bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Guideline-based treatment utilization, treatment time, and cost of chemotherapy for metastatic colon cancer patients treated in U.S. community oncology practices from 2005 to 2009.
Authors: Phung Yen , Wang Zhaohui , Aksamit Inga , Green Sarah G. , Todoroff Karen , Bergstrom Kimberly A.
Published: March 2020

e14118

Background: Adherence (Ad) to national treatment guidelines (TG) is important in improving the quality, outcomes, and cost of cancer treatment (TX) in the U.S. We examined regimens (Reg) utilized, TG-Ad, time on metastatic TX, and cost of chemotherapy prescribed by U.S. community oncology practices to treat patients (Pts) with metastatic colon cancer (MCC) in 2005 and 2009. Methods: Adult colon cancer Pts beginning first line metastatic treatment (LOT-1) in each full calendar year for 2005 and 2009 were reviewed from a large U.S. medical oncology clinical database derived from web-based drug dispensing technology. Reg utilized and 2-yr time on metastatic TX were analyzed and compared to TG recommendations. Reg costs based on Medicare reimbursement were compared. Results: The average number of LOT and number of unique drugs Pts were exposed to were similar between 2005 and 2009. About 70% of Pts received only one LOT. In LOT-1 and 2, TG regs were prescribed more often than Non-TG regs for both groups. TG-Ad was significantly higher in 2009 than in 2005 for LOT-1 (p < 0.0001). Pts receiving TG-Ad Reg for LOT-1 had a significantly longer total metastatic treatment time in both 2005 and 2009. In both 2005 and 2009, FOLFOX+Bev was the most frequent LOT-1 Reg given (37% of Pts), while FOLFIRI+Bev was the most frequent LOT-2 Reg given. 69% of Pts received Bev with LOT-1 in both 2005 and 2009; of those, 28-30% continued to receive Bev with LOT-2. Costs for the top 5 LOT-1 Regs were $17,031 to $34,400 and $5,512 to $39,835 for 2005 and 2009, respectively. Conclusions: U.S. community oncology practices significantly improved guideline Ad in the TX of MCC from 2005 to 2009. In LOT-1, TG Regs were prescribed more than non-TG Regs for both groups. TG Ad for LOT-1 significantly improved time on metastatic TX in both groups. FOLFOX+Bev and FOLFIRI+Bev were most frequently prescribed for LOT-1 and LOT-2, respectively. Costs for the five most utilized Regs vary considerably. [Table: see text]
Treatment of diatal rectal cancer with preoperative intensity-modulated radiation therapy (IMRT) combined with chemotherapy: Updated 5-year results of 42 patients.
Authors: DeNittis Albert S. , Marks John , Troicki Filip , Zeger Erik L. , Nassif George , Marks Gerald J.
Published: March 2020

e14157

Background: Preoperative chemoradiotherapy is currently the standard of care for patients with distal rectal cancer. With Intensity Modulated Radiation Therapy (IMRT), more conformal doses of radiation can be delivered to tumor while sparing normal tissue. It is our intent to present updated data showing 5 year follow up on patients treated concurrently with chemotherapy and IMRT reporting on local control, overall survival, and toxicity. Methods: From April 2007 to February of 2012 a sequential retrospective study of 42 patients at Lankenau Medical Center were treated for distal rectal cancer using IMRT. Patients staged from T2N0M0 to T3N1M0 and all received 5580 cGy to the pelvis using a 9 field plan to tumor, involved and uninvolved lymph nodes. All but one patient received 5FU based chemotherapy and four patients also received oxaliplatin. All patients then went on to surgery 8 – 12 weeks following neoadjuvant therapy. Twenty six patients underwent transabdominal transanal mesorectal (TATA) resection, 9 patients underwent a transanal endoscopic microsurgery (TEM), and 1 patient had an open low anterior resection. 3 patients have yet to go to surgery. FOLFOX was given to 25 of 42 patients adjuvently. Patients were analyzed for local control (LC), median survival (MS), overall survival (OS), and toxicity. Results: The median follow-up was 35 months. Complete pathological response was achieved in 12 (30.7%) patients, partial response was achieved in 25 (64%) patients, and 2 had stable disease at the time of surgery. There were no patients with local failure and only six (14%) patients progressed with distant metastatic disease. OS at 5 years was 92.8% with a MS of 37 months. Toxicity was acceptable with eight patients with grade 1, 5 patients with grade 2, and 3 grade 3 diarrhea. There were 3 (7%) patients with grade 1 neutropenia. Three patients experienced disease related death. Conclusions: With 5 years of follow-up data, our experience has shown that neoadjuvant chemoradiotherapy using IMRT to treat advanced stage rectal cancer is well tolerated and effective. Still further follow-up and additional studies will be required to confirm our findings.
A randomized, placebo-controlled, double blind, multicenter phase II adjuvant trial of the efficacy, immunogenicity, and safety of GI-4000 plus gem versus gem alone in patients with resected pancreas cancer with activating RAS mutations/survival and immunology analysis of the R1 subgroup.
Authors: Muscarella Peter , Wilfong Lalan S. , Ross Sharona B. , Richards Donald A. , Raynov Julian , Fisher William E. , Flynn Patrick J. , Whiting Samuel H. , Rosemurgy Alexander , Harrell Frank E , Mercaldo Nathaniel D. , Kosten Scott , Quiring John , Speyer Sue , Richman Joni , Ferraro John , Coeshott Claire , Cohn Allen , Rodell Timothy C. , Apelian David
Published: March 2020

