bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-scale X-ray tomography and machine learning algorithms to study MoNi4 electrocatalysts anchored on MoO2 cuboids aligned on Ni foam
Authors: Topal Emre , Liao Zhongquan , Löffler Markus , Gluch Jürgen , Zhang Jian , Feng Xinliang , Zschech Ehrenfried
Published: March 2020

For a systematic materials selection and for design and synthesis of systems for electrochemical energy conversion with specific properties, it is essential to clarify the general relationship between physicochemical properties of the materials and the electrocatalytic performance and stability of the system or device. The design of highly performant and durable 3D electrocatalysts requires an optimized hierarchical morphology and surface structures with high activity. A systematic approach to determine the 3D morphology of hierarchically structured materials with high accuracy is described, based on a multi-scale X-ray tomography study. It is applied to a novel transition-metal-based materials system: MoNi4 electrocatalysts anchored on MoO2 cuboids aligned on Ni foam. The high accuracy of 3D morphological data of the formed micro- and nanostructures is ensured by applying machine learning algorithms for the correction of imaging artefacts of high-resolution X-ray tomography such as beam hardening and for the compensation of experimental inaccuracies such as misalignment and motions of samples and tool components. This novel approach is validated based on the comparison of virtual cross-sections through the MoNi4 electrocatalysts and real FIB cross-sections imaged in the SEM.
Plant food anti-nutritional factors and their reduction strategies: an overview
Authors: Samtiya Mrinal , Aluko Rotimi E. , Dhewa Tejpal
Published: March 2020

Legumes and cereals contain high amounts of macronutrients and micronutrients but also anti-nutritional factors. Major anti-nutritional factors, which are found in edible crops include saponins, tannins, phytic acid, gossypol, lectins, protease inhibitors, amylase inhibitor, and goitrogens. Anti-nutritional factors combine with nutrients and act as the major concern because of reduced nutrient bioavailability. Various other factors like trypsin inhibitors and phytates, which are present mainly in legumes and cereals, reduce the digestibility of proteins and mineral absorption. Anti-nutrients are one of the key factors, which reduce the bioavailability of various components of the cereals and legumes. These factors can cause micronutrient malnutrition and mineral deficiencies. There are various traditional methods and technologies, which can be used to reduce the levels of these anti-nutrient factors. Several processing techniques and methods such as fermentation, germination, debranning, autoclaving, soaking etc. are used to reduce the anti-nutrient contents in foods. By using various methods alone or in combinations, it is possible to reduce the level of anti-nutrients in foods. This review is focused on different types of anti-nutrients, and possible processing methods that can be used to reduce the level of these factors in food products.

Graphical abstract

A brief overview of beneficial effects of anti-nutrients and reduction strategy.
Passive coherent dual-comb spectroscopy based on optical-optical modulation with free running lasers
Authors: Gu Chenglin , Zuo Zhong , Luo Daping , Deng Zejiang , Liu Yang , Hu Minglie , Li Wenxue
Published: March 2020

Dual-comb spectroscopy is a powerful spectroscopic tool with ultrahigh-resolution, high-sensitivity properties, which opens up opportunities for the parallel detection of multi-species molecules. However, in its conventional form, highly stable laser combs with sophisticated control systems are required to perform dual-comb spectroscopy. Here, a passive mutually coherent dual-comb spectroscopy system via an optical-optical modulation method is addressed, where all fast phase-locking electronics are retired. Without post computer-based phase-correction, a high degree of mutual coherence between the two combs with a relative comb-tooth linewidth of 10 mHz is achieved, corresponding to a coherent time of 100 s. To demonstrate the performance and versatility of the system, the dual comb spectrometer is applied to record the mode-resolved single molecular spectra as well as parallel detected spectra of mixed gases including CO2, CO and C2H2 that well agree with the established spectral parameters. Our technique exhibits flexible wavelength tuning capability in the near-infrared region and can be potentially extended to the mid-infrared region for more applications.
OncoMX: A Knowledgebase for Exploring Cancer Biomarkers in the Context of Related Cancer and Healthy Data
Authors: Dingerdissen Hayley M. , Bastian Frederic , Vijay-Shanker K. , Robinson-Rechavi Marc , Bell Amanda , Gogate Nikhita , Gupta Samir , Holmes Evan , Kahsay Robel , Keeney Jonathon , Kincaid Heather , King Charles Hadley , Liu David , Crichton Daniel J. , Mazumder Raja
Published: March 2020

PURPOSE

The purpose of OncoMX 1 knowledgebase development was to integrate cancer biomarker and relevant data types into a meta-portal, enabling the research of cancer biomarkers side by side with other pertinent multidimensional data types.

METHODS

Cancer mutation, cancer differential expression, cancer expression specificity, healthy gene expression from human and mouse, literature mining for cancer mutation and cancer expression, and biomarker data were integrated, unified by relevant biomedical ontologies, and subjected to rule-based automated quality control before ingestion into the database.

RESULTS

OncoMX provides integrated data encompassing more than 1,000 unique biomarker entries (939 from the Early Detection Research Network [EDRN] and 96 from the US Food and Drug Administration) mapped to 20,576 genes that have either mutation or differential expression in cancer. Sentences reporting mutation or differential expression in cancer were extracted from more than 40,000 publications, and healthy gene expression data with samples mapped to organs are available for both human genes and their mouse orthologs.

