bluuebunny/crossref_metadata_2025_split huggingface dataset:
Doxorubicin-induced vascular toxicity: Targeting potential pathways to reduce procoagulant activity.
Authors: Bar-Joseph Hadas , Ben-Aharon Irit , Tzabari Moran , Savion Naftaly , Shalgi Ruth , Stemmer Salomon M. 
Published: March 2020

e13080 Background: In a former study in mice using the gonads as an end-organ prototype, we have characterized by real-time intravital imaging an acute deleterious effect of doxorubicin (DXR) on the gonadal vasculature, manifested by a reduction in blood flow and disintegration of the vessel wall. We hypothesized this pattern may represent the formation of microthrombi. We aimed to further characterize the effect of DXR on platelets’ function and to use potentially protectants to reduce DXR acute effect on the blood flow. Methods: 100 µg/mouse 24 hours and 1 hour prior to DXR treatment (8 mg/kg), or with eptifibatide (integrilin,75µg/mouse) 90min prior to DXR treatment. Testicular arterial blood flow was examined in real-time by pulse wave Doppler ultrasound. Platelet adhesion to confluent endothelial cells (EC) was evaluated following exposure of EC to DXR (100 µM) for 4h followed by exposure to whole blood under defined shear rates. Fixed platelets were immunostained by anti- CD41a antibody. DXR effect on platelet adhesion was determined by pre-incubation of platelet rich plasma for 15min with increasing concentrations of DXR and induction of aggregation by ADP. For in vivo study, mice were injected with either LMWH (Enoxaparin; Clexane). Results: There was a significant 3.6-fold increase in platelet adhesion to DXR-exposed EC (p<0.002) reflecting the toxic effect of DXR on EC. Yet, significant DXR- dose dependent decrease in platelet aggregation was observed reaching up to 40% inhibition at 100 µM (p<0.001). Testicular arterial blood flow was preserved as a result of pre-treatment with LMWH or eptifibatide prior to DXR (P<0.01). Conclusions: DXR-induced acute vascular toxicity may trigger the coagulation pathway while enhancing platelet adhesion yet inhibiting massive aggregation, which result in compromised blood flow due to microthrombi formation. Anti-platelet/anti-coagulant agents appear to be effective in reducing the detrimental effect of DXR on the vasculature.
A phase I, multicenter, open-label dosimetry study of I-131-CLR1404 in patients with relapsed or refractory advanced solid tumors who have failed standard therapy or for whom no standard therapy exists.
Authors: Chao Joseph , Mortimer Joanne E. , Cho Steve Y. , Marshall John , Wong Terence 
Published: March 2020

e13116 Background: I-131-CLR1404 is a small-molecule, iodophenyl-containing phospholipid ether analog that selectively delivers a cytotoxic beta-emitting radioisotope to cancer cells. In human tumor xenograft models, I-131-CLR1404 slowed malignant tumor growth and extended survival. Methods: A multi-center study evaluating total body and organ dosimetry, safety, and pharmacokinetics of 131-I-CLR1404 was conducted in 8 subjects with refractory solid tumors. We sought to determine the millicurie (mCi) dose of I-131-CLR1404 expected to deliver 35-40 centigray (cGy) to marrow, which will serve as the starting dose in a subsequent maximum tolerated dose (MTD) study. Subjects received a single dose of 10 mCi of I-131-CLR1404. Serial whole body planar scintigraphy images were obtained from 15 minutes to 6 days after I-131-CLR1404. Blood and urine samples were for biodistribution and pharmacokinetics. Results: Dosimetry calculations demonstrated consistency of organ and total body dosimetry in the 8 subjects. SPECT/CT images in a subset of patients indicated tumor-selective uptake of 131-I-CLR1404, showing a relative lack of uptake in adjacent normal tissue or bone marrow. No deaths or serious adverse events were reported during the study. A total of 7 subjects reported 19 AEs, 5 of which (all Grade 1) were considered by the investigator to be related to study medication. Based on the average red marrow dose of 0.56 mSv/MBq (2.09 rem/mCi), an administered activity of approximately 740 MBq (20 mCi will deliver 40 cGy (40 rem) to marrow, the starting dose in the Phase 1b (MTD) study. Conclusions: As a broad-spectrum, cancer-targeted molecular radiotherapeutic agent, I-131-CLR1404 may address at least two key limitations of current cancer therapies - lack of drug target expression and off-target toxicity. These results showan acceptable safety, dosimetry profile and selective uptake in malignant tumors. Further study of I-131-CLR1404 in cancer patients is warranted.
Effect of brazilin on apoptosis and suppression of histone deacetylase in multiple myeloma U266 cells.
Authors: Kim Bonglee , Kim Sung Hoon 
Published: March 2020

