bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final results of a phase I trial with the novel anthracycline derivative RTA 744 in patients with primary brain tumors
Authors: Conrad C. A. , Maher E. , Cloughesy T. , Groves M. , Gilbert M. , Madden T. , Levin V. , Priebe W. , Meyer C. , Yung W. 
Published: March 2020

2062 Background: RTA 744 is an anthracycline derivative that was shown preclinically to cross the blood-brain barrier, not be a substrate for P-gp or MRP, and improve survival in an orthotopic murine model of glioblastoma. A trial of RTA 744 was conducted in patients with progressive high-grade gliomas. Methods: RTA 744 was administered as a 2-hour intravenous infusion on each of the first 3 days of a 21-day cycle. Five dose levels were tested until an MTD was reached. Pharmacokinetic samples were taken at multiple time points on days 1–5 of cycle 1. Tumor activity was assessed according to the MacDonald criteria. Results: As of December 2006, RTA 744 has been administered to 20 patients at doses ranging from 1.2 to 9.6 mg/m2/day. The MTD was determined as 7.5 mg/m2/day, and the DLTs were neutropenia and thrombocytopenia. No neurotoxicity, cardiotoxicity, alopecia, or drug-related nausea and vomiting were reported. The pharmacokinetic profile indicates dose proportionality, with a mean plasma half-life of 35 hours. Clear evidence of anti-tumor activity has been reported in 7 of 20 patients. A Complete Response was observed in a patient with GBM after seven cycles at 2.4 mg/m2/day, the patient continues greater than 5 months post-RTA744 treatment. Additionally, a Partial Response (81% tumor reduction) has been observed in a patient with AO after two cycles at 7.5 mg/m2/day who continues on treatment at this time. A Minor Response was observed at 2.4 mg/m2/day, and several patients have experienced Stable Disease of several months duration. Two patients with stable disease have shown radiographic evidence of necrosis. Median time to tumor progression was 6 weeks (range 2 to >50). Median number of cycles was 2 (range 1 to 7). The study is now enrolling additional patients at the MTD to further profile the drug’s safety and activity. Additionally, a once-weekly dosing schedule is being tested in a satellite cohort. Conclusions: RTA 744 is well tolerated when administered at doses up to and including 7.5 mg/m2/day for the first three days of a 21-day cycle. Based on clear evidence of drug activity, pivotal trials of RTA 744 in high-grade gliomas are planned as well as trials in patients with brain metastases. [Table: see text]
Phase II open-label, safety, pharmacokinetic and efficacy study of 2-methoxyestradiol nanocrystal colloidal dispersion administered orally to patients with recurrent glioblastoma multiforme
Authors: Kirkpatrick J. , Desjardins A. , Quinn J. , Rich J. , Vredenburgh J. , Sathornsumetee S. , Gururangan S. , Sidor C. , Friedman H. , Reardon D. 
Published: March 2020

2065 Background: 2-methoxyestradiol (2ME2) inhibits tumor cell proliferation and induces apoptosis by inhibiting microtubule polymerization and increasing reactive oxygen species-induced cell damage. In addition, 2ME2 downregulates HIF-1a at the posttranscriptional level and inhibits HIF-1a-mediated VEGF expression. Preclinical studies confirm significant in vitro and in vivo anti-glioma activity including tumor regression in combination with temozolomide. We therefore performed a single-center, phase 2 study to evaluate 2ME2 in recurrent glioblastoma multiforme (GBM) patients. Methods: Key eligibility include: adults with GBM at first or second recurrence; measurable disease; Karnofsky performance status = 70% and adequate organ function. 2ME2 was given orally 4 times/day at a dose of 1000mg for the first 11 patients and then escalated to 1500 mg for remaining patients. Patients are evaluated after every 28-day cycle. The primary efficacy endpoint is 6-month progression-free survival. Results: Sixteen patients (14 male) have been enrolled, including 7 at first recurrence and 9 at second recurrence. The median age is 52 years (range, 32–64 years). Thirty-five cycles have been administered to date. Grade II-IV, attributable toxicities include transaminase elevation (grade 3, n=3; grade 2, n=1); hypophosphatemia (grade 3, n=1); anorexia (grade 2, n=1) and rash (grade 2, n=1). Six patients (38%) have achieved stable disease including one minor response. PK studies revealed similar 2ME2 exposures to those achieved among solid tumor patients treated at the same dose level and no differences between GBM patients on or not on CYP3A-inducing anti-epileptic agents. Further accrual and follow-up is ongoing. Conclusions: Continuous daily 2ME2 dosing, administered as a monotherapeutic, is well tolerated and is associated with modest anti-tumor activity among recurrent GBM patients. Combination studies with temozolomide are underway. No significant financial relationships to disclose.
Rechallenge of malignant gliomas with temozolomide —Can it be effective?
Authors: Strik H. M. , Buhk J. H. , Bock H. C. , Nitsche M. , Giese A. , Baehr M. 
Published: March 2020