CONCLUSION

OncoMX has prioritized user feedback as a means of guiding development priorities. By mapping to and integrating data from several cancer genomics resources, it is hoped that OncoMX will foster a dynamic engagement between bioinformaticians and cancer biomarker researchers. This engagement should culminate in a community resource that substantially improves the ability and efficiency of exploring cancer biomarker data and related multidimensional data.
Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors (GIST): A meta-analyis based on 1,640 patients (pts)
Authors: Van Glabbeke M. M. , Owzar K. , Rankin C. , Simes J. , Crowley J. ,   GIST Meta-analysis Group (MetaGIST)
Published: March 2020

10004

Background: The MetaGIST project aims to further explore the data of the two randomized studies comparing two doses of imatinib (400 mg od vs bid) for the treatment of GIST: EORTC/ISG/AGITG 62005 (EU-AUS) and SWOG/CALGB/NCI-C/ECOG/ICAS S0033 (US-CDN). Methods: End-points were progression free (PFS) and overall survival (OS). Investigated cofactors included age, sex, performance status (PS), primary tumor site, time from diagnosis, prior therapies, baseline biology, and KIT / PDGFRa mutations for a subset of 772 pts (47%). The logrank test (stratified) and the Cox multivariate model with interaction terms were used for the analysis. Results: The median follow-up was 45 months. A small but significant PFS advantage was documented for the high dose arm, consistently in both studies. OS was identical in the two arms (see table ). Males and pts with a poor PS, GIST from bowel origin, baseline low hemoglobin and high neutrophils counts (ANC) had a significant worse PFS (multivariate analysis); these factors are consistent between studies. In pts analyzed for mutations, wild type pts (HR=1.56), KIT exon 9 mutants (HR=2.17) and pts with other mutations (HR=2.56) had a worse prognosis than KIT exon 11 mutants (univariate analysis); all 3 factors remained in the multivariate model. The US-CDN study included significantly (P<0.01) more females, more GIST from bowel or stomach origin, less KIT exon 9 mutants and pts with a lower baseline ANC. In KIT exon 9 mutants, the PFS advantage with high dose imatinib previously reported in the EU- AUS study was not confirmed in the US-CDN dataset, but remains significant in the pooled dataset. The interaction between dose effect on PFS and prognostic factors was siginficant for KIT exon 9 mutations but not for other factors. Conclusions: This analysis confirms a small PFS advantage of high dose imatinib, essentially amongst KIT exon 9 mutants, but no OS advantage. Heterogeneity between the two studies is being further explored.

[Table: see text]

[Table: see text]
Regional hyperthermia (RHT) improves response and survival when combined with systemic chemotherapy in the management of locally advanced, high grade soft tissue sarcomas (STS) of the extremities, the body wall and the abdomen: A phase III randomised pros
Authors: Issels R. D. , Lindner L. H. , Wust P. , Hohenberger P. , Jauch K. , Daugaard S. , Mansmann U. , Hiddemann W. , Blay J. , Verweij J.
Published: March 2020

10009

Background: Patients (Pts) with locally advanced, high-grade STS are at significant risk for local failure and for metastasis. We evaluated the ability of RHT to improve the outcome in pts who are treated with neoadjuvant chemotherapy. Methods: Eligibility included pts with STS = 5 cm, grade II/III, deep and extracompartmental, stratified according to site (E = extremity vs. Non-E = body wall and abdomen). Pts were randomly assigned to systemic chemotherapy (etoposide 250 mg/m2; ifosfamide 6 g/m2; adriamycin 50 mg/m2) alone (EIA) or to systemic chemotherapy combined with RHT (EIA + RHT) administered for 4 cycles every 3 weeks both prior and after local aggressive therapy (surgery + radiotherapy), respectively. Primary endpoints were local progression free survival (LPFS) and disease free survival (DFS). Objective (CR + PR) response rate (ORR) evaluated after 4 cycles (EIA vs EIA + RHT) was a secondary endpoint. A total of 340 pts was required to show an improvement in median LPFS of 19.2 mos for EIA + RHT (a=5% type I, 20% type II error). Results: Pts characteristics were well balanced between treatment arms. After median follow-up of 24.9 months (mos) an intention-to-treat analysis showed a significantly superior DFS for pts who received EIA + RHT (n=169) compared to those treated with EIA alone (n=172) (median DFS: 31,7 mos and 16,2 mos; log-rank p=0.003; Hazard ratio=0.65; CI95=0.48- 0.87, p=0.004). The median LPFS was estimated 45,3 mos for EIA + RHT and 23,7 mos for EIA (log-rank p=0.015; Hazard ratio=0.66; CI95=0.48 - 0.90, p=0.01). At 2 years, LPFS rates for E (149 pts) and for Non-E (192 pts) were significantly better for EIA + RHT vs EIA alone (E: 84% vs 64%; Non-E: 57% vs 39%) (p<0.02). The ORR was significantly better for EIA + RHT (28,7%) vs EIA alone (12,6%) (p=0.002). Conclusions: Compared to chemotherapy alone, RHT combined with chemotherapy yields a statistically significant improvement in tumor response , DFS and LPS, in patients with locally advanced, high-grade STS. (Supported by Deutsche Krebshilfe and HGF VH-VI- 140)

[Table: see text]
Non-metastatic Ewing's family tumors: High-dose chemotherapy with stem cell rescue in poor responder patients. Preliminary results of the Italian/Scandinavian ISG/SSG III protocol
Authors: Ferrari S. , Alvegard T. , Luksch R. , Tienghi A. , Hall K. S. , Bernini G. , Brach del Prever A. , Picci P. , Bacci G. , Smeland S.
Published: March 2020

