 and grade 4 neutropenia without fever. No patients experienced exacerbation of pre-existing peripheral neuropathy. Two patients had stable disease of 3 months or greater duration, four (36%) had complete responses (CA125 decrease > or = to 75% baseline), and the remainder had progressive disease. Conclusions: Biweekly cisplatin and gemcitabine is an active combination in patients with refractory ovarian cancer. Limited toxicity and ease of administration suggest a role for this combination in consolidation therapy. [Table: see text]