bluuebunny/crossref_metadata_2025_split huggingface dataset:
A new mechanism of estrogen action in prostate cancer: Inhibition of tissue androgen production and prostate cancer growth by Estradiol in androgen independent prostate cancer xenografts
Authors: Montgomery B. , Nelson P. , Hess D. L. , Vessella R. , Corey E. 
Published: March 2020

15509 Background: Estrogens are effective agents in treating prostate cancer in patients in which serum androgens are already at ‘castrate‘ or anorchid levels. The mechanisms whereby estrogens inhibit ‘androgen-independent‘ prostate cancer are unclear. Methods: The androgen-independent human prostate cancer xenograft LuCaP 35V was implanted into orchiectomized male SCID mice and established tumors were treated with placebo pellets, 17β-estradiol (E2) slow-release pellets or E2 with the estrogen receptor antagonist ICI 182,780 as previously described (Clin Cancer Res 8:1003). Effects of E2 on tumor growth and tissue testosterone (T) and dihydrotestosterone (DHT) levels were evaluated by radioimmunoassay. Results: E2 significantly inhibited growth of androgen-independent LuCaP35V ( ∼35% inhibition at 4 weeks, p=0.0047, and increased survival of tumor bearing animals, (p trend =0.03) . The estrogen receptor antagonist ICI 182,780 did not block E2 inhibition of tumor growth, suggesting a receptor independent mechanism of tumor suppression. We then examined the effect of E2 on tissue T and DHT. E2 suppressed levels of tumor T and DHT in treated tumors. Tissue androgens in placebo treated LuCaP35V xenografts were; T=1.21 (± 0.18) pg/mg and DHT=3.54 (±1.07) pg/mg, and in E2-treated LuCaP35V T=0.23 (±0.09) pg/mg and DHT =0.44 (±0.14) pg/mg, (p<0.001). Levels of T and DHT in control liver tissue from both placebo and E2-treated animals were equivalent, at less than 0.2 pg/mg. Conclusions: We have shown that E2 inhibits growth of the androgen- independent human prostate cancer xenograft LuCaP35V, and that this inhibition is estrogen receptor independent. E2 significantly suppressed tumor tissue T and DHT suggesting a new mechanism of E2 mediated growth inhibition of androgen independent prostate cancer, potentially through inhibition of tumoral steroidogenesis. This model of ‘intracrine‘ tumor androgen production can be used to evaluate other inhibitors of tissue steroidogenesis. No significant financial relationships to disclose.
The importance of continued surveillance of high risk cancer families as illustrated in a family with Gardner’s syndrome
Authors: Legare R. D. , Scalia-Wilbur J. , Kent J. 
Published: March 2020

1551 Background: The scientific community continues to rapidly discover cancer predisposition genes allowing high risk families to identify underlying genetic abnormalities providing more individualized medical management. Therefore, continued follow-up becomes critical and is exemplified by Family A, a case that had been lost to follow-up for almost 40 years. Family A was first reported in the literature in 1955 by Weiner and Cooper presenting with a dominant inheritance pattern of osteomatosis, multiple soft tissue tumors and colorectal adenomatosis polyposis consistent with several families previously reported by Gardner et al. between 1950–1953. The clinical diagnosis of Gardner syndrome was established. In 1969 Coli et al. further described the phenotypic manifestations of Family A’s second and third generations after which the family was largely lost to follow-up until two second generation members presented to our high-risk clinic. Methods: An updated family history was collected and compared to that previously reported in the literature. Results: An updated pedigree revealed new cases of breast, ovarian and primary peritioneal cancers in the second and third generations. A 39 year old woman diagnosed with a glioblastoma was also discovered. No family members had undergone genetic testing, however, analyses of the APC and BRCA genes are underway. Conclusions: The presence of multiple newly reported cases of breast and ovarian cancers within Family A raises concern for two independent cancer predisposition syndromes, Hereditary Breast and Ovarian Cancer Susceptibility syndrome (HBOCS) as well as Familial Adenomatous Polyposis (FAP). Though rarely gynecological tumors have been reported in FAP, this case emphasizes the need for practitioners to be aware of the potential presence of multiple hereditary cancer syndromes in one family. The dynamic changes in the pedigree of Family A underscore the importance of continued follow up for cancer families in which the underlying etiology is unknown. Such families should be followed in cancer genetics clinics to update family histories, ensure that appropriate screening regimens are followed, and to offer genetic testing if the appropriate analysis becomes available. No significant financial relationships to disclose.
An open label phase I study of ABR-215050 in patients with prostate cancer refractory to hormone therapy and with rising PSA for determination of MTD and long-term tolerability and safety
Authors: Damber J. , Bratt O. , Ahlgren G. , Häggman M. , Björk A. , Kilany S. , Hannander K. 
Published: March 2020