10014

Background: Poor response to induction chemotherapy negatively affects prognosis for Ewing's sarcoma (ES) patients. To improve outcome, high-dose chemotherapy (HDCT) with stem cell rescue was added to conventional chemotherapy in patients poor responders after induction treatment. Methods: Non-metastatic ES patients aged <= 40 years were eligible. All patients received VAC (vincristin 2 mg-doxorubicin 80 mg/m2-cyclofosfamide 1,200 mg/m2) weeks 0 and 6, IVAc (ifosfamide 9g/m2-vincristin 2 mg-actinomycin 2 mg) week 3 and IE (ifosfamide 9g/m2-etoposide 450 mg/m2) week 9 as induction therapy. Poor response was histologically defined as persistence of microfoci of viable tumor cells and radiologically as persistence of soft tissue mass. As maintenance treatment good responders (GR) received three cycles of VAC-IVAc-IE. Poor responders (PR) received VAC (weeks 13,19), IE (week 22), CE (mobilizing cycle, cyclophoshamide 4g/m2, etoposide 600 mg/m2, week 16) and HDCT with BuMel (busulfan 4 mg/kg × 4 days orally and melphalan 140 mg/m2 with stem cell support week 25). Results: Starting from 1999, 296 patients were enrolled with a median age of 15 years (3–40). 54 % of the tumors were located to the extremities and 46% in the axial skeleton. 274 patients underwent local treatment: surgery in 222 (81%) patients (with post operative Rxt in 70), RxT alone in 52 (19%). 10 patients progressed during treatment. No toxic deaths were recorded. Response evalutation was available for 262 patients: 135 (52%) were PR. 116 of them completed protocol treatment and 19 did not receive HDCT (5 poor harvest, 5 medical contraindication, 9 refusal).With a median follow-up of 37 months (1–89) 5-year overall and event-free survival were 74 % and 65.5% respectively. 5-year event-free survival was 71% (95% CI 62–81%) for GR, 68% (95% CI 58–78%) for PR treated with HDCT and 35% (95% CI 10–60%) for PR who did not receive HDCT. Conclusions: The preliminary survival data show for PR similar outcome as for GR. The treatment including HDCT is feasible with no toxic death recorded. Longer follow-up will confirm its efficacy.

No significant financial relationships to disclose.
Rare incidence of congestive heart failure (CHF) in gastrointestinal stromal tumor (GIST) and other sarcoma patients (pts) receiving imatinib mesylate (IM) therapy
Authors: Khakoo A. Y. , Steinert D. M. , Patel S. R. , Plana J. C. , Ludwig J. , Benjamin R. S. , Trent J. C.
Published: March 2020

10026

Background: Potential IM cardiotoxicity has not been evaluated in patients with GIST or other sarcomas. CHF has been reported in leukemia pts on IM. Objectives: To determine the incidence of CHF in GIST and other sarcoma pts receiving IM. Methods: From our clinical trial database we reviewed all Grade III/IV potential cardiac adverse events (PCAEs) including dyspnea, dyspnea on exertion, chest pain, edema, pleural effusion, ascites, cardiac ischemia, and arrhythmia. Results: 219 pts were enrolled on clinical trials with IM from Dec 27, 2000 to May 11, 2006. 18 pts (8.22%) were identified as having PCAEs. The median age was 65.5 yrs (range, 21 to 88 yrs) and 7 were women. Their diagnoses were advanced GIST (13 of 125 pts, 10.40 %), primary GIST (4 of 48 pts, 8.33 %), or osteosarcoma (1 of 46 sarcoma pts, 2.17%). The osteosarcoma pt had received prior anthracycline therapy. The median time from start of IM to a PCAE was 173.5 days (11 to 1,568 days). IM dose at the time of the PCAE was 400 mg/d in 10 pts, 600 mg/d in 4 pts, and 800 mg/d in 4 pts. 13 pts had a past medical history of risk factors for coronary artery disease (CAD) or established heart disease: diabetes (4 pts, 22.22%), hypertension (9 pts, 50%), CAD (2 pts, 11.11%), hypertrophic obstructive cardiomyopathy (1 pt, 5.56%), peripheral vascular disease (2 pts, 11.11%), hyperlipidemia (3 pts, 16.67%) or arrhythmia (1 pts, 5.56%). None of these patients had evidence of pulmonary vascular congestion by chest film. 8 pts had an ECHO or MUGA scan at the time of the PCAE, and 1 of them had documented low ejection fraction; in only 2 of these 8 pts was there an ECHO prior to IM (LVEF >50% in both). The single pt with LVEF<50% at the time of the PCAE had prior a history of hypertension, multi-vessel CAD and coronary artery bypass grafting 12 years prior to the PCAE. All of the pts continued IM therapy with dose adjustments and toxicity-specific management with no further complications. Conclusions: Pts who develop PCAEs on IM should be treated with diuretics, ACE-inhibitors, and beta-blockers with continuation of IM as clinically indicated. CHF in sarcoma patients treated with IM is rare and was observed in only one elderly patient with known prior cardiac disease.

No significant financial relationships to disclose.
Objective response rate in a phase II multicenter trial of pertuzumab (P), a HER2 dimerization inhibiting monoclonal antibody, in combination with trastuzumab (T) in patients (pts) with HER2-positive metastatic breast cancer (MBC) which has progressed during treatment with T
Authors: Baselga J. , Cameron D. , Miles D. , Verma S. , Climent M. , Ross G. , Gimenez V. , Gelmon K.
Published: March 2020

1004

Background: T and P bind to different epitopes on the extra cellular domain of HER2. Unlike T, P binds to the dimerization domain and blocks homo- and hetero-dimerization of HER2 with other HER kinase family members. Xenograft models support the hypothesis that the complementary mechanisms of action could result in augmented efficacy when T and P are combined. Methods: Two-stage design, criteria to proceed to the 2nd stage were: ≥ 2 partial responses (PR) or 1 PR and 12 stable disease (SDs) or 13 SDs. Eligibility included: measurable, centrally-tested HER2 positive breast cancer; up to 3 lines of prior chemotherapy plus T (including adjuvant chemotherapy plus T); disease progression during T as most recent treatment for metastatic disease; baseline left ventricular ejection fraction (LVEF) ≥ 55% and no decrease of LVEF to below 50% during prior T treatment. Consenting Pts received T i.v. weekly or every 3 weeks at 2 mg/kg or 6 mg/kg respectively (with re-loading dose if required) plus 420mg fixed dose of P i.v. every 3 weeks following loading dose 840mg. Study treatment was initiated within 9 weeks of the last dose of T given as most recent therapy. An independent data safety monitoring board has overseen the 1st stage safety data. Results: Recruitment into 1st stage is complete. The main adverse events were diarrhea (71%), fatigue (46%), nausea/vomiting (38%) and rash (25%). Most AE’s were mild to moderate (there was 1 case of Grade 3 diarrhea) and none was treatment-limiting. There were no clinical cardiac events, and central review revealed no case of fall in LVEF of ≥10% and to ≤50%. Response status: 5 confirmed PR (21%); 12 SD (50%). Responses have been observed in lymph node and liver metastases. Recruitment into the 2nd stage of the trial has commenced. Conclusions: The combination of the P and T is active and well tolerated in patients with pre-treated HER2 positive breast cancer which has progressed during treatment with T.