e14501

Background: Patients with resected pancreas cancer treated with standard of care Gem have a median overall survival of 22 months (vs 20 months w/ observation). Activating mutations in ras occur in > 90% of pancreas cancer cases. GI-4000 is whole, heat-killed recombinant S. cerevisiae yeast that expresses mutated Ras proteins. This trial is designed to evaluate the efficacy, immunogenicity, and safety of GI-4000 plus Gem in patients with Ras mutant + resected pancreas cancer. Methods: The study enrolled 176 Ras mutant + pancreas cancer subjects post resection randomized 1:1 to GI-4000 plus Gem or placebo plus Gem (stratified by resection status; R0 or R1). Three weekly injections of GI-4000 or placebo were followed by 6 cycles of Gem 1000 mg/m2 iv (day 1, 8, 15 every 28 days). Monthly GI-4000 or placebo were administered on the Gem off-weeks and continued monthly until intolerance, disease recurrence, or death. The primary endpoint is RFS. Data for the 39 R1 subjects (GI-4000 n=19, Placebo n=20) have been unblinded and analyzed. Results: The GI-4000 group had an 11.4 week advantage in median overall survival (524 Days vs 444 Days), 16% advantage in 1 year survival (72% vs 56%), and a 4.6 week advantage in median RFS (287 Days vs 255 days). The GI-4000 group showed a significantly higher rate of mutation specific T cell response to Ras by ELISpot assay; 7/15 (47%) vs 1/12 (8%), p=0.032,with a more pronounced survival benefit in GI-4000 treated immune responders; 21.7 week advantage in median survival (596 Days vs 444 Days) compared to placebo. No significant novel toxicities have been observed to date. Conclusions: GI-4000 in combination with adjuvant Gem showed a clinically meaningful point estimate for the treatment effect on survival in R1 subjects with Ras mutant + pancreas cancer. GI-4000 was immunogenic and well tolerated. Ras specific immune response was associated with a more pronounced benefit in median survival. These data warrant further study in a definitively powered clinical trial for GI-4000 in the adjuvant setting in R1 subjects.
Relationship between tissue factor expression by human pancreatic cancer cells and activation of coagulation and thrombosis in a mouse model.
Authors: Geddings Julia E. , Wang Jian-guo , Cardenas Jessica C , Chantrathammachart Pichika , Williams Julie C , Back Ronald R , Church Frank C , Pawlinski Rafal , Key Nigel , Yeh Jen Jen , Mackman Nigel
Published: March 2020

