bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of newly developed platinum complexes against osteosarcoma, bone-targeting platinum, and proteasome inhibitory platinum.
Authors: Igarashi Kentaro , Yamamoto Norio , Shirai Toshiharu , Hayashi Katsuhiro , Nishida Hideji , Takeuchi Akihiko , Tanzawa Yoshikazu , Kimura Hiroaki , Miwa Shinji , Inatani Hiroyuki , Shimozaki Shingo , Odani Akira , Tsuchiya Hiroyuki 
Published: March 2020

10075 Background: Cisplatin is one of the most effective anti-cancer drugs available for the treatment of human solid tumors including osteosarcoma. As we had already reported, we have utilized caffeine in our chemotherapy protocol. And we achieved excellent clinical results. But effectiveness of cisplatin has been limited by side effects, and resistance. Here we developed two novel platinum compounds. 3Pt is trinuclear platinum complex bearing geminal bisphosphonate moieties, 1Pt is mononuclear platinum complex which has proteasome inhibitory activity. We performed comparative studies of our novel platinum compounds with osteosarcoma. Methods: Two novel platinum complexes were synthesized by Prof. Odani at school of pharmaceutical sciences of our university and cisplatin and caffeine were obtained from constructor. Three cell lines (MG63, 143B, and LM8) were used. Cell survival after a 72 hrs exposure to these compounds was assessed by WST-8 assay, and IC50 value was calculated for each compound. Apoptosis was assessed by DNA fragmentation and Annexin V-FITC/propidium iodine assay. Results: Each compound strongly caused concentration-dependent cytocidal effect. IC50 value of trinuclear compound is superior to cisplatin, and both complexes showed caffeine potentiation. Apoptosis induction and acetylation of histon H2AX were observed. In vivo, 1Pt showed almost same, 3Pt showed strong antitumor effect compared to cisplatin. Conclusions: Two novel platinum compounds that we developed showed strong ant-tumor effect in osteosarcoma in vitro and in vivo. As bisphosphonate has high affinity to calcium ions, 3Pt targets bone tissue and expected to reduce side effects at extraskeletal sites and to overcome the drug resistance. Proteasome inhibitory platinum compound has never been reported before, we will investigate its anti-tumor mechanism precisely.
EURAMOS-1 study: Recruitment, characteristics, and initial treatment of more than 2,000 patients (pts) with high-grade osteosarcoma.
Authors: Whelan Jeremy , Hook Jane , Bielack Stefan S. , Marina Neyssa , Smeland Sigbjorn , Jovic Gordana , Krailo Mark D. , Kühne Thomas , Eriksson Mikael , Butterfass-Bahloul Trude , Teot Lisa A. , Kager Leo , Gelderblom Hans , Sundby Hall Kirsten , Hogendoorn Pancras C. W. , Sydes Matthew Robert , Bernstein Mark L. ,   EURAMOS
Published: March 2020

10081 Background: EURAMOS is a transAtlantic collaboration formed to improve survival in osteosarcoma by conducting RCTs in a clinically relevant timeframe. EURAMOS-1, the largest study conducted in this rare cancer, has completed accrual. It includes two randomized comparisons investigating treatment optimization on the basis of histological response to neoadjuvant chemotherapy. Methods: Pts ≤40yrs with resectable, high grade extremity or axial osteosarcoma were eligible for registration. All were planned for 2 cycles of neoadjuvant methotrexate, doxorubicin, cisplatin (MAP) then surgical resection of the primary tumour. Pts with complete macroscopic resection and no disease progression were eligible for randomization: [i] “good responders”, <10% viable tumor, MAP +/- 18m maintenance pegylated interferon; [ii] “poor responders”, ≥10% viable tumor, MAP vs MAPIE (MAP + ifosfamide, etoposide). Target sample size was ~1,260 pts randomized requiring ~2000 pts registered estimating a non-randomization rate of 30-35%. Results: From Apr 2005 to Dec 2011, 2,260 pts were registered and 1,332 randomized from 17 countries, 320 sites: median age 14yrs (IQR 11-17); 59% male; 50% femoral site; 23% definite/possible metastases; 92% conventional osteosarcoma (diagnostic biopsy). At Sep 2011 planned IDMC review, neoadjuvant treatment data were known for 2024 pts; 1926 (95%) completed 2 cycles pre-operative MAP with 3 treatment related deaths. 59% pts were randomized; non-consent was the most frequent reason for non-randomization. Relative to expected age-specific incidence (UK NCIN 1979-2007) there was apparent under recruiting of older pts: females ≥15yrs and all pts >19yrs, with greater under recruitment of females than males <35yrs. Pts 20-29yrs were less likely to be randomized than those aged 5-19 and ≥30 yrs, 52% vs 57-62%. Conclusions: EURAMOS-1 demonstrates that large RCTs are feasible in rare cancers with inter-continental collaboration and is a model for future trials. Neoadjuvant MAP was safe in a geographically diverse cohort. Improving clinical trial access and randomization rates for young people is still required. Multiple funders detailed at bit.ly/ymUR9w.