No significant financial relationships to disclose.
Perioperative morbidity in metastatic gastrointestinal stromal tumors (GIST) undergoing surgery of residual disease following imatinib (IM)
Authors: Gronchi A. , Fiore M. , Radaelli S. , Coco P. , Fumagalli E. , Stacchiotti S. , Collini P. , Tamborini E. , Pilotti S. , Casali P. G.
Published: March 2020

10043

Background: To review the morbidity of post-IM surgery of residual disease in a consecutive series of metastatic, IM- sensitive, GIST pts. Methods: Between November 2002 and September 2006, 29 pts with metastatic GIST were operated on, being progression- free on IM for at least 6 months. Median preoperative IM duration was 17 mos. Only patients deemed to be completely resectable on CT/MRI were considered for surgery. Major surgical procedures were generally excluded. Results: Surgery consisted in explorative laparotomy with resection of residual visible disease, omentectomy in 13 cases, intestinal resections in 10, minor hepatic resections in 7, radiofrequency ablations of liver nodules in 2, spleno-pancreatectomy in 2. Macroscopically complete surgery could be performed in 90% of pts. Median operative time was 180’ (range 120–420). Median post-surgery discharge time was 9 days (range 4–35). Median preoperative Hb level was 12.2 mg/dL and the median perioperative whole blood and fresh frozen plasma units required was 1.5 and 2.9 (range 0–16 and 0–44), respectively. In 28% of pts, there was post-operative ascites (daily peritoneal effusion of >200 ml), which generally responded to medical therapy in one week. Postoperative levels of AST/ALT reached twice the baseline in 48% of pts, independently of whether liver resections had been carried out. Postoperative pneumonia was observed in 38% of patients. Major surgical complications occurred in 14% (one bleeding, one evisceration, and two anastomotic leakages). After a median follow up of 36 mos from surgery, PFS was 69% at 2 yrs (65% at 4 yrs from IM-onset). Conclusions: While this was a series of favorably selected patients, and major surgical procedures were preferably avoided, surgical perioperative morbidity turned out to be higher than expected. This reinforces the view that post-IM surgery of residual disease in metastatic GIST pts should be considered investigational, as long as its efficacy in improving prognosis is not demonstrated.

[Table: see text]
Long term progression-free survival correlates with KIT/PDGFR mutational status in advanced GIST patients treated with imatinib (IM)
Authors: Cioffi A. , Emile J. F. , Domont J. , Ray-Coquard I. , Blay J. Y. , Terrier P. , Bonvalot S. , Le Péchoux C. , Perol D. , Le Cesne A.
Published: March 2020

10053

Background: IM is the first-line treatment for advanced GIST and must be given continuously until disease progression or intolerance. The median progression free survival (PFS) of pts included in consecutive prospective trials is around 2 years. Pt characteristics and the exact mutational status of GIST who benefit the most from IM in term of prolonged response to IM and prolonged PFS are unknown. Methods: two hundred and seventy six pts were included in 2 consecutive prospective trials since 2001 in 2 centers. Pts receiving IM for at least 3 yrs (3 to 5 yrs) who have no exhibited any kind of progression and receiving IM continuously until december 2006 have been retrospectively analyzed both clinically and biologically. KIT and PDGFR mutations were analyzed using DHPLC and direct sequencing of frequently mutated exons (KIT 9, 11, 13, 14, 17, PDGFR 12, 14, 18). Results: after a median follow-up of 4 yrs (3–5yrs), 31 pts are free of progression and received IM continuously. The characteristics of these long term survivors favorable cohort of pts are as following: man (61%), small bowel origin (60%), liver involvement (80%), synchronous metastasis at inclusion (58%), and normal initial hemoglobin level (92%>10 g/dl). As of now, 15 pts are evaluable for mutational analysis. All but one (exon 9) pts had an exon 11 mutation. The most commun genetic alteration was an in frame deletion between 550 to 558. Conclusions: Pts with metastatic GIST arising from small bowel harboring an exon 11 mutation in the vicinity of codon 557–558 may be a very favorable subgroup.

No significant financial relationships to disclose.
A phase II evaluation of aerosolized GM-CSF (AGM-CSF) plus standard I-MAP/ GM-CSF/MAP/ surgery/ irradiation in the reduction of pulmonary metastases (P-METS) in soft tissue sarcoma (STS) patients (PTS)
Authors: Okuno S. H. , Mahoney M. R. , Kabat B. F. , Marks R. M. , Maples W. J. , Fitch T. J. , Petersen I. A. , Beauchamp C. P. , O’ Connor M. I. , Sim F. H.
Published: March 2020