15510 Background: Preclinical studies have demonstrated that ABR-215050, an orally active 3-quinoline-carboxamide derivative with anti-angiogenic abilities, consistently inhibits growth of established prostate cancer in rodent and human xenografts model systems. Tumor vessel density was inhibited by 44–65% consistent with the 41–78% inhibition in tumor weights. The anti-angiogenic response was correlated with an increase in both tumor hypoxic and apoptotic fraction. Based upon these results, ABR-215050 is now tested in the clinical setting. Methods: Cohorts of 6 patients (pts) with hormone refractory prostate cancer and rising PSA were to receive escalating doses of ABR- 215050 (0.5, 1.0, 2.0 and 3.0 mg daily) for 28 days in addition to the androgen ablative therapy. Pts showing stable disease at day 28 were offered to enter a one year extension period at the MTD level to assess long-term tolerability and safety. The primary endpoint in the 28-day study was determination of MTD. Secondary endpoints included changes in PSA levels. Results: Two DLTs (sinus tachycardia and amylase, G3) occurred in the 1.0 mg cohort. The MTD was therefore set to 0.5 mg. Additional 11 pts were enrolled at the MTD level. A total of 17 pts received 0.5 mg and 7 pts 1.0 mg of ABR-215050 once daily. The most frequently related AEs reported during the first 28 days were muscle or joint pain, nausea and fatigue, all of which being mild and transient. Laboratory changes were also seen, such as a transient increase in CRP and amylase. Fifteen out of 17 pts continued into the extension period. Fourteen out of 15 pts remained on treatment = 4 months. The AE profile in the extension period was similar to that reported during the first 28 days of treatment. Nine out of 14 pts had a >50% decrease in PSA velocity at 4 months compared to the pre-treatment period. Six of these pts exhibited a decrease in PSA from baseline, ranging from 8% to 58% (mean 29%). Conclusions: ABR-215050 0.5 mg is well tolerated with manageable side effects. In addition available PSA results suggest stabilization/lowering of the PSA levels. No significant financial relationships to disclose.
Delayed toxicity of whole brain radiotherapy (WBRT) in germ cell tumor (GCT) patients with central nervous system (CNS) metastases
Authors: Doyle D. M. , Einhorn L. H. 
Published: March 2020

15511 Background: CNS metastases are uncommon in GCT. Incidence is 2–3% and is usually associated with extensive pulmonary metastases and/or high serum human chorionic gonadotropin levels. CNS metastases have been managed with WBRT and concomitant cisplatin-based combination chemotherapy. Our prior publication did not observe serious CNS toxicity (Int J Rad Oncol Biol Phys 22:17–22, 1991). Methods: We observed 5 patients with delayed CNS toxicity. Initial diagnosis was 1981 through 2003. Median age 23 years (range 21–34). All 5 patients had advanced disease by the International Germ Cell Consensus Collaborative Group. Three of five patients had CNS metastases at the time of diagnosis, and two patients relapsed with CNS metastases. These 5 patients received WBRT 4,000–5,000 cGy in 18- 28 fractions concurrently with cisplatin-based chemotherapy. Results: All five patients developed delayed symptoms consistent with progressive multifocal leukoencephalopathy (PMLE), including seizures, hemiparesis, expressive and receptive aphasia, cranial neuropathies including facial droop, tremors, headaches, blindness, dementia, decreased level of consciousness, ataxia, and parasthesias. Median time from WBRT to CNS symptoms was 72 months (range 9–228 months). Brain imaging revealed multiple abnormalities consistent with gliosis and diffuse cerebral atrophy. One patient was diagnosed with glioblastoma multiforme in the area of radiation-induced gliosis. 3 of 5 patients had progressive symptoms, and the other 2 had stable symptoms. Treatment with surgery and steroids had modest benefit. The PMLE resulted in significant debility in all five patients, resulting in death (2 patients), loss of work, steroid-induced morbidity, and recurrent hospitalizations. Conclusions: WBRT is not innocuous in young patients with GCT and can cause late CNS toxicity. We are now cautious about the use of WBRT and reserve it for multiple CNS metastases that are symptomatic or resistant to chemotherapy. No significant financial relationships to disclose.
Phase I/II trial of GM-CSF and lenalidomide in patients with hormone refractory prostate cancer (HRPC)
Authors: Dreicer R. , Garcia J. , Smith S. , Elson P. , Triozzi P. , Hodnick S. , Rini B. , Klein E. 
Published: March 2020