A retrospective safety analysis of adult patients treated with high-dose methotrexate for osteosarcoma in Stockholm, Sweden.
Authors: Alm Daniel , Linder Stragliotto Christina , Folin Annika , Bergh Jonas , Foukakis Theodoros 
Published: March 2020

10083 Background: Patients with osteosarcoma are routinely treated with pre- and post-operative chemotherapy that includes high-dose methotrexate. The treatment is associated with a risk of severe renal and hepatic toxicity. Methods: All patients with osteosarcoma that had received at least one cycle of high-dose methotrexate at the adult oncology department, Karolinska University Hospital were retrospectively identified. Treatment toxicity, including hematologic, renal, hepatic toxicity, infections and oral mucositis were registered and graded according to CTCAE v 4.0. A possible relationship between methotrexate blood concentration and toxicity was investigated. Results: Sixteen eligible patients that had received a total of 103 cycles of high-dose methotrexate were identified. Ten patients experienced a severe hepatic toxicity, (Grade 3, n=5 and Grade 4, n=5). Grade 3 renal toxicity was seen in one patient and although reversible, it led to treatment interruption. Reversible, grade 2 elavation of serum creatinine occured in 5 cases. Four grade 3 infections were seen in 2 patients and 8 patients had at least one occurrence of Grade 3 oral mucositis. Thrombocytopenia was a common event (Grade 3, n=5 and Grade 4, n=2) but no severe bleeding complications were observed. One patient died as a result of multi-organ failure two days after methotrexate administration. Methotrexate blood concentration at 24 hours from administration could predict for renal toxicity (p<0.005, by chi-square test), but not for other toxicity. Conclusions: High-dose methotrexate in adult patients with osteosarcoma was frequently associated with severe, however reversible toxicity.
Early assessment of MCV to predict clinical outcome in patients with advanced gastrointestinal stromal tumors (GIST) receiving imatinib.