10058

Background: P-METs remain illusive with standard treatments for STS. AGM-CSF demonstrated tolerability with promising efficacy in reducing P-METS. We evaluated the 2-yr P-MET free rate in chemonaiive pts with extremity STS. Methods: ECOG PS 0/1 and Gr 3/4 primary STS of the limb girdle/extremities, were required. Treatment sequence: 2 cycles of IMAP (Ifosfamide, Mitomycin, Doxorubicin, Cisplatin) plus s.q. GM-CSF (preload d -6 to -3, d1–14); MAP (d0, 28) during irradiation (d1–35) plus AGM-CSF 250 mcg bid (d1–7, 15- 22, 28–35); surgery; post-op irradiation plus AGM-CSF 250 mcg bid (d1–7, 15–22, 28–35, 42–49). 6 of 35 pts with P-METS in ≤ 2 yrs implied lack of efficacy w.r.t. reducing P-METS. Results: 38 eligible pts were enrolled (20 male, median age 51 yrs, 24 PS 0). Median size of tumor 9 cm (2.3–26.7 cm).Location of tumors included: proximal extremity-16, distal extremity-11, and limb girdle-12. 79% received debulking surgery; 29 rendered disease-free. 38 pts are evaluable for toxicity (see table ). More common Gr 3+ events related to treatment appear below. 79% had Gr 4 neutropenia, despite s.q. GM-CSF. 6 pts have died, with 2.5 yrs median follow-up on survivors (range .4- 4.6). No treatment related fatalities occurred. 10 pts had P-METS ≤ 2 yrs. The estimated 2 yr P-MET free rate is 75% (95% CI 62–91). Conclusions: Although high, neutropenia was as expected. AGM-CSF failed to improve the 2 yr P-MET free rate in this group of STS pts. Other strategies need to be explored. Supported by NIH Grant CA15083–32 and Berlex Corporation. Max Severity (Gr 3+)

[Table: see text]

No significant financial relationships to disclose.
A phase II study of gimatecan as salvage treatment in patients with advanced or metastatic soft tissue sarcoma (STS) relapsing after anthracycline / ifosfamide - based chemotherapy regimens
Authors: Biron P. , Reichardt P. , Grosso F. , Le Cesne A. , Poveda A. , McCanna S. , Zanna C. , Brienza S. , Ray-Coquard I. , Blay J. Y.
Published: March 2020

10063

Background: Gimatecan, a new oral camptothecin derivative, showed early clinical activity in patients with STS during the phase I clinical development. Methods: Patients with different histological types of STS, including rhabdomyosarcoma and Ewing's sarcoma of soft parts, and advanced or metastatic disease pretreated with anthracycline and ifosfamide were included. The principal inclusion criteria were: disease not curable with surgery and/or radiation, presence of a measurable progressive lesion(s), pretreatment with 1–3 lines of chemotherapy including adjuvant regimens, ECOG PS 0 to 1, age = 18 years. Gimatecan 0.8 mg/m2 was administered orally daily for five consecutive days every 4 weeks. Radiological response was assessed every two cycles by RECIST. A multicenter two stage Simon's optimal design was used to evaluate the single agent activity of gimatecan, also by means of a hierarchical Bayesian model to evaluate treatment effects within the histological subtypes, using the rate of progression free survival at 4 months (PFS- 4) (Van Glabbeke, Eur J Cancer 38: 543–549, 2002). Other objectives were safety, TTP, pharmacokinetics and biomarker evaluations. Results: From August 2005 to December 2006 40 patients, 24 (60%) males and 16 (40%) females, median age 48 years (range 21 - 77), were included in 5 European sites. As of December 2006, 14 patients (35%) achieved stable disease after a median of 4 (range 3–9) cycles, and the PFS-4 is 15% (hystotypes: leiomyosarcoma, liposarcoma, Ewing, synovial and unclassified); all PFS-4 patients had liver or pleuropulmonary metastases. A prolonged arrest of progression was observed in one Ewing (up to 9 months), in one leiomyosarcoma and one liposarcoma (up to 8 and 7 months respectively, both patients still on treatment). Main G3/4 toxicity was hematological, namely anemia (7.5%), thrombocytopenia (5%) and neutropenia (2.5%). Conclusions: These data suggest that oral gimatecan has produced durable disease stabilization and is well tolerated with less than 10% grade 3/4 haematological toxicities.

[Table: see text]
Natural course and clinical features of myxoid and round cell liposarcoma (MRCL) - a retrospective single center analysis
Authors: Mispelaere B. , Sciot R. , Debiec-Rychter M. , Wozniak A. , Wolter P. , Dumez H. , De Wever I. , Samson I. , Amant F. , Schöffski P.
Published: March 2020

10066

Background and methods: MRCL, the 2nd most common type liposarcoma, represents ∼10 % of adult soft tissue sarcomas. In most pts the karyotypic hallmark is t(12;16)(q13;p11), leading to fusion of CHOP and FUS genes and generation of a hybrid protein. MRCL has unique sensitivity to antineoplastic agent ET-743 (Yondelis, Trabectidin), which induces specific morphological change and long-lasting response. We made a retrospective analysis of MRCL cases in our center. Results: 33 pts had histological diagnosis of MRCL with a mean (mn) follow-up of 45 mo (range, 2–214). By karyotyping or FISH analysis CHOP-FUS fusion was present in 12 and CHOP-EWS in 2 pts. The mn age at diagnosis was 45 yrs (range, 18–71), male:female ratio 1:0.8. Frequent primary sites: lower limb (25), abdomen (5), retroperitoneum (2), neck (2). Stage grouping at diagnosis: IA (2), IB (6), IIA (5), III (14), IV (2), not known (NK) (4). 2 had distant spread, 9 metachronous metastasis with a mn interval of 24 mo (range, 5–84). Main sites involved: abdomen (5), lung (3), bone (3). Surgery was performed with curative intent in 26/28 pts (5 NK), R0 resection in 23. 17/28 pts are alive without disease (16 previously R0-resected). 6/28 are alive with disease, 5 died due to MRCL. Relapse after R0 resection occurred after a mn of 24 mo (range, 5–84). Radiotherapy was used in 15/28 (5NK) with neoadjuvant (1), adjuvant (13) or palliative (3) intent (total doses 50–66 Gy). Chemotherapy (CT) was given in palliative (11) or neoadjuvant (1) fashion, after a mn of 1.3 surgical interventions (range, 0–3). 1st-line CT: doxorubicin- based combinations (7), single-agent doxorubicin (3), ET-743 (1). Best response: PR (5), NC (4), PD (1), NE (1). Mn duration of response was 6.3 mo (range, 1–15). 2nd-line CT: ET-743 (3), other agents (4). Best response: CR (1), PR (1), NC (3), PD (1), NE (1), with mn response duration of 7 mo (range, 1–13). 2 had further CT (PR 1, SD 1). Conclusions: MRCL is a chemosensitive sarcoma with variable clinical course. Local treatment can be curative, but systemic spread is frequent. Pts may respond to conventional CT or new agents such as ET-743. To evaluate the relative value of systemic treatment we need randomized trials in this unique clinical setting.