e13514 Background: Brazilin [7, 11b-dihydrobenz(b)indeno[1,2-d]pyran-3, 6a, 9, 10(6H)-tetrol] isolated from Caesalpinia sappan has been showed various biological activities such as anti-inflammationy, anti-bacteria and anti-platelet aggregation. However, there is no report on its anti-cancer activity. Methods: In the present study, the anti-cancer mechanism of brazilin was investigated on apoptosis and cell cycle arrest in human multiple myeloma U266 cells. Results: Brazilin significantly increased sub-G1 population and TUNEL-positive cells undergoing apoptosis. Also, brazilin activated caspase-3 and regulated the expression of Bcl-2 family proteins including Bax, Bcl-xL and Bcl-2, via mitochondria-dependent pathway. Futhermore, cell cycle analysis revealed that brazilin induced G2/M arrest of cell cycle along with apoptosis induction in U266 cells. Consistently, brazilin elevated the expression of cyclin-dependent kinase (CDK) inhibitor proteins p21 and p27 and activated G2 checkpoint-related proteins such as Chk1, Chk2 and γ-H2Ax. Of note, brazilin significantly inhibited the activity of histone deacetylases (HDACs), transcription factors involved in the regulation of apoptosis and cell cycle arrest and the expression of HDAC-1 and -2 at both protein and mRNA levels. Notably, brazilin significantly potentiated the cytotoxic effect of chemotherapeutic agents such as bortezomib or doxorubicin in U266 cells. Conclusions: Taken together, our findings suggest that brazilin has a chemotherapeutic potential, via HDAC-mediated apoptosis and G2/M arrest for multiple myeloma treatment.
A study on position variation of liver cancer and interested structures during respiration by 4DCT and 3DCT.
Authors: Zhang Yingjie , Li Jianbin , Xing Jun 
Published: March 2020

e13529 Background: The movement of liver cancer targets could be infected by respiration.The aim of this study was to investigate the position difference of liver cancer in free-breathing condition between 3DCT and 4DCT simulation, and to investigate the correlation of position movement of primary tumor with normal tissues and skin markers. Methods: 12 patients with liver cancer after TACE were scanned at free breath condition by simulation 4DCT and 3DCT. A coordinate system was created based on image of T20 (maximum intensity projection) reconstructed from 4DCT, gross tumor volume (GTV), normal tissues and skin markers of end expiration, end inspiration and T20 of 4DCT and 3DCT were contoured. The three dimensional position variation of them were measured and their correlation were analyzed. Results: Corresponding to target position of T20, the targets position of end expiration and end inspiration were different from 3DCT in x-axis(χ2=2.552, p=0.579), y-axis(χ2=6.938, p=0.031), z-axis(χ2=10.606, p=0.005). The target movement range of liver cancer in three dimensional direction was different, that was 8.44±6.52mm in z-axis, 3.78±3.07mm in y-axis, 1.11±1.27mm in x-axis,. 9.88±6.43mm in three dimensional vector. There was statistical significant correlation for movement range of GTV with that of liver, gallbladder, right diaphragmatic dome and right skin marker(r=0.738-0.922, p=0.037-0.001), but there was no significant correlation for movement range of GTV with that of kidney, pancreas, spleen, and middle skin marker. Conclusions: Corresponding to target position of T20, there was great difference between individual GTV position of 3DCT and 4DCT. What's more, it was not all of the movement of abdominal normal tissues correlated to the movement of GTV. These uncertain factors may infer dose mapping of GTV and abdominal risk organs.
MGCD265, a multitargeted oral tyrosine kinase receptor inhibitor of Met and VEGFR, in combination with docetaxel.
Authors: Beeram Muralidhar , Patnaik Amita , Amaravadi Ravi K. , Haas Naomi B. , Papadopoulos Kyriakos P. , Tolcher Anthony W. , Smith Lon S. , Harlacker Kathleen , Espino Guillermo , Drouin Michel A. , Tawashi Manal , Wang James , Karam Andre , Hunt Wendy , Maroun Christiane R. , Fournel Marielle , Mehran Mariam , Besterman Jeffrey M. , O'Dwyer Peter J. 
Published: March 2020