15515 Background: Administration of GM-CSF in combination with thalidomide induces PSA responses in 20–25% of pts with HRPC. When administered in the neoadjuvant setting, this combination induces T cell and dendritic cell (DC) infiltration in prostate tumor tissue. Lenalidomide is an immunomodulatory analogue of thalidomide. In an effort to evaluate the clinical and immune activity of GM-CSF plus lenalidomide, we conducted a phase I/II trial in pts with HRPC. Methods: Pts had progressive asymptomatic HRPC by Consensus Criteria. Prior immunotherapy or chemotherapy was not permitted. A phase I safety phase followed by a phase II trial was undertaken. All pts received GM-CSF at 250 μg administered SC three times weekly along with lenalidomide 25 mg/day orally on days 1–21 of a 28-day cycle. Primary endpoints were safety and objective and PSA responses. Exploratory endpoints included activation of circulating DC, regulatory T cells (Treg) and cytokine production. Results: To date 19 of 34 planned pts are enrolled (13 with evidence of metastases; 6 with PSA-only disease). Seventeen pts are eligible for response (2 pts too early) Median age is 71 (49–80), median PSA is 19.1 (2.1–153.1). Median cycles of therapy is 4 (range: 1–14+). Overall, 13 of 17 pts (76%) experienced a reduction in PSA (<20% 2/17; 20–40% 7/17,>50% 4/17). Objective and PSA partial responses were observed in 2 and 4 of 17 pts respectively. Nine pts discontinued therapy (5 due to PD, 3 due to toxicity, and 1 withdrew consent). No pts on the phase I portion of the trial experienced a DLT. Grade (G) 1–2 toxicities for all 17 pts included neutropenia (20%), thrombocytopenia (13%), diarrhea (43%), dizziness, (25%), and fatigue (90%). Three pts developed G4 toxicities (PE, neutropenia, and emesis). The number of Treg cells decreased after 2 cycles of therapy. Similarly, Th1 cytokine and TNF-a production was increased after therapy. Although mean serum VEGF levels were decreased after therapy, changes in the mean serum levels of IL-8 and bFGF were not observed. Conclusions: The combination of GM-CSF and lenalidomide is relatively well tolerated with evidence of antitumor activity. Exploratory studies support the ability of this therapy to modulate immune cells. Accrual to this study is ongoing. [Table: see text]
Von Hippel-Lindau gene mutation status is associated with a dichotomous response in primary and metastatic tumors in patients receiving bevacizumab and erlotinib for metastatic renal cell carcinoma
Authors: Tsavachidou D. , Tannir N. M. , Wood C. G. , Corn P. , Do K. , Tamboli P. , Smith L. A. , Matin S. , Jonasch E. 
Published: March 2020

15522 Background: A single arm phase II study is underway evaluating the safety and clinical benefit of presurgical bevacizumab and erlotinib in the management of patients with untreated conventional renal cell carcinoma (RCC). It is not known how the presence or absence of von Hippel Lindau (VHL) mutations affect the response to therapy in the primary or metastatic site, and whether VHL mutational status is predictive for either. Methods: Patients enrolled had conventional RCC, measurable metastatic disease, a primary tumor in place, no prior systemic therapy, a PS of 0 or 1 and no brain metastases. A total of 35 patients were enrolled as of January 8, 2007. Patients were treated with bevacizumab for 4 cycles and erlotinib for 8 weeks, and underwent cytoreductive nephrectomy at week 10 (4 weeks after the last dose of bevacizumab). A VHL gene mutation and methylation analysis was completed on nephrectomy specimens from the first 18 evaluable patients. Patients were grouped according to the presence or absence of functional VHL gene inactivation (mutation and/or methylation). Two-sample T-test and Fisher’s exact test were performed. Results: Ten patients (55%) demonstrated either VHL mutation or methylation ( table 1 ). Patients with no VHL gene inactivation demonstrated more robust primary tumor shrinkage, but did not demonstrate partial responses (PRs). Table 1 . Conclusions: These findings, although preliminary, suggest a dichotomous response in the primary and metastatic disease sites according to VHL functional status. Ongoing evaluation of new treatment strategies using antivascular/targeted agents in RCC may benefit from molecular stratification. [Table: see text] No significant financial relationships to disclose.
Potential targets in prostate tumor–associated stroma
Authors: Richardson A. , Player A. , Wang Y. , Rodriguez-Canales J. , Erickson H. , Kawasaki E. , Woodson K. , Chuaqui R. , Emmert-Buck M. 
Published: March 2020