No significant financial relationships to disclose.
Prolongation of TTP by maintenance therapy with PLD in a multicenter phase III randomized trial following standard chemotherapy for MBC: GEICAM 2001–01 study
Authors: Alba E. , Ruiz-Borrego M. , Martín M. , Margelí M. , Rodríguez-Lescure Á. , Sánchez-Rovira P. , Ruiz A. , Ribelles N. , Calvo E. , Casado A.
Published: March 2020

1007

Background: We had previously shown that sequential A→T is a reference treatment as first-line CT for MBC patients (pt) (JCO 2004, (22), 2587–2593). However, responses are short-lived and time to progression (TTP) is also short. Maintenance chemotherapy (MCT) with LPD could improve TTP without relevant additional toxicity. Methods: All pt received an induction CT with 6 cycles (cy) of A→T. Pt with a complete or partial response (CR, PR), or stable disease (SD) were randomly assigned to either LPD (40 mg/m2 q4wk × 6 cy) or observation (O) from May 2002 to Dec 2006. Eligible pt had adequate bone marrow, renal, hepatic and cardiac functions (by left ventricular ejection fraction, LVEF). The study hypothesis assumed a median TTP since start of induction CT in O arm of 10.5 months (m), and a prolongation of TTP of 66% with MCT. Therefore, 154 pt (77 per arm) were necessary (one-sided a and 1-β errors of 0.01 and 0.8). Results: Pt accrual was completed in December 06. 122 and 136 pt (60/66 in LPD vs. 62/70 in O) are currently evaluable for efficacy and safety. Median age was 57 yr (30–74). Status disease in pt assigned to LPD vs. O: 2 (3%) vs. 6 (9%) of pt had CR, 31 (47%) vs. 43 (61%) had PR; 33 (50%) vs. 21 (30%) had SD. 291 cy of LPD were administered (median 6, range 0–6). Neither relevant LVEF decrease nor clinical congestive failure were seen. Nausea/vomiting and alopecia incidence was negligible. G3 hand-foot syndrome was present in 3 pt/3 cy (5/1%). Median TTP in LPD arm was 16.04 m (14.06–18.02), vs. 9.96 m (8.87–11.05) in O arm, p=0.0001. Conclusion: Maintenance therapy with LPD significantly prolongs TTP in MBC pt after a first-line CT without significant clinical toxicity.

No significant financial relationships to disclose.
Can ERCC1 and topoisomerase II-alpha predict histological response and outcome after induction chemotherapy in locally advanced soft tissue sarcomas (LASTS)?
Authors: Ruiz-Soto R. , Auger N. , Castaing M. , Drusch F. , Bonvalot S. , Terrier P. , Le Pechoux C. , Domont J. , Bénard J. , Le Cesne A.
Published: March 2020

10074

Background: The impact of histological response (± 95% of necrosis) on patients (pts) outcome with LASTS treated by induction chemotherapy (CT) is still debated. Methods: From 1995 to 2005, 79 LASTS pts received induction CT consisting in two cycles of API-AI regimen and results were already reported (Gomez-Abuin, ASCO 2004). ERCC1, HER2 and Topoisomerase IIa (TopoII) was assessed by IHC on initial biopsies after paraffin embedding and correlated to histological response and pts outcome. Results: The median age of the 43 males and 36 females was 43 years (yr) (range 18–68) and the median tumor size at diagnosis was 109 mm (range 10–250 mm). CR was achieved in 4 pts, PR in 25 pts, SD in 45 pts and PD in 5 pts. R0 surgery was possible in 82% of pts; histological necrosis (HN) after chemotherapy was >95% in 25 pts, between 50–95% in 28 pts and <50% in 25 pts (median HN was 70%). All pts but one received postoperative radiotherapy. Relapse occurred in 37 pts; local in 3, distant in 33 and both in 1. After a median follow-up of 48 months (9–118 months) 51 pts are alive. The 5 yr DFS and OS were 45% and 60% respectively. Multivariate analysis correlated median HN to a better EFS and a non grade 3 to a better OS. Regarding protein expression (54 pts analyzed), a higher protein expression of TopoII was correlated to a better EFS (p=0.032) by univariate analysis and to OS by multivariate analysis (p=0.025). ERCC1 protein expression was not related to EFS and/or OS. There is no correlation between over expression of both proteins and any percentage of HN. Conclusions: A high rate of HN (> 70%) after induction chemotherapy treatment is predictive for a better EFS. TopoII expression seems to be a relevant early predictive marker for outcome of pts with LASTS treated with doxorubicine-containing induction CT.