e13604 Background: MGCD265 is a multi-target oral tyrosine kinase receptor inhibitor that targets Met, VEGFRs 1, 2, 3, Tie and Ron. The maximum tolerated dose (MTD) of MGCD265 in combination with docetaxel was initially determined using micronized tablets. MGCD265 formulation was improved and the MTD of MGCD265 in combination with docetaxel using the updated formulation was re-evaluated. Methods: Patients (pts) with metastatic or advanced solid tumors were enrolled in this Phase I, open-label, dose-escalating study to assess safety, pharmacodynamics (PD) and pharmacokinetics (PK) as well as anti-tumor activity of the combination. MGCD265 was administered every day over a 3-week cycle and docetaxel (50 then 75 mg/m2) was given intravenously once every 3 weeks (q3w). Results: As of January 11, 2012, 34 pts were enrolled (M/F: 19/15; ECOG 0/1: 19/15; median age: 64 years old). The MTD of the combination was initially defined as MGCD265 (72 mg/m2 BID)+docetaxel (75 mg/m2 q3w) based on the occurrence of dose limiting toxicities (DLTs) in 2 pts who were treated with MGCD265 at 96 mg/m2 BID (fatigue in 1 pt and diarrhea & lipase elevation in the other pt). The updated formulation of MGCD265 was introduced at 48 mg/m2 BID (n=3) with dose escalation to 72 mg/m2 BID (n=3) and 96 mg/m2 (n=4) with no observed DLTs, though the exposure of the two formulations were generally comparable. Overall, objective partial responses (per RECIST 1.1) were observed in 2/9 pts with NSCLC, 1/3 pts with prostate cancer and 1/1 pt with endometrial cancer. Stable disease for 6 cycles or more was observed in 6 pts. Treatment-related ≥ grade 3 toxicity reported in ≥ 2 pts were neutropenia, leukopenia, diarrhea and elevated lipase. The PD profile indicated an increase in the plasma level of VEGF and a decrease in plasma level of HGF at Cycle 1 Day 8 compared to baseline in some patients. Conclusions: MGCD265 was found to be well tolerated using the updated formulation in combination with full-dose docetaxel. Anti-cancer activity, supporting Phase II development of the combination, was observed.
Results of a phase II study assessing efficacy and tolerance of fluorouracil (FU), leucovorin, irinotecan, and bevacizumab (FOLFIRI + B) in first-line metastatic colorectal cancer (MCRC): The Omega Trial (NTC 00467142).
Authors: Robert Jacques , Becouarn Yves , Cany Laurent , Pulido Marina , Dauba Jérôme , Beyssac Richard , Bechade Dominique , Lalet Caroline , Mathoulin-Pelissier Simone , Brunet Rene , Fonck Marianne 
Published: March 2020

e14023 Background: This phase II study evaluates efficacy and tolerance of FOLFIRI+B in first-line MCRC treatment and assesses several genetic polymorphisms as potential markers of treatment activity or toxicity. Methods: Adult patients (pts) with histologically-proven, non-resectable MCRC, ECOG≤2, were included in this two-stage Simon’s design requiring 61 evaluable pts. 14-day cycles consisted of B (5mg/kg), irinotecan (180mg/m²), bolus FU (400mg/m²) and leucovorin (400mg/m²) followed by a 46-hour infusion of FU (2400mg/m²). UGT1A1, thymidylate synthase and VEGFA promoter SNPs were assessed. Primary endpoint was response rate according to RECIST criteria. Results: Sixty-two pts (25 male) from 7 centers were enrolled between Jan07 – Aug09. Median age: 68 years (1st-3rd quartile : 60.4-75.4]); ECOG 0-1 (95.2%); primary tumor location was colon (85.4%) or rectum (14.6%). Principal MCRC locations were: liver (54 pts), lung (28 pts) or peritoneum (17 pts). All pts were evaluable for toxicity. 1058 cycles were administered, median of 13 (range 3-62). Grade 3/4 toxicities were: neutropenia 19.4%; no febrile neutropenia; diarrhea 11.3%; nausea-vomiting 1.6%. No hypertension, thrombotic events, proteinuria or gastrointestinal perforation were observed. 59/62 pts were evaluable for efficacy with 28 pts in PR (47.5%; 95%CI 34.3-60.9), 20 with SD (33.9%) and 11 in PD (18.6%). Median response duration: 9.5 months (range 2.7-20); median time to progression: 10.3 months (range 8.8-11.7); median overall survival (OS) 25.7 months (range 20.2-29.7). 11/59 unresectable pts could finally be resected. To date, three VEGFA polymorphisms have been identified and associations with OS tested. The common genotype of rs25648 is associated with better OS (HR: 0.277; 95%CI: 0.12-0.64). Conclusions: FOLFIRI+B has a good safety profile, is active, with a long median OS leading to resect 18.6% of initially unresectable pts. Genetic polymorphism rs25648 has currently been identified as a marker of better OS, and further analyses for potential UGT1A1 and thymidylate synthase markers are underway.
Impact of delaying adjuvant chemotherapy in colon cancer: A Brazilian experience.
Authors: Aquino Luciana Carla Martins de , Pereira Bruno dos Santos Vilhena , Oliveira Ivanir Martins , Casali-da-Rocha Jose Claudio , Matta-Castro Thalita , Small Isabele Avila , Gil Roberto de Almeida , Moreira Rubem , Duque Cristiano Guedes 
Published: March 2020

