bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypermethylation of the KEAP1 gene in colorectal cancer and association with disease progression.
Authors: Maiello Evaristo , Parrella Paola , Latiano Tiziana Pia , Barbano Raffaela , Muscarella Lucia Anna , Pasculli Barbara , la Torre Annamaria , Coco Michelina , Di Maggio Gabriele , Fazio Vito Michele 
Published: March 2020

e14655 Background: Aberrant methylation of the KEAP1 (Kelch-like ECH-associated protein 1) gene promoter is emerging as a main mechanism of dysregulation of the NrF2 (nuclear factor-erythroid 2-related factor 2 ) which plays a pivotal role in the cellular response to oxidative stress. Under basal conditions, Nrf2 is retained in the cytoplasm by the binding with Keap1 and it is maintained at a reduced level by the Keap1-dependent ubiquitination and proteasomal degradation systems. Reduced Keap1 expression by promoter aberrant methylation allows Nrf2 to translocate in the nucleus and to activate the detoxification pathway leading ultimately to drug resistance. Methods: We determined KEAP1 promoter methylation status in 50 metastatic colorectal cancer (CRC) and 9 normal colonic mucosa samples by using quantitative methylation specific PCR in real time (QMSP). The median age of the patients cohort was 65 (IQR 57-74) years. At diagnosis 12 patients were staged Duke D and 38 were staged as Duke C. As first line treatment the FOLFOX or FOLFIRI therapeutical schemes were used. Results: Methylation was detected in 20 out of 50 CRC (40%) and methylation levels were significantly higher in tumour samples (Median 0.65, IQR 0-8.28) as compared with normal colonic mucosa (Median 0, IQR 0-0.08) (P=0.03). Tumours from patients who experieced disease progression had significantly higher methylation levels (Median 0.53; IQR 0-7.61) as compared with patients showing partial response (Median 0, IQR 0-2.21) or disease stability (Median 0, IQR 0-0) (P=0.03 Kruskall Wallis Test). Conclusions: Our results suggest that Keap1 aberrant methylation is a frequent event in colorectal cancer and is associated with response to chemotherapeutical treatments.
Double KRAS and BRAF mutations in colorectal cancer in a single oncologic department series.
Authors: Guglielmini Pamela Francesca , Rossi Maura , Grosso Federica , Orecchia Sara , Galliano Marco , Bennicelli Elisa , Zai Silvia , Fusco Vittorio , Libener Roberta , Mariani Narciso , Spinoglio Giuseppe , Piovano Pierluigi 
Published: March 2020

e14657 Background: KRAS and BRAF mutations have prognostic and predictive value in colorectal cancer and are predominantly mutually exclusive. Only a few cases of double mutations (DM) have been reported so far but the actual incidence and presumed role in worsening prognosis is still unknown. Here we report on a series of KRAS and BRAF mutations, focusing on three cases of KRAS and BRAF DM. Methods: since May 2010, 316 consecutive colorectal cancer samples were collected by our Oncology Department; ten patients (3%) had high risk localized disease and 306 (97%) metastatic disease. Genome DNA from formalin-fixed paraffin embedded samples with tumor cells > 50% was analyzed by reverse dot blot with KRAS-BRAF StripAssay kit (Nuclear Laser Medicine). Results: KRAS point mutations were found in 141 patients (44.6%): 32% G12V, 30.5% G12D, 14.9% G13D, 6.4% G12S, 5.7% G12C, 4.9% G12A, 4.9% G12R, 0.7% G13C; V600E BRAF point mutation was found in 21 patients (6.6%). Three patients (1%) displayed DM: 2 KRAS G13D + BRAF V600E (A and B) and 1 KRAS G12V + BRAF V600E (C). Patients A and C, both aged 59, presented with metastatic disease. Patient A had a rectal primary, a single lung lesion and mediastinal nodes. He failed first line FOLFOX4 plus bevacizumab and underwent salvage surgery both on primary and metastatic disease. He relapsed in 3 months with liver and brain metastasis and died after one year from diagnosis. Patient B had huge liver lesions at presentation. She progressed after 3 courses of FOLFIRI and died after 6 months from diagnosis. Patient C was operated on for a right colon cancer, G3, pT2N2, stage IIIB with lymph vascular invasion and had adjuvant FOLFOX 4. The 6-month assessment did not show relapse. Conclusions: in our series KRAS mutation incidence was in line with literature, but G12V was far more frequent. KRAS-BRAF DM accounted for 1% of all cases and the 2 patients with metastatic disease had an aggressive course with a much lower than expected survival. To our knowledge no series of DM have been described, hindering the understanding of their biological meaning. According to our experience, metastatic double mutated patients do not respond to standard therapy and should be treated with new drugs combinations in clinical trials.
Impact of K-ras status on FOLFOX and XELOX regimens efficacy in metastatic colorectal (mCRC) patients (pts).
Authors: Fedyanin Mikhail , Tryakin Alexey , Pokataev Ilya , Bazin Igor , Aliev Vechaslav , Gordeev Sergey , Garin August , Tjulandin Sergei 
Published: March 2020