No significant financial relationships to disclose.
Combination of trabectedin (T) and doxorubicin (D) for the treatment of patients with soft tissue sarcoma (STS): Safety and efficacy analysis
Authors: Blay J. , von Mehren M. , Samuels B. L. , Fanucchi M. P. , Ray-Coquard I. L. , Buckley B. , Gilles L. , Lebedinsky C. , Elsayed Y. A. , Le Cesne A.
Published: March 2020

10078

Background: T is a novel marine-derived DNA minor-groove binder that interferes with gene activation, nucleotide excision repair, and induces DNA strand breaks and cell cycle arrest in S and G2. T is active in STS and exhibits preclinical synergy with D. The objective of this study was to determine the combination regimen that is tolerable and associated with manageable neutropenia. Other objectives included safety, clinical activity and pharmacokinetics (PK) Methods: This was a dose escalation phase I study. Eligible patients (pts) had metastatic or recurrent STS, PS 0–1, and adequate organ function. Pts with more than 1 prior chemotherapy, prior anthracyclines or radiation to more than 20% of bone marrow were excluded. On day 1 of each 3-week cycle, pts received D starting at 60 mg/m2 followed by T starting at 0.9 mg/m2. Incremental doses were explored. D was discontinued after 6–8 cycles. Treatment was administered as an outpatient. PK samples were collected. A modified dose escalation and dose modifications were implemented Results: Forty one pts were treated in three sequential cohorts. In cohort 1 (D60 mg/m2 + T0.9 mg/m2), 4/11 pts without G-CSF experienced unmanageable neutropenia and subsequently prophylactic G-CSF was instituted. No unmanageable neutropenia was seen in the subsequent18 evaluable pts in this cohort. 1/13 and 2/6 DLTs were seen in cohort 2(D60 mg/m2 + T1.1 mg/m2) and cohort 3(D60 mg/m2 + T1.3 mg/m2) respectively. The most frequent grade 3/4 AEs were: neutropenia(71%), ALT elevation(46%), thrombocytopenia34%), AST(24%), anemia (22%), Febrile neutropenia (17%). One pt discontinued due to grade 3 asthenia. The MTD and recommended dose is D60 mg/m2 + T1.1 mg/m2. Anti-tumor activity included 17% ORR (1 CR and 6 PR), 80% stable disease (45% SD>6 months). Median PFS is 8.9 months (95% CI 5.6–11.8). 3-month and 6-month PFS are 85.4% and 58.2% respectively. Mature overall survival and PK data will be presented Conclusions: The combination of T and D with G-CSF support is safe, tolerable and active in pts with metastatic or recurrent STS

[Table: see text]
Lapatinib (L) with paclitaxel compared to paclitaxel as first-line treatment for patients with metastatic breast cancer: A phase III randomized, double-blind study of 580 patients
Authors: Leo A. Di , Gomez H. , Aziz Z. , Zvirbule Z. , Arbushites M. , Oliva C. R. , Koehler M. , Williams L. S. , Dering J. , Finn R. S.
Published: March 2020

1011

Background: L is an oral tyrosine kinase inhibitor of EGFR/HER2, active as monotherapy and in combination for HER2-overexpressing advanced/metastatic breast cancer (BC). A Phase I study of L with paclitaxel (P) indicated no unexpected adverse events (AEs). PK profile indicated no relationship between peak plasma concentration of P+L and neuropathy, neutropenia, diarrhea, rash or myalgia. We report here blinded efficacy and safety data for patients (pts) with incurable Stage IIIb/IIIc/IV BC at first diagnosis or relapse, untested or negative (0/1+ IHC or FISH neg) for HER2. Unblinded data will be presented at ASCO 2007. Methods: Between Jan 2004 and Jul 2005, 580 pts from 24 countries were stratified by metastatic site and randomized 1:1 to L 1500 mg QD + 175 mg/m2 P q3w or placebo QD + 175 mg/m2 P q3w. Primary endpoint was TTP; secondary endpoints were AEs, ORR, PFS, CBR, RFS, and OS. Tumor tissue was obtained from the most recent biopsy of 451 (78%) pts and was centrally analyzed in blinded fashion for biomarker patterns. Serum samples were collected for central EGFR and HER2 ECD analysis. Results and Conclusions: 579 pts were analyzed; 87% presented with Stage IV BC. 55% received prior adjuvant chemotherapy or anti-hormonal therapy. No pts received previous trastuzumab. At the time of analysis, 561 (97%) pts progressed or otherwise withdrew. Most common AEs were alopecia (58%), neurological (55%, gr=3:8%), diarrhea (42%, gr=3:9%), nausea (32%), and rash (32%, gr=3:2%). Neutropenia and thrombocytopenia AEs related to study treatment were 18% and <1%, respectively. LVEF decrease of 20% relative to baseline and below LLN was reported 15 times. 12% of AEs led to treatment withdrawal. Blinded data analysis revealed a median TTP of 25 wks and ORR of 30%. CNS relapse was reported in 11 pts (2%). Enrollment predominantly came from countries with limited HER2 testing capacity thus a subgroup of pts is expected to be HER2+ve. Blinded analyses of HER2, ER and PR are ongoing at this time and final biomarker evaluations will be presented with unblinded efficacy data.

[Table: see text]
Safety and efficacy of capecitabine (C) plus bevacizumab (B) as first-line in metastatic breast cancer
Authors: Sledge G. , Miller K. , Moisa C. , Gradishar W.
Published: March 2020

