bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined activity of the cancer metabolism inhibitor MPC-8640 and 5-fluorouracil in xenograft models.
Authors: Baichwal Vijay R. , Bradford Chad , Patton J. Scott , Reeves Leslie , DeMie Lynn , Fotheringham Lori , Roman Orvelin , Douce Thomas B , Brown Brita , Carlson Robert O. 
Published: March 2020

e13581 Background: Nicotinamide (Nam) phosphoribosyltransferase (Nampt) catalyzes the rate-limiting step in NAD biosynthesis from Nam. Nampt inhibition causes NAD depletion, inhibition of ATP synthesis and cell death. MPI-0487316 is a selective Nampt inhibitor with potent tumoricidal activity against cancer cell lines of diverse origin. MPC-8640, an orally bioavailable prodrug of MPI-0487316, induces regressions in xenograft models. Combining Nampt inhibitors with 5-fluorouracil (5-FU) results in synergistic tumoricidal activity in cells. We have explored the combination of MPC-8640 with 5-FU in a colon carcinoma xenograft model. Methods: In vitro studies were done in HCT-116 human colon carcinoma cells. Cell viability was measured by determining ATP levels. Xenograft studies were done with cells implanted subcutaneously into athymic mice (nu/nu). MPC-8640 was dosed orally at 12 to 48 mg/kg daily on Days 1-7 and 15-21. 5-FU was dosed intraperitoneally, weekly at 100 mg/kg. Results: MPI-0487316 showed synergistic tumoricidal activity in vitro with 5-FU. In xenograft studies, the prodrug MPC-8640, at 12, 24 and 36 mg/kg, resulted in tumor growth inhibition (TGI) of 64%, 98% and 91%, respectively, at the end of dosing on Day 22 and tumor regression of 5%, when dosed at 48 mg/kg. In the 36 and 48 mg/kg group, 20% and 10% of the mice, respectively, had no detectable tumors by the end of the study on Day 42. In another study, mice were given 5-FU or MPC-8640 as single agents or in combination. Combining 5-FU with MPC-8640 at 24 mg/kg resulted in 45% tumor regression on Day 21 compared to TGI of 88% and 78% for MPC-8640 or 5-FU, respectively, dosed as single agents. Similarly, combining 5-FU and MPC-8640 at 32 mg/kg resulted in 83% tumor regression on Day 21 compared to TGI of 86% and 78% for MPC-8640 and 5-FU, respectively, dosed as single agents. The combinations of 5-FU and MPC-8640 were well-tolerated with <10% change in median body weight. Conclusions: A combination of MPC-8640 with 5-FU causes tumor regression in a colon carcinoma xenograft model and is more effective than either agent dosed alone. Thus, MPC-8640 may have potential for treating cancers as a single agent or in combination with antimetabolites.
Interim results of an open-label, single-arm trial of ultratrace I-131-iobenguane in patients with metastatic pheochromocytoma/paraganglioma (Pheo).
Authors: Pryma Daniel A. , Coleman R. Edward , Noto Richard , Goldsmith Stanley J. , Perini Rodolfo F. , Jimenez Camilo , Pampaloni Miguel H , Serafini Aldo N. , Wahl Richard L. , Kostakoglu Lale , Conley Jennifer , Ford Kathy , LaFrance Norman David , Babich John W. 