e14505

Background: The increased risk of thrombosis in patients with cancer has been well established. However, the triggers in these patients have yet to be fully defined. Under pathological conditions, the potent procoagulant protein Tissue Factor (TF) is found in the circulation and may trigger thrombosis. Methods: We evaluated the level of TF expression in 4 different human pancreatic cancer cell lines. We also measured TF microparticle (MP) release from these tumors in vivo by flow cytometry and TF activity assay. We then used these lines in a mouse model of pancreatic cancer to evaluate the sources of TF that activate coagulation and contribute to thrombosis using a saphenous vein model. Results: We found that mice bearing orthotopic pancreatic tumors which express higher levels of TF (HPAC and HPAF) show increased activation of coagulation (measured by thrombin-antithrombin complex) as compared to mice bearing TF negative tumors (MIA-PaCa-2 and PANC-1). This activation of coagulation could be reduced by treatment with a human TF antibody. Further, mice bearing tumors derived from TF high cell line HPAC demonstrated an activation of coagulation despite a lack of circulating TF-positive MPs. Mice bearing TF expressing pancreatic tumors also demonstrated increased thrombosis by a saphenous vein model. Treatment of tumor-free mice with TF MPs did not result in an activation of coagulation or increased thrombosis unless mice were given 40-100 fold higher levels of TF bearing MPs than are found in the circulation of tumor bearing mice. Conclusions: The data suggest that TF on the tumor itself is involved in the activation of coagulation whereas circulating TF-positive MPs is likely to contribute to thrombosis. Elevated levels of TF-positive MPs may be used as a biomarker to identify cancer patients at risk for thrombosis.
Phase II study of weekly intravenous and intraperitoneal paclitaxel combined with oral S-1 for advanced gastric cancer with macroscopic peritoneal metastasis.
Authors: Yamaguchi Hironori , Ishigami Hironori , Emoto Shigenobu , Yamashita Hiroharu , Kitayama Joji
Published: March 2020

e14530

Background: This phase II study was performed to evaluate the efficacy and the tolerability of weekly intravenous and intraperitoneal paclitaxel (PTX) combined with oral S-1 in gastric cancer patients with macroscopic peritoneal metastasis. We previously reported a phase I and II study with the same regimen in gastric cancer patients with peritoneal metastasis, including patients with positive peritoneal washing cytology but negative macroscopic peritoneal metastasis. This trial was scrutinized and approved by a committee appointed by the Ministry of Health, Labour, and Welfare in Japan and performed under the special interim system for Advanced Medical Technology so as to generate an evidence for future approval of the treatment by the Ministry. Methods: Gastric cancer patients with primary tumors with macroscopic peritoneal metastasis confirmed by staging laparoscopy were enrolled. PTX was administered intravenously at 50 mg/m2, and intraperitoneally through a subcutaneous implanted access port at 20 mg/m2 on days 1 and 8. S-1 was administered orally twice daily at 80 mg/m2/day for 14 consecutive days followed by 7 days rest, repeated every 3 weeks. The primary endpoint was the one-year overall survival rate. Secondary endpoints were the response rate, efficacy against malignant ascites and safety. Results: In total, 35 patients were enrolled. All patients had several to numerous metastases to the distant peritoneum. The median number of administration course was 11 (range 2-29). The one-year overall survival rate was 77.1%. Massive malignant ascites decreased in 6 of 9 (66.7%) patients. Peritoneal washing cytology turned negative in 28 of 29 (96.7%) patients. The incidences of grade 3/4 hematological and non-hematological toxicities were 34% and 9%, respectively, all of which were reversible. Grade 3/4 toxicity was observed for neutropenia (34%), leukopenia (23%), anemia (9%). There were no treatment-related deaths. Conclusions: The combination chemotherapy regimen of weekly intravenous and intraperitoneal PTX combined with oral S-1 was well tolerated and active in gastric cancer patients with macroscopic peritoneal metastasis.
Intensity-modulated radiation therapy (IMRT) for anal cancer: Results from a multi-institutional retrospective cohort study.
Authors: Call Jason Andrew , Prendergast Brendan M , Jensen Lindsay G , Ord Celine B , Goodman Karyn A. , Jacob Rojymon , Mell Loren K. , Thomas Charles R. , Jabbour Salma , Miller Robert C.
Published: March 2020