15529 Background: The past 20 years have seen a shift in the paradigm that the stromal compartment in tissues is merely a passive, supporting tissue for epithelial cells. Recent evidence shows that it plays a critical role not only in normal tissue development and homeostasis, but also in the progression of cancer. Further, as the stromal compartment is more readily accessible to vascular-delivered agents, this region might be particularly amenable to clinical intervention. As such, a broad-based study of the carcinoma-associated changes in stromal cells from patient samples could yield a wealth of information on the molecular mechansisms of tumorigenesis, and identify clinically important molecular targets. Methods: Five whole-mount frozen prostatectomy specimens were microdissected in four regions: normal epithelium, tumor epithelium, normal stroma, and tumor-associated stroma. Extracted and amplified mRNA was hybridized to the Human Genome U133 Plus 2.0 GeneChip (Affymetrix). Using the intersection of two statistical analysis packages (GCOS and RMA), we identified differentially expressed genes between the dissection groups. Quantitative RT-PCR was used to validate selected transcripts and immunohistochemistry to evaluate potential stromal molecular targets. Results: Tumor-associated stroma showed a distinctly different expression pattern compared to normal stroma with 675 differentially expressed transcripts, the majority of which were up-regulated. In contrast, tumor epithelium showed more down-regulation in the 829 transcripts that were differentially expressed relative to normal epithelium. Classes of up-regulated genes in the tumor-associated stroma showed a strong linkage to cell adhesion and migration as well as the calcium, MAPK, and TGF-beta signaling pathways. Quantitative RT-PCR was conducted to verify GeneChip findings and revealed over 80% concordance with the original data. Immunohistochemical staining further supported the expression differences. Conclusions: Global mRNA expression analysis of stromal cells within tumors provides insight into prostate cancer progression, and yields novel targets for future diagnostic and therapeutic intervention. No significant financial relationships to disclose.
Analysis of lymphangiogenetic factors in invasive bladder cancer—A tissue microarray analysis
Authors: Wulfing C. , Herrmann E. , Kopke T. , Eltze E. , Neumann J. , Bierer S. , Hertle L. 
Published: March 2020

15530 Introduction: Vascular endothelial growth factors (VEGF) -C, -D and their receptor Flt-4 play an emerging role in lymphangiogenesis of different tumor types. Our aim was to determine the role of VEGF-C, VEGF-D and Flt-4 in invasive transitional cell carcinoma of the bladder. Material and Methods: Archival tumor tissue of 286 patients, who had previously undergone radical cystectomy at our institution, was reviewed and representative tumor blocks were selected for constructing a tissue microarray (TMA). Paraffin sections were assessed immunohistochemically using mono- and polyclonal antibodies against VEGF-C, VEGF-D and Flt-4. Staining results were analysed semiquantitatively and correlated with various clinicopathological factors. Results: Overexpression of VEGF-C, VEGF-D and Flt-4 was found in 24.1%, 37.4% and 46.3% of cases, respectively. While there was no association of VEGF-C to histopathological parameters and clinical outcome, patients with VEGF-D overexpression had higher pathological tumor stages (p=0.021) and regional lymph node metastases (p=0.016). Furthermore, they had significantly worse disease-free survival (p=0.042). Overexpression of Flt-4 was found in the subgroup of G3- and G4-tumors (p=0.001) and correlated with a shorter period of disease- free survival (p=0.033). Conclusion: VEGF-C, VEGF-D and Flt-4 are overexpressed in bladder cancer. VEGF-D predicts higher tumor stages and regional lymph node metastases. It is associated with a worse disease-free survival as well as Flt-4 in the subgroup of high-grade tumors. Further studies should be initiated to evaluate VEGF-D and Flt-4 as potential targets in bladder cancer. No significant financial relationships to disclose.
Pre-prostatectomy study of the effect of celecoxib versus placebo on androgen receptor (AR) expression in prostate cancer
Authors: Garzotto M. , Janeba N. , Eilers K. M. , Sekhon H. , Beer T. M. 
Published: March 2020