2072 Background: No standard treatment of recurrent malignant glioma is established. Moreover, it is unclear if a rechallenge with temozolomide is effective. We present here feasibility and first treatment results of a dose-dense, individually dose adapted 21-day regimen with temozolomide. Methods: 13 consecutive patients with recurrent malignant gliomas (11 glioblastomas [GBM], 1 anaplastic astrocytoma, 1 anaplastic oligodendroglioma) were treated. The basic data are: median time to first relapse 8.3 months; median Karnofsky performance status 60% (7 x 50+60%; 6 x 70–100%); median age 52.2 (32–73) years; gender: 9 males (69%), 4 females (31%). All patients were pretreated with radiochemotherapy and temozolomide 200mg/m2 days 1–5/28 in first line. In eight of the 13 patients, therapy was switched without delay to the dose-dense schedule: temozolomide 100mg/m2 day 1–21/28. During treatment, the dosage was adapted individually, aiming towards total leukocyte counts of approximately 4,000/μL. Results: The 21/28-days regimen was better tolerated than the 5/28-days schedule regarding nausea and fatigue. Blood counts decreased continuously, enabling a gradual dose adaptation. The dosage was kept at 100mg/m2 in 9 patients, reduced to 75 mg/m2 in 3 and gradually increased to 130 mg/m2 in 1 patient. Hematotoxicity was WHO grade 3 in 2, and grade 4 in 1 patient without clinical signs. One patient had a pneumonia WHO grade 4 in the terminal stage of the disease several weeks after discontinuation of the chemotherapy. Response after 2 months was: 3 partial and 1 complete remission (31%; GBM only: 18%), 4 stable diseases (31%), 5 progressive diseases (38%). The progression free survival at 6 months (PFS) was 54.5% (GBM: 44%). In the 9 glioblastoma patients with an observation period of more than 6 months, the median survival time after relapse was 35.8 weeks, median overall survival 18.2 months. Conclusions: Second line treatment with dose dense temozolomide at 100 mg/m2 day 1–21/28 and individual dose adaptation is feasible for recurrent malignant gliomas. Even in this series with relatively unfavorable prognostic criteria, the rate of objective responses and 6-months PFS after rechallenge with temozolomide compares well with other series. The results will be controlled in a prospective study. No significant financial relationships to disclose.
Longitudinal assessment of childhood optic gliomas: Relationship between brain imaging and optic pathway function
Authors: Falsini B. , Lazzareschi I. , Ruggiero A. , Ziccardi L. , Placentino L. , Colosimo C. , Di Rocco C. , Riccardi R. 
Published: March 2020

2087 Background: To evaluate longitudinally the relationship between brain imaging and functional findings in childhood optic gliomas (OG) by comparing over time magnetic resonance imaging (MRI) with flicker visual evoked potential (FVEP) changes. Methods: Fourteen children (median age 3 yrs, range: 2–7) suffering from OGs involving chiasm and retro-chiasmatic visual pathways underwent serial MRI and FVEP examinations over a median follow-up time of 38 months (range 12–76). FVEPs were monocularly recorded in response to 8 Hz sine-wave flicker stimuli presented in a mini-Ganzfeld according to a published technique (Trisciuzzi et al., Clin. Neurophysiol., 2004). MRI examinations were performed according to standard procedures. Longitudinal results of both tests were examined in a blind fashion by independent evaluators. FVEPs were judged to be improved, stable or worsened if changes in the amplitude and/or phase of the fundamental response component exceeded the limits of test-retest variability (±90th percentile) established in the same patients. MRI results were judged to show regression, stabilization or progression of OG based on its changes in size (±20%) or extension. Two to seven pairs (< one month apart) of FVEP/MRI examinations per patient (median: 4, range 2–7) were collected. Agreement between test changes over time were evaluated by K-statistics. Results: Based on a total of 38 pairs of longitudinal FVEP/MRI examinations, both tests agreeed in showing worsening (progression), stabilization and improvement (regression) in 5, 10 and 15 cases, respectively. In 3 cases, FVEPs showed a worsening and MRI a stabilization, while in 5 cases FVEPs showed an improvement and MRI a stabilization. Agreement between FVEP and MRI changes was 78.9% (95% CI: ± 37%, K = 0.67, p < 0.001). Conclusions: The results indicate that changes over time in FVEPs, an objective and non-invasive test of visual function, can accurately predict associated changes in OG size and extension as assessed by MRI, and suggest that the latter changes may have a significant impact on visual function during developmental age. No significant financial relationships to disclose.
A substantial change in breast cancer (BC) biology arises after 50 years old regardless of patient (pt) menopausal status
Authors: Veys I. , Durbecq V. , Ameye L. , Desmedt C. , Paesmans M. , Sirtaine N. , Sotiriou C. , Nogaret J. , Piccart M. , Larsimont D. 
Published: March 2020