Authors: Constantinidou Anastasia , Krikelis Dimitrios , Olmos David , Scurr Michelle R. , Jones Robin Lewis , Ashley Sue , Judson Ian Robert 
Published: March 2020

10086 Background: In patients with advanced GIST, imatinib trough levels have been associated with a lower rate of clinical benefit. Anecdotal observations have suggested that commencing treatment with imatinib may be associated with an increase in red blood cell size as measured by MCV and MCH, indicating the effect of imatinib on KIT signalling in the bone marrow. Methods: In this retrospective review we examined a possible connection between changes in MCV and MCH after the first 3 months (mo) of treatment with imatinib and progression-free survival (PFS). Data for patients with inoperable advanced or metastatic GIST treated between 2000 and 2011 were available for analysis. Patients were categorised in quartiles according to the distribution of the percentage of change of MCV and MCH between start of imatinib (baseline) and 3 (+/- 0.5) mo (ratio %=MCV change at 3 mo/MCV at baseline). PFS curves were plotted using the Kaplan-Meier method and compared using the log rank test. Results: One hundred and thirty patients were eligible for analysis and the demographics were: male:female 84:46, median age at presentation: 60.5 (23.5-86.5) years, commonest primary tumour sites: stomach (72/130) and small bowel (44/130), commonest metastatic site: liver (76/130). In the patients with a 10% or over increase in MCV (p75-p100) at the 3 mo (+/-0.5) time point a significantly longer PFS was observed compared to those with a smaller magnitude of change (PFS of 37.1 mo vs 24.3 mo, p=0.032). A similar trend although not statistically significant was observed in patients with MCH of 15% or over (p75-p100) with PFS of 34.0 mo vs 25.8 (p=0.125). The two parameters (MCV and MCH) showed a high correlation of percentage change (r2=0.85). The patients with a 10% MCV increase and /or 15% MCH increase (total=40) showed a significantly longer PFS (34.0 mo) compared to those with lower percentage change (PFS= 24.3) p=0.035. Conclusions: Simple laboratory parameters may be indicators of imatinib pharmacokinetics and may therefore be used as surrogate markers of clinical outcome. Larger prospective studies are required to confirm the results of this study.
Final analysis of phase II study of EZN-2208 (PEG-SN38) in metastatic breast cancer (MBC).
Authors: Osborne Cynthia R. C. , O'Shaughnessy Joyce , Holmes Frankie Ann , Kim Hyun Sue , Kocs Darren M. , Steinberg Michael S. , Richards Paul D. , Vukelja Svetislava J. , Berkowitz Noah C. , Buchbinder Aby 
Published: March 2020

1017 Background: EZN-2208 is a water-soluble PEGylated conjugate of SN38. EZN-2208 results in prolonged exposure of tumors to SN38 via preferential accumulation of EZN-2208 in the tumor and prolonged release of SN38. These data represent the final analysis of our study evaluating EZN-2208 in MBC. Methods: EZN-2208 9 mg/m2 (SN38 equivalents) was delivered as a 60-minute IV infusion, weekly for 3 wks in 4‑wk cycles. The primary objective was to determine the overall response rate (RR) in female patients with metastatic breast cancer (MBC) who had received prior adjuvant or metastatic therapy with either 1) anthracycline and taxane (AT) or 2) anthracycline, taxane, and capecitabine (ATX). Secondary objectives included evaluation of RR based on tumor receptor status, duration of response, progression-free survival (PFS), overall survival (OS), and safety. Results: Patients with MBC (n=164) were treated with a median (range) of 3.3 (0.3-22) cycles of EZN-2208. The objective response rate (RR) was 20% for AT and 9% for ATX. The clinical benefit rate (CBR=%CR + %PR + %SD ≥6 months) was 41% and 27% in patients in the AT and ATX cohorts, respectively. The RR and CBR among ER+ patients were 11% (10/91 pts) and 41.8% (38/91 pts). In patients who progressed during or within 30 days of prior platinum-containing regimens (Platinum Progressors), the CBR was 20% (8/40 pts). Among triple negative breast cancer (TNBC) patients, the RR and CBR were 22.5% (11/49 pts) and 36.7% (18/49 pts). For TNBC, Platinum Progressors, the CBR was 26.1% (6/23 pts). Overall, most common reported drug-related adverse events were diarrhea, nausea and neutropenia. Conclusions: EZN-2208 has notable activity in patients with previously treated MBC and appears to be an active agent for treatment of TNBC. Patients with TNBC, who had been previously treated with a platinum-based regimen, also derive clinical benefit from EZN-2208. The safety profile of EZN-2208 is acceptable with good tolerability in most patients. Further evaluation of EZN-2208 in MBC in general and TNBC in particular is warranted.