1013

Background: C alone has good activity and tolerability in metastatic breast cancer (MBC) and when combined with docetaxel improves response and survival. C combined with B in heavily pretreated MBC improved the response rate but not PFS. In untreated MBC, the addition of B to chemotherapy significantly improves progression-free survival (PFS) which suggests that B, is most effective in early disease. Methods: Primary objective of this single-arm, 2-phase study, is to evaluate PFS in MBC patients receiving first-line treatment with C 1,000 mg/m2 twice daily on days 1–15 (28 doses) and B 15 mg/kg on day 1. Treatment was repeated every 21 days until progression. Eligibility criteria included HER2-negative MBC previously untreated for metastatic disease; ECOG performance status =1; no prior anti-angiogenic or oral fluoropyrimidine therapy. A sample size of 109 patients (including dropouts) was required to give 90% power to test an improvement from 4 months median PFS to 5.6 months with the two-sided test (a 5%) Results: At data cut-off, 103 patients had received study medication. Present results are based on 103 patients (ITT population), except tumor response which is based on 91 patients who had response evaluation. The average # of cycles received in first phase is 6.8. 84 pts.are alive at this time. 38.5% (35/91) pts. have had a response: complete response 5.5%; partial response 33.0%. Stable disease is 42.9% with 81.4% clinical benefit. Planned dose received is 77.7 % for C and 99.0 % for B. The majority of adverse events (AEs) were mild or moderate. The most common grade 3 AEs were hand-foot syndrome (13%) and pain (10%); grade 4 pulmonary embolism occurred in 2% in the first phase of the study. Conclusions: Updated results with longer follow-up including toxicity, TTP and PFS will be presented at the meeting. It appears that in first-line C+B is active for MBC and is well tolerated, with few grade 3/4 toxicities.

[Table: see text]
Detecting circulating tumor cells in metastatic breast cancer patients using fiber-optic array scanning technology
Authors: Marrinucci D. , Bethel K. , Lazarus N. , Leach M. , Kroener J. , Bruce R. , Kuhn P. , Nieva J.
Published: March 2020

1022

Background: Circulating tumor cell (CTC) detection and enumeration has been shown to be a valuable tool for determining prognosis in metastatic breast cancer patients. CTCs are rare, existing in the circulation at estimated concentrations of 1 in 1 - 10 million normal blood cells. To date, the most widely used technique to detect CTCs has used immunomagnetic enrichment based protocols. In this validation study, we sought to determine if an enrichment free approach using an immunofluorescent cell attachment protocol along with fiber-optic array scanning technology (FAST) could achieve similar results. Methods: We have developed and validated a scanning instrument using FAST that can be used in conjunction with an immunofluorescence staining protocol to efficiently detect CTCs. The protocol uses a pan anti-cytokeratin antibody cocktail directed against 9 cytokeratins along with a DAPI nuclear counterstain. FAST defines cell positions, so relocation and retrospective analysis of CTCs is possible. Using this system, we assayed 50 blood specimens obtained from metastatic breast cancer patients. Pathologic review of CTCs was performed identifying CTCs as cytokeratin positive and DAPI positive. Survival analyses were determined using Kaplan-Meier analyses. Results: 31 women with metastatic breast cancer were enrolled in the study and provided 50 peripheral blood specimens. The median CTC count for patients with progressive disease was 8.5, while the median CTC count for patients with stable or responding disease was 1. At a median follow-up of 1 year, 11 patients had died. Patients with =5 CTCs had a median survival of 212 days, while the median survival for patients with 0–4 CTCs had not been reached after 1 year (p=0.0012). Patients with progressive disease had significantly higher CTC counts (p<0.0001) than those who were stable or responding to therapy. Conclusions: This study confirms the previously reported efficacy of CTC enumeration in determining the prognosis of metastatic breast cancer patients and establishes the potential utility of the FAST cytometer as a method for CTC enumeration.

No significant financial relationships to disclose.
A randomized trial of capecitabine (C) given intermittently (IC) rather than continuously (CC) compared to classical CMF as first-line chemotherapy for advanced breast cancer (ABC)
Authors: Stockler M. , Sourjina T. , Grimison P. , Gebski V. , Byrne M. , Harvey V. , Francis P. , Nowak A. K. , Van Hazel G. , Forbes J.
Published: March 2020

1031

Background: Intensive treatment is not indicated for many women having first line chemotherapy for ABC. We sought to determine for such women whether oral C was preferable to classical CMF, and whether C given continuously (CC) was preferable to the same total dose given intermittently for 14 of every 21 days (IC). Methods: 325 women were randomized between June 01 and July 05 to either IC (2,000mg/m2/d for 14 of every 21d), or CC (1,300mg/m2/d for 21 of every 21d), or CMF (cyclophosphamide 100mg/m2/d p.o. d1–14; methotrexate 40mg/m2 and 5-FU 600mg/m2, IV d1&8, every 28d). Treatment was continued until disease progression (PD), unacceptable toxicity, or intolerance. Clinical and quality of life (QOL) assessments were 3–4 wkly, and imaging was 3 monthly, both until PD. The primary endpoint was quality adjusted progression-free survival (QAPFS). Overall survival (OS), PFS, response rates (RR=CR+PR), QOL, acceptability of chemotherapy and adverse events (AE) were secondary endpoints. The analysis plan was to first compare IC v CC, and if p>0.05, then to combine the two arms (C = IC + CC) for comparisons v CMF. Primary analyses were with the logrank test. Cox’s models were used to calculate hazard ratios (HR), 95% confidence intervals (CI), and to adjust for other factors. All p-values and CI are 2-sided. Results: OS was longer with C than CMF (HR .72, CI .55 to .94, p=.02, medians 22 v 18 mo). PFS was similar for C and CMF overall (HR .86, CI .67 to 1.1, p=.2, median 7 mo), and over the first 6 mo (HR 1.15, CI .81 to 1.6), but longer on C than CMF beyond 6 mo (HR .62, CI .44 to .87). Response rates were similar on C and CMF (21% v 18%, p=.8). Febrile neutropenia, infection, and sore mouth were more common on CMF; hand-foot syndrome was more common on C. Chemotherapy was continued beyond 6 mo in 40% on C but only 21% on CMF. PFS, OS, RR and AE were similar for IC and CC (p>0.4). Cox’s models adjusting for baseline factors corroborated all results and conclusions. Analyses of QAPFS, QOL, and acceptability of chemotherapy will be available in June 07. Conclusion: C improved overall survival with less toxicity and greater tolerability than classical CMF. C is a good first line option when more intensive treatment is not indicated.

[Table: see text]