21002 Background: To explore the hypothesis that ageing alters BC biology, we correlated pt age at diagnosis with biopathological data collected retrospectively from 2723 BC pts treated at the Bordet Institute between 2000 and 2003. Pt's characteristics: Median pts’ age was 56 years old [25–96] and 36% of pt had nodal invasion. Seventy-eight and 63% of the BC were ER+ and PR+ respectively, 33% were grade 3, 24% overexpressed Ki67 (>25%) and 8% were Her2 FISH+. Results: Pts <40 years old had the highest Her2 FISH+ (12%) and hormone-independent (39%) BC rates. More than 50% of the BC were undifferentiated (grade 3) and highly proliferative (Ki67>25%). Moreover, lobular BC were almost absent in young pts (p<.0001); in agreement with the fact that lobular BC were less aggressive than ductal ones (less grade 3, Her2 FISH+ and ER- BC; p<.0001). Hence pts <40 years had a statistically higher rate of “Her2” and “basal-like” BC subtypes. On the contrary, pts >50 years had ‘better prognostic luminal-A” BC with 60% of hormone-dependent BC and a significant drastic decrease of Ki67 expression, tumor grading and Her2 FISH+ (all p=.002). No biological difference was observed between BC of pts >50 years. However, in this group we observed that high ER scores (7–8 vs 3–6) were statistically associated with Her2 FISH- and PR+ characteristics (all p<.0004). Interestingly, the 40–50 years old group which contains 16% of postmenopausal pts, appeared as a transition group according to its biology. Nevertheless, no statistically biological difference could be observed between the BC of pre- and postmenopausal pts. Additionally, when considering the postmenopausal pts from all ages, a clear difference was observed for the different parameters between tumors from pts <50 years compared to older ones (ER, p=.046; grade, p=.0007; Ki67, p=.0001), suggesting that age, and not the menopausal status, is responsible for changes in BC biology Conclusions: BC biology is greatly different in pts before and after the age of 50 but after 50 years old, all pts have BC with similar characteristics. Nevertheless, menopausal status can not account by itself to all these differences and pt ageing appears to have a great impact on BC biology (i.e. Her2 FISH+). No significant financial relationships to disclose.
Relapse free survival in a prospective cohort of hormone receptor/Her2neu defined breast cancer patients
Authors: Kaplan H. G. , Malmgren J. A. , Atwood M. K. 
Published: March 2020