10-year update of E2197: Phase III doxorubicin/docetaxel (AT) versus doxorubicin/cyclophosphamide (AC) adjuvant treatment of LN+ and high-risk LN- breast cancer and the comparison of the prognostic utility of the 21-gene recurrence score (RS) with clinicopathologic features.
Authors: Sparano Joseph A. , O'Neill Anne , Gray Robert James , Perez Edith A. , Shulman Lawrence N. , Martino Silvana , Badve Sunil S. , Baehner Frederick L. , Childs Barrett H , Yoshizawa Carl N. , Rowley Steve , Davidson Nancy E. , Shak Steven , Goldstein Lori J. 
Published: March 2020

1021 Background: At 5 years, AT did not improve disease free survival or overall survival and RS was a more accurate predictor of relapse than standard clinicopathologic characteristics for patients with hormone receptor (HR) positive tumors. Methods: A Phase III Intergroup trial tested adjuvant AT vs. AC. Women with 1-3 N + or N - and T-size > 1cm were randomized to 4 cycles of AT (60 mg/m2/60 mg/ m2) or AC (60 mg/m2/600 mg/m2) q 3 wk x 4. Patients(pts) with ER + and/ or PR + tumors received tam for 5 yrs. Pts were stratified by nodal, HR (ER+ PR+, ER+PR-, ER-PR+, ER-PR-, ER/PR unk) and menopausal status. The primary endpoint was DFS. A sample of 465 pts with HR + breast cancer with 0 to 3 positive axillary nodes who did (N =116) or did not have a recurrence had tumor tissue evaluated using the 21- gene assay. Grade and HR expression were evaluated locally and centrally. Results: 2952 pts were randomized between 7/30/98 and 1/21/00. 2883 were eligible and analyzable. Arms were balanced for age, HR, menopause, nodes, surgery, grade and T-size: median age 51; 64% ER +; 65% LN-; grade: 10% low, 38% int., 46% high; and median T-size - 2.0 cm. At a median follow-up of 11.5 years the DFS/OS results are shown in the table below. RS was a highly significant predictor of recurrence including node negative and node positive disease (P < .0001) and predicted recurrence more accurately than clinical variables. Conclusions: At 11.5 yrs. median follow-up, there remains no difference in DFS or OS, although there continue to be fewer events in the AT arm in the prespecified ER/PR negative subgroup. At 10 years, the RS continues to be a more accurate predictor of relapse than standard clinical features. [Table: see text]
Breast cancer multifocality-multicentricity and locoregional recurrance.
Authors: Lei Xiudong , Lynch Siobhan P. , Hsu Limin , Meric-Bernstam Funda , Buchholz Thomas A. , Zhang Hong , Hortobagyi Gabriel N. , Valero Vicente , Gonzalez-Angulo Ana M. 
Published: March 2020

1029 Background: The impact of multifocality (MF) and multicentricity (MC) on locoregional (LR) control for invasive breast cancer, and the optimal local treatment strategy for these tumors, is unknown. In particular, there is disagreement in the literature regarding the use of Breast Conservation Therapy (BCT). We evaluated a large single institution cohort of MF and MC breast cancers to determine if they had inferior LR control rate when compared to their unifocal counterparts. Methods: MF and MC were defined pathologically as more than one lesion in the same quadrant and more than one lesion in separate quadrants, respectively. Patients were categorized by presence or absence of MF or MC disease and by the LR treatment modality received – BCT (n=256), mastectomy alone (n=466), or mastectomy plus post-mastectomy radiation therapy (n=184). 10 patients who underwent BCT for MC disease against physician advice were excluded. MF and MC tumors were analyzed both as a group and as separate entities. Kaplan-Meier product limit method was used to calculate 5-year LR control rate. Cox proportional hazards models were fit to determine independent associations of MF/MC disease with LR control. Results: Median follow up was 52 months. Out of 3722 patients with stage I-III disease who did not receive neoadjuvant chemotherapy, 906 (24%) had MF (n=673) or MC (n=233) disease. 5-year rate of LR control rate was 99% in the MF group, 96% in the MC group, and 98% in the unifocal group, (P = 0.44). Subset analysis revealed no statistical difference in LR control regardless of the type of LR treatment, (P = 0.67 in the BCT group, P = 0.37 in the mastectomy alone group, and P = 0.29 in the mastectomy plus post-mastectomy radiation therapy group). There were 21 in-breast recurrences after BCT (8.2%). After controlling for other risk factors, MF and MC did not have an independent impact on LR control rate. Conclusions: MF and MC disease are not independent risk factors for LR recurrence. Patients with MF and MC breast cancer had similar rates of LR control to their unifocal counterparts, regardless of LR treatment modality. Our data suggest that BCT is a safe option for patients with MF tumors and that MF or MC disease alone is not an indication for post-mastectomy radiation therapy.