Published: March 2020

e13592 Background: To evaluate the therapeutic efficacy of no carrier added (nca) I-131-MIBG in pheo as measured by > 50% reduction of all antihypertensive medication for ≥ 6 months. Secondarily, to evaluate safety (including radiation absorbed dose to normal organs) and the proportion of subjects with objective response per modified RECIST and biomarker response by change in Chromogranin A (CgA). Methods: Pts with metastatic pheo causing secondary hypertension were treated with up to two 500 mCi doses of 131I-nca-MIBG 3-6 months apart. The administered dose was limited by pretreatment organ dosimetry and normal tissue tolerance estimates of Emami (1991). Response and toxicity were evaluated for a minimum of 1 year. Results: To date, 41 pts (17-72 years) received at least one treatment (full analysis; FA); 34 pts received 2 treatments (per protocol; PP); All patients have been followed at least 1 year or until death. The primary endpoint of sustained reduction in HTN meds was achieved in 32% and 29% of PP and FA, respectively. In total, 25/41 subjects who received at least 1 treatment had ≥ 50% reduction in their HTN meds. Mean duration of the reduction was 7.7 ± 6.6 months (range 0.1 – 22.1 months). Objective PR was seen in 41% (PP) and 34% (FA). 56% of PP had at least objective MR. All subjects in PP had at least stable disease and 90% in FA had at least stable disease. At 8 months there was a 60±33% reduction in CgA from baseline in PP. Primary toxicity was myelosupression: grade 3 (17%), grade 4 (20%). Grade 3 GI disorders were 15%. There were 3 deaths during follow up, all due to disease. Biomarker response correlated well to objective response and HTN improvement. Thrombocytopenia was the most common treatment-emergent SAE (n=9) considered related to study drug. No other treatment-emergent SAE was considered related to study drug in > 2 subjects. Conclusions: 11 of 34 pts in PP in this ongoing study met the primary endpoint of a positive clinical benefit (decreased HTN meds), which correlated with objective tumor response and biomarker levels in this disease with no approved, efficacious therapies. Toxicity for all patients (n=41) was tolerable and predominantly limited to myelosupression.
Utility of the Edmonton Frail Scale (EFS) in identifying frail elderly patients during treatment of colorectal cancer (CRC).
Authors: Meyers Brandon M , Yelamanchili Radhika , Rask Sara , Al-Shamsi Humaid Obaid , Phillips Callista Maria , Papaioannou Alexandra , Zbuk Kevin M. , Gu Chu Shu , Jeyabalan Neera , Dhesy-Thind Sukhbinder K. 
Published: March 2020

e14001 Background: CRC is the second leading cause of cancer-related death, and 40-50% of patients are older than 70 years. Frailty is a concept that has been proposed by geriatricians as an indicator of functional age. The EFS is a 15 point incremental scale; it is quick (<5 min), and simple to administer. We conducted a pilot study to establish if the EFS would add utility beyond clinician’s expertise. The primary objective was to determine if there was an association between the EFS and receipt of chemotherapy. Methods: The EFS was administered to stage II-IV CRC patients ≥70 years, referred to a Medical Oncologist at a tertiary care centre. The EFS was completed by one of the investigators, with the treating oncology team blinded to results and a follow up 14 month chart review. Results: Forty-six patients were enrolled with the following characteristics: average age 76, 48% male, 78% performance status (PS) 0-1, and 21 (46%) started chemotherapy. The EFS was reproducible between visits (r = 0.81 [CI 0.64-0.9, p<0.0001]). There was no correlation between the EFS and receipt of chemotherapy for the study population as a whole. As none of the 16 stage II patients had high-risk features requiring chemotherapy, the analysis was repeated excluding these patients. There was a reduced likelihood of receiving chemotherapy for stage III/IV patients with higher EFS scores (Odds ratio 0.56 [CI 0.37-0.85, p<0.01] per unit increment). A similar effect was observed after multivariable analysis (adjusting for PS, age, stage and gender, Odds ratio 0.41 [CI 0.18-0.96, p<0.05] per unit increment). No correlation existed between EFS and upfront dose reductions, choice of less toxic regimens, or hospitalization secondary to grade 3/4 toxicities. Conclusions: This pilot study suggests the EFS can identify patients that Oncologists may have thought were too frail for chemotherapy, independent of PS. Therefore, the EFS has the potential to add a reproducible, and quantifiable measure of frailty to the clinician’s decision making armamentarium. The next study phase will employ the EFS real-time, and determine if using the EFS can minimize complications and unplanned health care utilization in elderly cancer patients.