21003 Background: Adjuvant trastuzumab for Her2/neu (Her2) positive breast cancer (BC) is now standard treatment. We describe hormone receptor (HR)/Her2/neu defined phenotypic BC subgroups and evaluate recurrence risk prior to widespread use of adjuvant trastuzumab. Methods: A prospective cohort of patients at our institution diagnosed with primary BC between 1998 and 2003 were categorized by HR and Her2 status into ER+/PR+/Her2- (HR+/Her2-) (N=1114), ER+/PR+/Her2+ (TP) (N=134), ER-/PR-/Her2- (TN) (N=176), and ER-/PR-/Her2+ (HR-/Her2+) (N=91) (n= 1550). Patients with discordant ER/PR status (n=262) or equivocal IHC Her2 results were excluded (n=179). Clinical variables including age, race, TNM stage, histologic type and detection method were chart abstracted and vital and disease status were updated annually. The endpoint was disease recurrence; local, regional, distant, or combination. Average length of follow up was 7 years and relapse free survival (RFS) was calculated using Kaplan-Meier procedures with Cox proportional hazards modeling for risk and 95% confidence intervals (CI). Results: Mean patient age at diagnosis was 57, ranging from 21–94 years. Compared to HR+/Her2- and TP patients, TN and HR-/Her2+ patients were significantly more likely to be younger, higher TNM stage, higher histologic grade and patient vs. mammography detected. Disease recurrence was 24% in HR-/Her2+ patients, 16% in TN patients, 8.4% in TP patients, and 3.3% in HR+/Her2- patients (Pearson chi square = 101.56, p<.001). Excluding TNM stage IV patients (n=35), RFS at five years was in rank order HR+/Her2- (95%), TP (89%), TN (84%), HR-/Her2+ (76%) (log rank test = 53.14, p<.001). When adjuvant trastuzumab treated patients (n=34) were removed from the analysis the 5 year RFS only changed in the HR-/Her2+ group to 73%. In a model adjusted for age, race, menopause, TNM stage and treatment using HR+/Her2- patients as the reference group, recurrence risk was 1.98 for TP (95% CI = 1.02 to 3.84), 2.32 for TN (95% CI = 1.32 to 4.08), and 4.25 for HR-/Her2+ patients (95% CI = 2.33, 7.75). Conclusions: All three subgroups had significantly worse RFS compared to HR+/Her2- patients. Even though TN and HR-/Her2+ share many poor prognostic characteristics, HR- /Her2+ BC had the highest risk of recurrence. No significant financial relationships to disclose.
Livin, a regulator of apoptosis protein, is deregulated in melanoma and serves as an independent prognostic factor—a study of 114 melanoma patients
Authors: Lazar I. 
Published: March 2020

21006 Background: Inhibitor of Apoptosis Proteins (IAP) family members inhibit apoptosis mainly by direct binding and inhibition of caspases. We previously identified the IAP Livin and demonstrated that following strong apoptotic stimuli the protein was cleaved by effector caspases to produce a truncated form with paradoxical pro-apoptotic activity. We also demonstrated that Livin is overexpressed in melanoma (M) and plays a role in chemoresistance and survival. More recently we identified synonymous single nucleotide polymorphism (SNP) in Livin at position 528(C/T) that determines expression levels of Livin protein. We found that Livin is expressed in a monoalleic manner. Normal heterozygous samples express the 528T mRNA allele and the Livin protein is not expressed. The monoallelic regulation is lost in metastatic M and the Livin protein is expressed. Methods: This study included 114 M patients that were grouped into clinical categories according to prognosis. Correlation between Livin expression and clinical parameters was examined using ANOVA, chi-square test and Kaplan-Mayer curves. Results: We found that in primary cultures from 114 M patients high, low and absence of Livin protein expression were associated with the T/C, CC and TT genotypes, respectively, at the 528(C/T) polymorphic site. Correlation of Livin expression with overall survival was significant: high expression of the Livin protein was associated with bad prognosis; survival in patients with medium expression of Livin was significantly longer compared with those without livin expression For 23 patients samples were obtained both at diagnosis and upon disease progression. All 23 first tumor sample did not express the Livin protein. Remarkably, Livin was expressed in second tumor samples from 9 of the 23 patients.and was associated with poor prognosis. Conclusions: We found that Livin expression is an independent prognosis factor in malignant M. furthermore, we describe a direct correlation between the level of Livin protein expression and survival of M patients. We also provide evidence for a novel mechanism associating synonymous SNP with control over protein expression and its deregulation during tumor progression. No significant financial relationships to disclose.
registHER: Patient characteristics, treatment patterns, and preliminary outcomes in patients with HER2-positive (HER2+), hormone receptor-positive (HR+) metastatic breast cancer (MBC)
Authors: Yardley D. A. , Kaufman P. A. , Mayer M. , Ulcickas Yood M. , Tan-Chiu E. , Brufsky A. M. , Rugo H. S. , Tripathy D. , Paik S. , Brammer M. G. 
Published: March 2020