Pathologic complete response rates observed in women with locally advanced and inflammatory breast cancer receiving neoadjuvant carboplatin and paclitaxel.
Authors: Shinde Arvind Manohar , Yim John H , Kruper Laura , Vito Courtney , Chen Steven L. , Paz Isaac Benjamin , Luu Thehang H. , Tagawa Tomoko , Yu Kim Wai , Wilczynski Sharon , Shaw Sally , Vora Lalit , Park Jinha Mark , Somlo George 
Published: March 2020

1035 Background: Pathologic complete response (pCR) following neoadjuvant chemotherapy (NCT) is predictive of outcome in patients with locally advanced breast cancer (LABC). A non-anthracycline containing NCT regimen (Sikov et al. JCO 10/09) may reduce the risk of associated secondary hematologic malignancies and cardiac toxicity while yielding comparable pCR rates. Methods: A retrospective review of all LABC and inflammatory breast cancer (IBC) cases treated from 4/09 to 12/11 with a NCT regimen of carboplatin (AUC of 6, administered on day 1) and paclitaxel 80 mg/m2 (given weekly on a 21-28 day cycle) was conducted at the City of Hope Cancer Center (COHCC). Pts with HER2+ (HER+) tumors received trastuzumab during the NCT treatment. All pCRs (pCR of primary only – "pCR1°"; pCR of primary and lymph nodes – "pCR-All") were determined by a COHCC pathologist based on final surgical specimens. Results: 38 pts were identified, with 39 breast primaries; 18% had IBC, 62% of LABCs/IBCs were hormone receptor positive (HR+), 46% of tumors were HER2+, and 26% were triple negative. Median age was 51 [27-63]. All pts completed the planned number of cycles. Four pts required carboplatin dose reductions, 4 pts required dose reductions in paclitaxel, 3 pts had paclitaxel changed to nab-paclitaxel, and 17 pts required G-CSF to complete their planned treatment. One pt receiving trastuzumab experienced asymptomatic LVEF decline below normal limits. Conclusions: A non-anthracycline-containing NCT regimen of carboplatin/paclitaxel was well tolerated and resulted in high pCRs when given to triple negative (HER2-/HR-) pts, and HER2+ pts, especially with HER2+HR- subtypes. The findings warrant further studies of this regimen in a prospective randomized setting. [Table: see text]
Estrogen receptor alpha (ESR1) gene amplification status and clinical outcome in tamoxifen-treated postmenopausal patients with endocrine-responsive early breast cancer: An analysis of the prospective ABCSG-6 trial.