Diabetes, metformin use, and colorectal cancer survival in women: A retrospective cohort study.
Authors: Cossor Furha Iram , Adams-Campbell Lucile L. , Chlebowski Rowan T. , Gunter Marc J , Johnson Karen , Martell Robert E. , McTiernan Anne , Simon Michael S. , Rohan Thomas , Wallace Robert B , Paulus Jessica 
Published: March 2020

e14005 Background: Observational studies have associated metformin use with lower colorectal cancer incidence but few studies have examined survival impact. We examined the relationship between metformin use, diabetes, and survival in postmenopausal women diagnosed with colorectal cancer while participating in the Women’s Health Initiative (WHI) Clinical Trial or Observational Study. Methods: 2,066 postmenopausal women with colorectal cancer diagnosed while enrolled in the WHI were followed for a median of 4.1 years, with 589 deaths overall and 414 colorectal cancer deaths. In this cohort, overall and colorectal cancer-specific survival were compared among women with diabetes who reported ever using metformin (n=84); those with no reported use of metformin (n=128); and women without diabetes (n=1854). Cox proportional hazard models were used to estimate the associations between metformin use, diabetes and survival outcomes from the time of colorectal cancer diagnosis. Two strategies were used to adjust for potential confounders: multivariate adjustment with known predictors of colorectal cancer survival and construction of a propensity score for the likelihood of receiving metformin, with model stratification by propensity score quintile. Results: After adjusting for age and stage at diagnosis, women with diabetes on metformin had no significant difference in colorectal-cancer specific survival compared to metformin non-users (HR 0.75; 95% CI 0.40 -1.38, p=0.67) or compared to women without diabetes (HR 1.00; 95% CI 0.61 - 1.66, p=0.99). With propensity score adjustment, the HR for colorectal cancer-specific survival in women with diabetes on metformin compared to non-users was 0.90 (95% CI 0.48 – 1.69, p=0.75). Women with diabetes reporting metformin use had no significant difference in overall survival compared to non-users (HR 0.84; 95% CI 0.51 – 1.37; p=0.48) or non-diabetics (HR 1.20; 95% CI 0.80 - 1.79; p=0.39). Conclusions: In postmenopausal women with colorectal cancer and diabetes, no statistically significant difference was seen in colon-cancer specific survival in those who used metformin. Analyses in larger populations of colorectal cancer patients are warranted.
Current practices in 1st- (1L), 2nd- (2L), and 3rd-line (3L) treatment for metastatic colorectal cancer (mCRC).
Authors: Thompson Stephen F , Iqbal Sheikh Usman , Naoshy Sarah , Ng Daniel B , Andria Michael L , Sherman Steven A , Malangone Elisabetta , Stern Lee , Gorritz-Kindu Magdaliz 
Published: March 2020

e14028 Background: Up-to-date information concerning the optimal regimen assignment and sequencing of therapies is lacking for the treatment of mCRC patients. By tracking trends in treatment choice, this retrospective, observational study assesses current treatment patterns in mCRC patients by line of therapy. Methods: Using electronic medical record data from one of the largest US oncology databases (SDI), treatment regimens for 1L, 2L, and 3L were assessed for patients age ≥18 yrs diagnosed with mCRC from 1/1/04-7/31/11 who received anticancer agents. Results: 1,793 stage IV patients were identified in 1L, 1,050 in 2L, and 504 in 3L. Overall mean age was 60.4 yrs, and 54.6% were men. The most common comorbidities were hypertension (18.0%), lipid metabolism disorders (10.6%), and diabetes (8.6%). 47.8% had commercial insurance, 37.2% Medicare, 8.5% Medicaid, and 4.6% self pay. 1,026 patients received bevacizumab (B) in 1L, 583 in 2L, and 204 in 3L. Patients were more likely to receive FOLFOX (FX) + B in 1L and 2L. The top 3 regimens are shown in the table below. For patients who began treatment with B and continued B in a subsequent regimen, mean dose of B increased from 443.7 mg/kg (1L) to 567.0 mg/kg (2L) and 618.1 mg/kg (3L). Conclusions: FX is the regimen of choice in mCRC. In terms of biologics, B is more commonly used in 1L/2L than 3L. Given that approximately half the mCRC patients progressed to 2L/3L treatment, this likely reflects an unmet need for advanced therapies for the effective treatment of the disease. Furthermore, consistent dose escalation with continued B use across 2L/3L was seen despite that use of B in 3L mCRC is inconsistent with NCCN guidelines. Additional research on outcomes implications is needed, including mortality, patient toxicity, and costs. [Table: see text]
Prognostic significance of KRAS and BRAF mutations in Japanese patients with colorectal cancer.