e14027 Background: The optimal timing to initiation adjuvant chemotherapy in colon cancer is unknown. Studies suggest that the delay to start chemotherapy may compromise the therapeutic outcome. The purpose of this study was to assess the reasons for delaying adjuvant treatment and the implications in clinical outcome of patients treated in a public institution from Brazil. Methods: Retrospective analysis of medical records of patients enrolled in National Institute of Cancer in Brazil, from 2000 to 2006, with colon adenocarcinoma, stage II and III. Patients were dichotomized into early and late treatment groups. Results: Of 327 patients studied, 172 underwent adjuvant chemotherapy, the majority of these (62%) were stage III. Time to onset ranged between 10 and 142 days (mean 61). Eighty patients (45%) started treatment with more than 60 days after surgery, the reasons for delay were: postoperative complications 8.7%, related to the system (delay in the histopathological, referral, or surgery at other institutions) 72.5%, related to patients 5% and for medical reasons 7.5%. In 6.2% of cases the reason for the delay was not identified. There was no difference in progression-free survival or overall survival between those who received adjuvant chemotherapy within 60 days post surgery compared with those who received it after more than 60 days. Conclusions: Despite the high rate of delaying for start adjuvant treatment in the study population, no difference was observed in clinical outcomes. The referral system and test results should be reviewed, since the main causes of delay were related to the system.
Tumor assessments according to RECIST versus volumetry: Impact on early changes in tumor size in metastatic colorectal cancer (mCRC).
Authors: Laubender Ruediger Paul , Sartorius Ute , Schlichting Michael , Modest Dominik Paul , Mansmann Ulrich Robert , Graser Anno , Heinemann Volker 
Published: March 2020

e14043 Background: We previously proposed an algorithm for reconstructing the true volume of a tumor lesion by using the longest diameter (LD) and the longest orthogonal diameter (LOD). The following analyses aimed to replicate the previous findings, and evaluate the agreement between RECIST-based tumor assessments (TA) and volumetry in the quantification of early changes in tumor size. Methods: mCRC patients (pts) from the FIRE-3 trial (FOLFIRI + cetuximab vs FOLFIRI + bevacizumab) underwent routine staging using contrast-enhanced CT scans. At least 2 hepatic target lesions per pt were defined for 2 raters at baseline and measured every 8 weeks using semi-automated volumetry (Siemens Syngo Via Oncology, Siemens Healthcare) and manual measurement of the LD according to RECIST 1.1, and the LOD. Agreement between the tumor volume algorithm and volumetry for each rater and the corresponding inter rater agreement (IA) were investigated using Bland-Altman (BA) plots with limits of agreement (LOA). Agreement between the RECIST-based TAs and volumetry was quantified by intraclass correlation (ICC). Both raters and the statisticians were blinded to the treatment given. Results: 222 target lesions from 25 pts were measured at 99 TAs. BA plots indicate that the volume algorithm showed negligible constant bias for both raters (0.09 with p=0.25 and 3 observations outside LOA, and -0.05 with p=0.41 and 6 observations outside LOA). IA with regard to the volumetry showed a smaller constant bias (-0.16 with p=0.17, no observation outside LOA) compared with the volume algorithm (-0.31 with p=0.04, one observation outside LOA). The relative change in tumor size between baseline and first TA was investigated. The ICCs between RECIST-based TAs and volumetry for the 2 raters were 0.79 and 0.73. Data in relation to treatment efficacy will be presented. Conclusions: The algorithm for estimating the tumor volume was validated as shown by the negligible bias and low number of measurements outside the LOA in the BA plots. The moderate ICCs for early changes in tumor size indicate differences between RECIST- and volume-based TAs and suggest that volume measurements discern early changes in tumor size more precisely.
Proteinuria as a predictive factor in metastatic colorectal cancer patients treated with bevacizumab.
Authors: Uysal Mukremin , Bozcuk Hakan Sat , Goksu Sema Sezgin , Tatli Ali Murat , Arslan Deniz , Gunduz Seyda , Coskun Hasan Senol , Ozdogan Mustafa , Savas Burhan 
Published: March 2020