15538 Background: Cyclooxygenase (COX) inhibitor drug use is associated with a reduction in prostate cancer incidence and mortality. Numerous potential mechanisms for the COX-2 inhibitor, celecoxib have been proposed, including a reduction in AR transactivation (Clin Cancer Res 10:7727, 2004). We hypothesized that pre-prostatectomy celecoxib therapy would result in reduced tissue AR levels. Methods: 28 patients with localized prostate cancer were randomized to celecoxib (400 mg bid) or placebo for 4 weeks prior to prostatectomy. Both benign and cancerous tissues were embedded in a tissue microarray. A single blinded pathologist quantified the percent of positive nuclei in benign versus malignant epithelial cells. Results: An increased number of AR-positive nuclei were observed in the malignant versus benign cells (65.9± 35.2% versus 49.9 ± 33.5 %, p <.001). There was no difference in AR expression between treatment and placebo groups in either benign or cancerous tissue (p = .9, .85, respectively). The median serum PSA at baseline was 6.0 and 6.2 ng/ml for the celecoxib and placebo groups. Over the treatment period, there was no detectable effect of celecoxib on serum PSA (p=0.91). Conclusions: Short-term COX-2 inhibitor therapy did not result in a significant change in either tissue AR or serum PSA. If celecoxib has inhibitory effects on prostate cancer, these may occur without an effect of AR activity. No significant financial relationships to disclose.
Phase I trial of docetaxel (D) plus samarium153 (Sm 153) in patients (pts) with hormone refractory prostate cancer (HRPC)
Authors: Sinibaldi V. J. , Carducci M. A. , DeWeese T. , Weber J. , Drew R. , Moore-Cooper S. , Denmeade S. , Pili R. , Walczak J. , Sugar E. , Eisenberger M. A. 
Published: March 2020

15547 Background: Bone targeted approaches hold great promise for improving outcomes in HRPC. Docetaxel (D) and samarium 153 (Sm153 ) have individually demonstrated a clinical benefit and preclinical data strongly support biological synergism in HRPC. Preclinical data suggests that 24 hour after a dose of D, there is maximum G2M arrest. This results in the accumulation of cells in the most radiosensitive phase of the cell cycle. This phase I trial was designed to evaluate toxicity and preliminary efficacy of combined D and Sm153 administered sequentially in advanced HRPC. Methods: HRPC pts progressing after anti-androgen withdrawal; = 2 prior chemotherapy regimens; acceptable bone marrow, renal and hepatic function were eligible. Planned D treatment in 4 cohorts (N=3/cohort) includes: Cohort 1: D 50mg/m2 IV on days 1, 22, 91, and 112; cohort 2: D 75mg/m2 IV on days 1 and 22 followed by 50mg/m2 IV on days 91 and 112; cohort 3: D 75mg/m2 IV on days 1 and 22 followed by 75mg/m2 IV on days 91 and 112; cohort 4: D 75 mg/m2 IV on days 1, 22, 42, 91, 112, and 133. Sm 153 (1.0 mi/Kg) is administered IV days 2 and 92 of each cycle. Cycles are repeated Q 12 wks (max 2 cycles). The endpoint for this trial is dose limiting toxicity and maximal tolerated dose. Results: From 5/11/05 - 1/7/07 ten pts were enrolled. Median: age 69.5 yrs (range 58–76), ECOG performance status 1 (range 0–1), baseline PSA 76.65 ng/ml (range 9.6–1064 ng/ml ), prior hormonal manipulations 3 (range1–6). Three pts had prior taxotere and 3 pts had prior palliative RT. All had bone metastases and 2 also had soft tissue disease. Five pts completed 2 cycles of treatment as planned. Five pts had 1 cycle (one pt is on treatment, 3 pts had PD and 1 had prolonged grade 1 thrombocytopenia =3 wks). Nine of 10 pts had reversible grade 3 / 4 neutropenia (1 pt had reversible episode of neutropenia with fever). Seven of 7 symptomatic pts had improvement in pain. Four of 10 of pts had a 50 % decline in PSA level lasting = 4 weeks; no soft tissue disease responses. Conclusions: Our preliminary data suggest that Q 3 wk D and Q 3 month Sm153 may be administered simultaneously at full doses in extensively pretreated HRPC pts, with acceptable toxicity and significant activity. This study is supported by a grant from sanofi- aventis and Sm153 is provided by Cytogen. No significant financial relationships to disclose.