Authors: Oki Eiji , Nakanishi Ryota , Ando Koji , Saeki Hiroshi , Ohga Takefumi , Kakeji Yoshihiro , Tsujitani Shunichi , Kohnoe Shunji , Maehara Yoshihiko 
Published: March 2020

e14033 Background: Recent evidence highlights the potential prognostic and predictive value of BRAF and K-RAS gene alterations in patients with colorectal cancer. To determine whether differences exist in the molecular mechanisms driving colorectal cancer between Japanese and Western, we characterized Japanese patients with colorectal cancer by assessing genetic alterations involved in cancer progression and response to treatment. Methods: We retrospectively evaluated 254 Japanese diagnosed with colorectal cancer at our institution between 1994 and 2009. Mutations in KRAS codons 12 and 13 and BRAF codon 600 were identified by direct sequencing. Microsatellite instability (MSI) status was determined by genotyping in the 5 loci. Associations between KRAS or BRAF mutation and clinicopathological characteristics and prognosis were evaluated. Results: KRAS and BRAF mutation were detected in 33.5% and 6.7% of all patients, respectively. KRAS mutation was correlated with poor recurrence free survival (RFS) (p = 0.03), especially in stage II patients (p = 0.007). BRAF mutation was significantly correlated with the anatomical site of tumor (p < 0.001), tumor grade (p = 0.001) and high frequency of microsatellite instability (p < 0.001). BRAF mutation was also correlated with poor overall survival in all cases of patients (p = 0.009). Overall, the background of KRAS and BRAF mutation was almost similar between CRCs of Western countries and those of Japanese. However, KRAS mutation status was considered to be helpful to predict recurrence in Japanese patients with stage II CRC. Conclusions: Our findings indicate that BRAF and K-RAS mutation plays an important role in the tumorigenesis of colorectal cancer. These results indicate that molecular analysis for BRAF and K-RAS may be a useful biomarker for identifying patients with right-sided colon cancer with poor outcome who may benefit from a more individualized course of therapy.
Recombinant adeno-viral human p53 gene combined with FOLFOX4 in the treatment of advanced colorectal cancer.
Authors: Zhang Zhong-guo 
Published: March 2020

e14036 Background: Metastatic or recurrent colorectal cancers generally become unresectable and will not respond to radio- or chemo-therapy. Studies showed that p53 has a synergic effect with radio- or chemotherapy. This study is to determine the efficacy and safety of recombinant adenoviral human p53 gene (rAd-p53) combined with standard FOLFOX4 regimen in treatment of advanced colorectal cancer. Methods: From July 2008 to Dec. 2011, 56 patients with an advanced colorectal cancer or local recurrent disease were treated with rAd-p53 and standard FOLFOX4 regimen. For local tumor, 1-4×1012 viral particles (VP) of rAd-p53 diluted into 5 ml of saline solution was injected into tumor at multiple directions, once a week for 6 weeks. If tumor spreading into abdominal cavity, 4×1012 VPs diluted in 500 ml of saline solution were injected inraperitoneally, twice in 2 weeks. If having lung or liver metastasis, 2×1012 VPs diluted into 100 ml of saline solution were given intravenously twice in 2 weeks. Three days after the first gene therapy, the standard FOLFOX4 regimen was given for six cycles. Results: The follow-up time was 3~38 months with a median of 19.5 months. Among these patients, 8 (14.3%) patients were assessed as complete response, 31 (55.4%) as partial response and 11 (19.6%) as stable disease. After the combined treatment, a radical resection was successfully performed in 18 cases with local recurrent disease. All these patients were still alive at the last follow-up. Common adverse events were 38.4~40.5 oC self-limited fever, occurring in 86% patients. No serious adverse events were observed. Conclusions: rAd-p53 combined with FOLFOX4 is a safe and effective treatment for advanced colorectal cancer or local recurrent disease.