21007 Background: Approximately 50% of HER2+ breast cancers are HR+, however, the interaction between HER2 and HR is not completely understood. Patients with HR+/HER2+ or HR-/HER2+ tumors treated with trastuzumab + chemotherapy (CT) achieve similar clinical benefit. Retrospective analyses suggest that HER2+ tumors are resistant to hormone therapy (HT), particularly anti-estrogens, possibly due to estrogen receptor /HER2 interactions and quantitatively lower HR expression in HER2+/HR+ tumors. Conducting randomized clinical trials in HER2+/HR+ MBC is challenging given the small patient population. Methods: registHER is a prospective observational study of approximately 1000 patients with newly diagnosed (<6 months) HER2+ MBC treated in community or academic settings. Baseline characteristics and treatment patterns in patients with HR+ vs HR-, HER2+ MBC receiving first-line therapy were studied in this analysis. The influence of adjuvant HT on disease-free intervals (DFI) from time of diagnosis and MBC treatment selection in patients with HR+/HER2+ tumors was examined. Results: Of 976 patients with HER2+ MBC and recorded tumor HR status, those with HR+ MBC (54.9%) tended to be white (81.7% vs 77.0%), were more likely to have bone only metastases (18.1% vs 6.4%), less likely to have CNS metastases (2.8% vs 8.2%), and have fewer metastatic sites at diagnosis (49.1% vs 43.2%) than those with HR- MBC. Of patients with HR+ MBC, who were stage I- III at initial diagnosis, 51.3% received adjuvant HT, of which 73.2% received tamoxifen. Median DFI was 48.8 vs 29.4 mo for patients receiving tamoxifen vs an aromatase inhibitor. First-line MBC treatment regimens included: HT only (13.8%); HT + trastuzumab (8.4%); HT + trastuzumab + CT (6.2%); trastuzumab only (6.0%); CT only (11.0%); trastuzumab + CT (53.5%). Analyses of progression-free survival by HR status and first-line treatments (HT only, trastuzumab ± HT or ± CT), are ongoing and will be described. Conclusions: registHER represents the largest dataset of patients with HER2+/HR+ MBC and provides a unique opportunity to characterize treatment patterns, efficacy and safety, and the natural history of this subset of breast cancer patients. [Table: see text]
Correlation between the expression of hypoxia-inducible factor-1α or histone deacetylase 1/metastasis-associated protein 1 complex and poor prognosis on human pancreatic carcinoma
Authors: Miyake K. , Shimada M. , Imura S. , Sugimoto K. , Batmunkh E. , Ikemoto T. , Morine Y. , Yoshizumi T. 
Published: March 2020

21012 Background: Hypoxia-inducible factor-1a (HIF-1a) is a transcription factor that plays an important role in tumor growth and metastasis by regulating energy metabolism and inducing angiogenesis. Inhibition of histone deacetylase shows a marked inhibition of HIF-1a expression, however, the association between HIF-1a and histone deacetylase 1 (HDAC1) / metastasis-associated protein 1 (MTA1) is not fully understood. Here, we explored the involvement of HIF-1a and HDAC1/MTA1 in human pancreatic carcinoma. Methods: HIF-1a, HDAC1 and MTA1 expressions were detected by immunohistochemistry in surgical specimens obtained from 39 patients with pancreatic carcinoma. The correlations between the expression of HIF-1a, HDAC1 or MTA1 and clinical features, and the prognosis of patients with pancreatic carcinoma were then analyzed. Results: HIF-1a, HDAC1 and MTA1 positive stainings were found in 16 of 39 cases (41%), 22 of 39 cases (56%) and 12 of 39 cases (31%), respectively. There was no correlation between HIF-1a, HDAC1 or MTA1 expression levels and any of the clinical parameters examined. The five-year survival rate for pancreatic carcinoma patients with HIF-1a and HDAC1 positive stainings were significantly lower than for those patients with HIF-1a and HDAC1 negative stainings (P = 0.0243 and 0.0433). The MTA1 positive stainings group did not have a significantly worse prognosis than the MTA1 negative stainings group (P = 0.9694). In addition, the five-year survival rate for the HDAC1/MTA1 positive stainings group was statistically significantly worse than for the other groups (P = 0.0386). Conclusions: These results suggest that HIF-1a expression may be regulated through HDAC1/MTA1, which is associated with a poor prognosis on human pancreatic carcinoma, and indicate that HIF-1a and HDAC1/MTA1 is a promising therapeutic target in pancreatic carcinoma treatment. No significant financial relationships to disclose.