e14070 Background: Efficacy of bevacizumab -which is widely used at metastatic colorectal cancer (mCRC)- on clinical survival has been proved. But parameters predicting this clinical efficacy are unknown at present. With this study, we aimed to investigate the predictors of treatment benefit with bevacizumab based chemotherapy in patients with mCRC. Methods: Thirty-six successive patients with mCRC receiving bevacizumab based chemotherapy were enrolled into the study. Hypertension, 24-hour proteinuria and other routine parameters were recorded before and during the treatment with certain intervals. After a 1-year follow up, relationship of progression free survival (PFS) and response with various parameters and especially proteinuria, was evaluated. Results: Of 36 patients included, 20 (55.6%) were male and 16 (44.4%) were female, where mean age was 57. Overall median PFS was calculated as 275 days (9.8 months). Patients with basal proteinuria higher than 114 gr/day had a lower median PFS as 184 days (6.5 months) (p=0.046), where median PFS of patients with basal proteinuria equal to or lower than 114 gr/day was not reached. Therefore, higher level of renal proteinuria is a negative prognostic factor in these patients. Similarly, PFS was observed to be lower at patients with high LDH levels (p=0.0024, Exp(B)=23). Bevacizumab response was observed to be better at patients with favorable performance status (p=0.05), who have a single liver metastasis (p=0.034) and who tend to be hypertensive during the treatment (p=0.034). Conclusions: In conclusion, we demonstrated that basal proteinuria and LDH levels may be prognostic at patients with mCRC receiving bevacizumab-based treatment. In the literature, there has been no study up to now that questions basal proteinuria as a prognostic factor for patients receiving bevacizumab-based treatment. This observation is an important step for more focused use of bevacizumab. We believe that it is important to investigate whether basal proteinuria really has a predictive role in this group of patient with further studies, and this has practical and clinical implications.
Incidence of chemotherapy-induced amenorrhea in premenopausal women treated with adjuvant FOLFOX for colorectal cancer.
Authors: Cercek Andrea , Siegel Cara , Reidy Diane Lauren , Saltz Leonard 
Published: March 2020

e14112 Background: The gonadotoxicity of oxaliplatin-based chemotherapy is largely unknown. Studies indicate that the incidence of young women diagnosed with colorectal cancer is rising, thus there is an increasing number of female colorectal cancer (crc) survivors of premenopausal and child-bearing age. Adjuvant FOLFOX chemotherapy is the most widely used standard treatment for stage III and high-risk stage II colon cancer. The objective of this analysis was to evaluate the incidence of FOLFOX induced amenorrhea in women age 50 or younger treated with adjuvant therapy for colorectal cancer. Methods: A search of computerized pharmacy records identified 119 women age 50 or younger who received adjuvant FOLFOX chemotherapy at Memorial Sloan-Kettering for stage II or III colorectal cancer from January 2002 and January 2011 . Eligible patients were mailed an anonymous questionnaire. The returned surveys were reviewed and the results tallied. Results: Seventy three patients returned the questionnaire. Twenty four patients were excluded from analysis; 19 were treated with radiotherapy, 1 patient had undergone bilateral oophorectomy, 1 had a hysterectomy and 3 stopped menstruating prior to diagnosis. Forty nine patients were analyzed. In total, 41% experienced amenorrhea during chemotherapy. Sixteen percent had persistent amenorrhea approximately one year after completion of chemotherapy. The incidence of amenorrhea during chemotherapy and persistent amenorrhea was higher in patients age 40 or older than in patients under 40 (59% vs 31% (p=.17) and 24% vs 13% (p=.33), respectively). Conclusions: In this retrospective study, it appears that the incidence of FOLFOX chemotherapy induced amenorrhea is increased with age. Due to the small sample size the study may be underpowered to detect a statistical difference. Prospective studies are planned to more accurately characterize the impact of FOLFOX on early menopause and fertility.