Identification of a 14-gene signature that predicts survival in colorectal cancer with liver metastasis.
Authors: Chung Jo L , Pollack Jonathan , Chua Mei-Sze , So Sam , Lin Chii-Dean , Lin Albert Y. 
Published: March 2020

e14037 Background: Colorectal cancer (CRC) is the third leading cause of cancer death in men and women combined in the USA. Colorectal liver metastasis (CLM), the most common metastasis of CRC, accounts for at least two thirds of CRC deaths. The purpose of this study is to identify a gene signature that predicts patient survival in patients with CLM. Methods: We analyzed the gene expression profiles of specimens from 24 CLM patients (M:F = 14:10) who underwent metastatic liver resection and unmatched primary CRC specimens from an independent cohort of 30 patients (M:F = 14:16). The association between gene expression levels and survival outcome was evaluated using Cox proportional hazards regression. Random Forests and risk scores were used to construct a gene expression-based survival classifier. Results: Based on survival classifier of CLM patients, a 14-gene signature was developed. According to leave-one-out cross validation, all 24 CLM patients (median follow-up time of 25 months) were correctly assigned into high-risk or low-risk groups (p=0.001). This 14-gene signature was then validated in an independent cohort of 30 primary CRC patients (median follow-up time of 42.2 months; p= 0.03) and a subset of 11 patients who were diagnosed at presentation or follow-up with liver metastasis (M:F = 5:6; median follow-up time of 27.6 months; p=0.04). Conclusions: We have identified a 14-gene signature that predicts the survival of CLM patients after liver resection, with validation in an independent cohort. Although sample size is small, the significance level achieved with our survival analysis warrants further investigation of this 14-gene signature in a larger sample size.
Should bevacizumab (B) be included in the first-line treatment of elderly patients with advanced colorectal cancer (CRC)? Results from a community-based Italian observational study.
Authors: Lutrino Stefania Eufemia , Schirripa Marta , Calvetti Lorenzo , Rosati Gerardo , Giampieri Riccardo , Avallone Antonio , Cordio Stefano Sergio , Berretta Massimiliano , Rojas Llimpe Fabiola Lorena , Foltran Luisa , Loupakis Fotios , Scartozzi Mario , Lonardi Sara , Pinto Carmine , Falcone Alfredo , Cascinu Stefano , Bordonaro Roberto , Zagonel Vittorina , Fasola Gianpiero , Aprile Giuseppe 
Published: March 2020

e14040 Background: Data on B for elderly patients with advanced CRC are scarce, although recent analyses demonstrated safety for its use. To investigate the efficacy and safety of treating older pts with B and chemotherapy in the clinical practice a national cohort was analyzed. Methods: In this observational cohort study 213 elderly patients from 9 Italian centers who received first-line B combined with chemotherapy were enrolled. Demographics and comorbidities were captured, along with efficacy and toxicity results. Predefined endpoints were response rate, progression-free, overall survival, and safety. Survival curves were generated with Kaplan-Maier methodology. Results: Median age was 72 (66-84), PS was 0-1 in 96%. Comorbidities at study entry were reported in 153 pts (72%): cardiovascular (including hypertension) 107, diabetes 32, respiratory 15, endocrine 10, neurological 10, renal 7, other diseases 51. Comprehensive geriatric evaluation with ADL, IADL and CIRS scores was available for only 64 pts (29%) reporting median values of 6, 8 and 20 respectively. Companion chemotherapy was 5-FU alone for 27 (12.6%), oxaliplatin-based doublet for 75 (35.2%) and irinotecan-based combination for 111 (52.1%). 