e14555

Background: This study was done to assess the toxicity and efficacy of IMRT for anal cancer in a multi-institutional setting. Methods: Records of 152 total patients (pts) were reviewed retrospectively. Data on disease control and toxicity were collected as well as pt and treatment characteristics. Acute (<6 months) and late (>6 months) severe toxicity (grade >3) were recorded at each institution. Four were excluded for either presence of metastatic disease (2) or stage TX (2). There was data for late toxicity on 120 pts. Results: T stage was T1 in 28, T2 in 79, T3 in 29 and T4 in 12 pts. N stage was N0 in 77, N1 in 40, N2 in 19 and N3 in 12 pts. The median age was 56 yrs and median follow-up was 26.8 months. Cumulative IMRT dose was 51.25 Gy (median) (range: 4.32-61.2 Gy) in a median of 28 fractions (2-34). Chemotherapy was given in all but 2 pts and the most common regimen was 5- fluorouracil plus mitomycin-C. The median total elapsed treatment time was 40 days. Local control at 3 yrs was 87% and was significantly worse for patients with T3-4 disease (79% vs 90% at 3 years; p=0.04). There was no correlation between dose and local control. Regional control, distant control and overall survival were 97%, 91%, and 87% at 3 yrs, respectively. Nodal status was associated with regional and distal control as well as overall survival (p<0.01 for each). The most common acute severe toxicity was hematologic (41%). Severe acute GI, skin or other toxicity was 11%, 20% and 1% respectively. There were two grade 5 toxicities (hematologic and GI). Severe late toxicity was limited to skin (1%) and GI (3%). Conclusions: IMRT resulted in excellent local control in this multi-institutional cohort of pts. Although T stage did predict for worse local control, most pts with T3-4 disease were controlled with IMRT. Nodal status predicts for regional and distal control as well as overall survival. Severe toxicity was acceptable with this technique.
Defining eligibility of FOLFIRINOX for first-line metastatic pancreatic adenocarcinoma (MPC) in the province of British Columbia: A population-based retrospective study.
Authors: Gill Sharlene , Ho Maria Yi , Kennecke Hagen F. , Renouf Daniel John , Cheung Winson Y. , Lim Howard John
Published: March 2020

e14588

Background: FOLFIRINOX is a first line treatment option for patients with MPC and is associated with improved survival yet significantly more treatment-related toxicities than standard gemcitabine.. Our aim was to determine the proportion of patients with MPC who would be eligible for FOLFIRINOX therapy based upon the pivotal ACCORD study eligibility criteria. Methods: Patients with confirmed metastatic pancreatic cancer at the time of referral to the BC Cancer Agency between 2004-2007 were identified from the GI Outcomes Unit Database. Proportion of patients that met the ACCORD study eligibility criteria was determined by chart review. Criteria for FOLFIRINOX exclusion were assessed using descriptive statistics. Results: 100 consecutive patients with complete chart records and metastatic pancreatic cancer were identified. 52(52%) were male and the median age was 68. The most common sites of metastases were liver (63%) and peritoneum (22%). Only 26 patients fulfilled the ACCORD study eligibility criteria. The most common reasons for FOLIFIRINOX exclusion per ACCORD were poor ECOG score of 2 or greater (64%), age of 76y or greater (22%), elevated bilirubin (22%) and inadequate renal function (6%). Conclusions: Despite the proven survival benefit of FOLFIRINOX, only one-quarter of real-world patients with MPC would potentially be considered eligible for such combination chemotherapy.
Predictors for survival in hepatocellular carcinoma.
Authors: Misek Glen I. , Jayanti Venkata K
Published: March 2020

e14640

Background: The global incidence of HCC is over 700,000 patients making it the sixth leading cancer and the prognosis is poor with a 5 year survival of 11%. It is important to understand if there are differences in survival based on the presence of Hepatitis B or C or alcohol cirrhosis, ethnicity and/or treatments employed in various stages of the disease. Methods: A robust global retrospective study of HCC patients was conducted with nearly 4,000 patient records from US, Germany, France, Spain, Italy, China and South Korea in 2011. Of these nearly 800 included deceased patients. These records were analyzed to study if any known factors such as ethnicity, presence of Hepatitis B, Hepatitis C or alcohol cirrhosis and/or treatments used at diagnosis could serve as predictors for survival. Kaplan-Meier curves were plotted to understand the differences in survival based on ethnicity, Child-Pugh status and treatments employed at various stages. Results: One year survival is lower in China/ Korea compared to US and EU, however, five year survival rates are comparable across regions. Associated hepatitis or cirrhosis does not convey any differences in one year survival whether patients received sorafenib as first line treatment or not. Statistically significant higher one year survival rates are observed for HCC patients in Europe and USA receiving transarterial chemoembolization (TACE) compared with patients receiving sorafenib first line. However, in China and Korea there is no such difference. Across all three regions: USA, EU and Asia there is no difference in survival in stage IV patients receiving sorafenib or no sorafenib. No significant differences in one year survival are seen in USA, EU and Asia for patients with Hepatitis C or B or cirrhosis compared to those with no history of liver disease. The Child-Pugh C patients had lower survival compared to Child-Pugh A or B patients. Conclusions: Early diagnosis of HCC, early intervention and treatment appear to show survival benefits as opposed to drug treatment with sorafenib initiated in the later stages of the disease. Efforts should increase for screening, early detection and treatment initiation at early stage to improve outcomes in HCC patients.
Epidermal growth factor receptor (EGFR) status and prognosis in gallbladder cancer.
Authors: Martins Sandro José , Pais-Costa Sérgio Renato , Artigiani-Neto Ricardo , Farah José Francisco de Mattos , Franco Maria Isete Fares , Goldemberg Alberto
Published: March 2020