Authors: Singer Christian F. , Holst Frederik , Steurer Stefan , Burandt E C , Samonigg Hellmut , Jakesz Raimund , Stoeger Herbert , Greil Richard , Sauter Guido , Filipits Martin , Simon Ronald , Gnant Michael ,   ABCSG
Published: March 2020

10501 Background: Estrogen receptor alpha (ERα) expression is a prognostic parameter in breast cancer and predicts response to endocrine therapy. One of the factors important for protein expression is amplification of its encoding gene ESR1. We have investigated the value of ESR1 amplification in predicting the long-term clinical outcome in tamoxifen-treated postmenopausal women with endocrine-responsive breast cancer. Methods: 394 patients who had been randomized into the tamoxifen-only arm of the prospectively designed endocrine ABCSG-06 trial and in whom FFPE tumor tissue was available were included in this analysis. Immunohistochemical ERα expression was evaluated both locally and centrally using the Allred score, while ESR1 gene amplification status was evaluated by FISH analysis using the ESR1/CEN6 ratio. Results: ESR1 copy number gains were detected in 187 of 394 (47%) tumor specimen and was associated with favorable clinical outcome. At a median follow-up of 10 years, women with intratumoral ESR1 copy number gains had a significantly longer distant recurrence-free survival (adjusted HR for relapse 0.48; 95% CI 0.28-0.83; p=0.009) and breast cancer-specific survival (adjusted HR for death 0.46; CI 0.46-0.71; p=0.006) when compared to women with normal ESR1 copy numbers. Immunohistochemical ERα protein expression, evaluated by Allred score, was significantly correlated with ESR1 copy number alterations (p<0.0001; Chi-Square test), but did itself not allow to discriminate between patients with poor and good prognosis. Conclusions: ESR1 amplification status is an independent and powerful predictor for long-term distant recurrence-free and breast cancer-specific survival in postmenopausal women with endocrine-responsive early-stage breast cancer who received 5 years of tamoxifen.
Next-generation RNA sequencing reveals transcriptomic changes after brief exposure to preoperative nab-paclitaxel, bevacizumab, and trastuzumab.
Authors: Varadan Vinay , Kamalakaran Sitharthan , Janevski Angel , Banerjee Nila , Lezon-Geyda Kimberly , Bossuyt Veerle , Flowers-Poole Dava , Sinclair Natalie Faye , Abu-Khalaf Maysa M. , Sikov William M. , Dimitrova Nevenka , Harris Lyndsay 
Published: March 2020

10508 Background: Identification of differentially expressed transcripts after brief exposure to preoperative therapy can help determine likely response markers. We quantify and compare differential gene and isoform expression using RNA-seq on patient samples with 10 day exposure to one dose of trastuzumab, bevacizumab or nab-paclitaxel. Methods: We sequenced transcriptomes of 23 pairs of core biopsy RNA from breast cancers pre/post 10 day exposure to therapy. Paired-end sequencing was done on the Illumina GAII platform using amplified total RNA with 74bp read length, yielding data on transcript abundance for a total of 22,160 genes and 34,449 transcripts. Differential expression of transcripts between pre/post samples was estimated assuming Poisson-distributed read-counts, followed by multiple testing correction and enrichment analysis of 185 KEGG pathways. Results: PAM50-based clustering showed individual samples cluster together, demonstrating that tumor subtypes do not change over the 10-day treatment (SABCS 2011). We identified genes that were significantly differentially expressed (p<0.05; FDR<0.1) in at least 60% of samples within each therapy arm: 780 genes in trastuzumab, 302 in bevacizumab, and 176 in nab-paclitaxel. Surprisingly, only THAP11 and TINF2 were common amongst them. THAP11 is involved in stem cell maintenance and TINF2 is important for regulation of telomere length. Immune system and metabolism-related pathways were commonly affected (p<0.05) across all arms. The bevacizumab arm showed significant down-regulation of angiogenesis-associated genes: ESM1 and VEGFR2 in > 80% of samples. The nab-paclitaxel arm exhibited changes in TGF-beta signaling, Nod-like receptor and Wnt signaling. The trastuzumab arm exhibited consistent alteration of ErbB2 and mTOR pathways, with SOX11 and TOP2B downregulated in every sample. Conclusions: This is the first study to compare gene expression with brief exposure across therapies using RNA-seq technology. The unique aspects of transcriptional response to each treatment underscore the need for specific markers of therapeutic response to nab-paclitaxel, bevacizumab and trastuzumab.