81 pts had chemotherapy dose reduction, and 23 interrupted B before progression. Disease control was achieved in 86%, with median PFS/OS of 8.8/18.9 months. 76 pts were maintained on B alone or B plus 5-FU. Main toxicities were neutropenia (44%), anemia (37.5%), diarrhea (40.8%), mucositis (25.8%) and hand-foot syndrome (14.1%). Sensorial neurotoxicity was frequent among pts receiving oxaliplatin. Specific B-induced toxicities were induced or worsened hypertension in 48 pts (22.5%), proteinuria in 24 (11%), and venous or artherial thromboembolism in 16 (7.5%). Conclusions: To treat elderly CRC pts with B and chemotherapy is safe and major efficacy endpoints did not differ from expected. Geriatric evaluation is underused in the common practice and better tools are required to select elderly to be treated with antiangiogenics.
Effect and safety of FOLFOXIRI+b-mab as preoperative chemotherapy for multiple liver metastases of colorectal cancer.
Authors: Ichikawa Yasushi , Goto Ayumu , Shimamura Takeshi , Ishikawa Takashi , Watanabe Jun , Watanabe Kazuteru , Ota Mitsuyoshi , Fujii Shoichi , Akiyama Hirotoshi , Tanaka Kuniya , Endo Itaru 
Published: March 2020

e14047 Background: R0 resection for liver metastases of colorectal cancer is one of the promising treatment to improve prognosis of advanced colorectal cancer. Recently, effective anti-cancer drugs and various regimens using them were created and some advanced inoperable liver metastases were converted to operable by these chemotherapy. Therefore, development of powerful regimens to shrink liver metastases strongly is an important issue. In our department phase I/II study of FOLFOXIRI+B-mab including fluoroiuracil/oxaliplatin/irinotecan/bevacizumab for advanced liver metastases of colorectal cancer as pre-operative chemotherapy has been conducted now. Methods: The study was designed as a single-arm, open-label phase I/II trial. Phase I was conducted as sequential dose escalation to define the maximum-tolerated dose (MTD) of irinotecan. Patients who are colorectal cancer with 4 or more liver metastases and no other distant metastases are included. The regimen includes bevacizumab; 5 mg/kg, oxaliplatin; 85 mg/m2, l-LV; 200 mg/m2, 5FU; 400 mg/m2 administered on day 1, followed by 5FU; 2400 mg/m2 continuously administered for 46 hours. Dose escalation of Irinotecan was planned from level 1; 150 mg/m2 , level 2; 180 mg/m2 and level 0; 125 mg/m2. In phase II, R0 resection rate of liver metastases as primary endpoint will be evaluated using MTD of irinotecan estimated in phase I. Results: Currently, 6 patients were studied. One patient showed grade 3 diarrhea as dose-limiting toxicity. For the other 5 patients, the study was accomplished. Grade 4 neutropenia was detected in 60%, however no patient showed febrile neutropenia. Excluding hematological toxicity, grade 3 or worse adverse event was only one grade 3 diarrhea described above. All 5 patients were performed R0 resection. All 5 patients showed PR and average of reduction rate was 62.7%. There was no pathological CR in the 5 patients who was performed R0 resection. There was no severe postoperative complication in them. Conclusions: This regimen is safe and shows high PR rate. So, the regimen is effective and improve R0 resection rate for multiple liver metastases of colorectal cancer. Further investigation of this study is still ongoing now.