e14657

Background: Studies from USA, Asia and Australia showed EGFR over-expression in gallbladder cancer (GC), and recent case reports suggest a role for EGFR targeted therapies in this disease. Methods: We studied the prognostic role of EGFR expression and its association with clinicopathologic features in forty-two GC patients surgically treated at our center, from 1995 to 2006. None received targeted cancer therapeutics. Tissue microarray blocks containing neoplastic tissue and tumor-adjacent non-neoplastic biliary epithelia were obtained and assessed for immunohistochemical (IH) expression of EGFR, cyclo-oxygenase-2 (COX2), E-cadherin and p53 protein. Nonparametric correlations were assessed by Spearman’s rho; survival analysis was performed using the Kaplan-Meier method and Cox regression; and p-values were computed for two-tailed tests. Results: EGFR IH scores 0, +1, +2, and +3 were observed in 48.7%, 23.1%, 17.9%, and 10.3%, respectively. They were correlated with p53 staining (rho=0.48; p=0.002); T-stage (rho=0.38; p=0.016); serum CA-19.9 (rho=0.48; p=0.016); and serum CEA (rho=0.56; p=0.004). Median overall survival (OS) was 8.0 months (95% C.I.: 5.6 to 10.3); 1-year and 2-year survival rates were 43.7% and 23.5%, respectively. OS were 18.0 months, 14.0 months, and 4.0 months for tumors with 0, 1+ and 2+ to 3+ EGFR staining, respectively. Univariate analysis suggested a worse prognostic significance for low serum albumin (p=0.001); elevated CEA (p=0.007) and CA-19.9 (p=0.007) levels; positive surgical margins (p=0.001); gallbladder fundus tumors (p=0.007); histologic grade 3 (p=0.003); positive nodes (p=0.001); lymphovascular invasion (p=0.001); tumoral necrosis (p=0.004); perineural invasion (p=0.002); and EGFR expression (p=0.004). In the multivariate analysis, low serum albumin (p=0.006), tumoral necrosis (p<0.001) and EGFR expression (p<0.001) predicted poor OS. Conclusions: We found tumor immunoreactivity for EGFR in nearly half of the cases and it was independently associated with poor survival in GC patients.
Factors associated with local-regional failure after definitive chemoradiation for locally advanced esophageal cancer.
Authors: Amini Arya , Welsh James , Allen Pamela , Xiao Lianchun , Suzuki Akihiro , Blum Mariela A. , Hofstetter Wayne Lewis , Liao Zhongxing X. , Lee Jeffrey H , Bhutani Manoop S. , Komaki Ritsuko
Published: March 2020

e14669

Background: Esophageal cancer is often treated with a trimodality approach (chemotherapy and radiation followed by surgery). However a significant proportion of such patients achieve a clinical complete response (cCR) following chemoradiation alone. We retrospectively analyzed patients who reached cCR after definitive chemoradiation for locally advanced esophageal cancer to identify clinical predictors of local disease recurrence. Methods: We identified 141 patients who obtained initial cCR after definitive chemoradiation for esophageal cancer from January 2002 through January 2009. The initial response to treatment was assessed by endoscopic evaluation and biopsy results, with cCR defined as having no evidence of disease present. Patterns of failure were categorized as in-field (within the planned treatment volume [PTV]), outside the radiation treatment field, or both. Results: At a median follow-up of 22 months (range 6-87 months), 77 patients (55%) had experienced disease recurrence. Most first failures (32, or 23%) were outside the radiation field, followed by 30 (21%) within the field and 15 (11%) were both. In multivariate analysis, in-field failure after cCR was associated with a post-treatment standardized uptake value (SUV) on positron emission tomography of >3.5 (odds ratio [OR] 4.93, p=0.022), squamous histology (OR 0.07, p=0.010), and borderline for T3/T4 disease (OR 10.25, p=0.055). All failures, in-field and out-of-field, correlated with T3/T4 disease (OR 11.61, p=0.015), N1 disease (OR 5.07, p=0.010), pretreatment SUV >10 (OR 4.00, p=0.048), and post-treatment SUV >3.5 (OR 3.59, p=0.052). Conclusions: Clinical characteristics can be used to predict failure patterns after definitive chemoradiation. Such risk-assessment strategies can help individualize therapy.
The prognostic value of P53 in the nodal metastization of gastric cancer.
Authors: Quaresma Luisa , Fradique Antonio CALDEIRA , Cabrita Fernanda , Pupo Alexandra , DA Silva Guedes , Silva Gualdino , Esteves Jorge , Marques Mateus , Oliveira Mario , Pina Filomena , Bruno Da Costa Ligia
Published: March 2020

e14673

Background: Lymph node Metastases play a major role as an independent prognostic factor in gastric cancer. Presence of distal lymph node metastases assumes a pejorative prognostic significance, and represents a problem in terms of therapeutic approach. For this reason it’s of major interest to find predictive markers of distal lymph node chain involvement. The P53 tumor suppressor gene, a product of the TP53 gene works normally as a brake on DNA replication, as suppressor of angiogenesis and triggering of apoptosis. The gene most frequently mutated in gastric cancer is the TP53, that is responsible for the production of P53 mutant protein, which forms inactive complex with the native protein, and manifest by the overexpression of p53 in immunocytochemistry. The overexpression of P53 gene has been considered a bad prognostic factor associated mainly with lymph node metastases. Methods: This study seeks to determine the relation between the expression of P53 and the presence of distal lymph node metastases as an indicator for an extended lymphadenectomy. A total of 50 patients undergoing surgery with D2 lymphadenectomy for gastric carcinoma with curative intent were enrolled in this work. Therefore it was evaluated in 1,786 lymph nodes the correlation between the P53 expression with tumor location, size, histological type, depth , number of nodes involved, number of distal lymph node metastases and the TNM stage. Results: In all parameters, mutant P53 protein related with indicators of poor prognosis. In particular has demonstrated a statistical significant correlation (p=0.019) with the presence of distal lymph node metastases. The main objective of this study which was finding a prognostic predictor of distal nodal metastases has been reached. Conclusions: Mutant P53 protein is a good prognostic indicator, for the presence of distal lymph node involvement in gastric carcinoma.
Diffusion weighted MR imaging versus F18 FDG PETC CT in identifying small hepatic metastases.
Authors: Govindarajan Mallarajapatna , Nagaraj Kanakapura Ramanna , Kallur Kumar G , Prashanth Gothlu Ramachandra , Shivakumar Swamy , Sudhakar S , Rajkumar Krishnappa , Indresh Desai , Sridhar P S , Ajaikumar Basavalinga S.
Published: March 2020

e14675

Background: This exploratory study assessed the ability of diffusion weighted MRI imaging in identifying small liver metastases as compared to F18- FDG PETCT. Methods: Patients with diagnosis of carcinoma of breast, lung, colorectal, pancreas, neuroendocrine and HCC who were staged for their disease using PET CT and MRI were included in the study. We randomly analyzed and compared PETCT and MRI images of 40 patients with hepatic metastases for sensitivity in detection of metastatic lesions in the liver on PETCT and MRI. Where possible, biopsy was performed if MRI/PET CT showed one or two small lesions in the liver. We performed ANCOVA to detect differences between PETCT and MRI controlling for primary sites of disease as a covariate. Results: The mean number of small lesions detected on PETCT was 0.92 where as it was 3.96 in MRI. There was a significant increase in small (p=0.02) and total number of lesions (p=0.01) seen on MRI compared to PET CT but not in large lesions. MRI was able to detect subcentimeter lesions more accurately than PET CT. Random biopsies done on small lesions found on MRI were positive for disease. MRI was able to detect small subcentimeter lesions three times more accurately than PET CT. Conclusions: MR diffusion is more sensitive in indentifying subcentimeter metastatic deposits in the liver that could help in accurate staging when PET CT is negative for liver metastases or when locoregional treatment for oligometastases is contemplated. However, pixels of DWI MRI (like reduced Signal to noise ratio at high b value, artefacts at liver edges and left lobe due to exaggerated susceptibility weighting and spin dephasing) need to be addressed by using other morphological images.