e14674 Background: Predictive value of K-ras status for the treatment with anti-EGFR monoclonal antibodies is well established. There is a lack of data about predictive significance of K-ras status for oxaliplatin-based chemotherapy (CT). We retrospectively studied prognostic and predictive significance of mutant K-ras in mCRC pts treated with FOLFOX or XELOX in 1st line CT. Methods: We analyzed data on 127 pts with mCRC, who were treated in our department during 2008-2011 with oxaliplatin-based regimens. K-ras status was determined by PCR analysis in 51/127 (40,1%) pts. Mutant K-ras was detected in 16/51 (31,3%) pts: 13/16 (81,3%) – codon 12, 3/16 (18,7%) – codon 13. mFOLFOX6 was administered in 21/51 (41,2%), XELOX – in 30/51 (58,8%) pts. No pts received anti-EGFR mAb in the 1-st line. Median follow-up was 9 months (range, 2 - 41). The mean number of courses was 9 and 5 in FOLFOX and XELOX groups, respectively. PFS was chosen as a primary end-point. Results: Median PFS was 7,5 months for all 127 pts, 8,4 months in pts with FOLFOX and 7,5 months in pts with XELOX. Median PFS in pts with wild type K-ras was 10,3 months and 6,5 months in pts with mutant K-ras (p=0,1, HR 1,7, 95%CI 0,9-3,4). Negative prognostic significance of mutant K-ras was seen in XELOX group (PFS, 10,9 vs 5,7 months, р= 0,002) but not in FOLFOX group (PFS, 7,7 vs 9,3 months, р= 0,48). In pts with wild type K-ras XELOX lead to longer PFS than FOLFOX regimen - 10,9 vs 7,5 months, respectively (р=0,09, HR 0,52, 95%CI 0,23-1,14). And vice versa, in pts with mutant K-ras FOLFOX was more active than XELOX – median PFS was 9,3 vs 5,7 months, respectively (р=0,009, HR 0,3, 95%CI 0,05-0,64). Conclusions: Our findings probably suggest that K-ras status influences the efficacy of FOLFOX and XELOX regimens in mCRC pts. These data need to be confirmed in larger series of pts.
Evaluation of treatment benefit to an unselected population of patients with metastatic colorectal cancer, referred to oncological treatment.
Authors: Nielsen Svend Erik 
Published: March 2020

e14677 Background: Patients, with metastatic colorectal cancer (mCRC), participating in clinical trials are a selected group with a better performance status compared to all patients, who are referred to oncological treatment. The aim of the study was to evaluate the benefit of standard treatment modalities, offered to an unselected group of patients, referred to our Dept. of Oncology. Methods: Consecutive patients treated with more than one cycle of chemotherapy, registrated in our database from May 2003 to July 2012, were included. Clinical information was obtained from patient files. The outcome was overall survival for various groups. Following parameters were collected: Gender, age, primary tumor site, resection status of primary tumor, number of metastic sites, liver-only mets, number of chemotherapy regimens, +/- Bevazicumab and rate of palliative radiation. Results: 266 consequtive patients, treated with more than one cycle of chemotherapy, were included. Median age 67 (31-86) years, 150 male (59%). Distribution of the primary tumor was 35/37/28% for rectum/left colon/right colon. 192/59/15 (72/22/6%) had the primary tumor resected/not resected/stent. 54/37/9% had one metastic site/ two sites/three or more sites. 24% had liver only. As first line chemotherapy 29% received Capecitabine (CAP), 55% CAP + Oxaliplatin, and 8% CAP + Irinotecan. 44% received Bevacizumab. 69%/27% received either second and third line chemotherapy. 19% received palliative radiotherapy. Median OS for the whole population was 17 months CI ( 15-19). Patients with one, two or three, or more mets sites had a OS of 21(CI: 16-26)/17 (14-20)/9 (4-149) months, respectively. For patients receiving one, two, or three lines of chemotherapy OS was respectively 8/16/28 months. Addition of Bevacizumab to chemotherapy regimens had an OS of 27 months CI (24-30), compared to 20 months (16-24) for chemotherapy alone. Conclusions: Unselected mCRC patients, treated with standard chemotherapy regimens, seem to obtain the same OS benefit as seen in clinical trials. Survival benefit was dependent on the number of metastatic sites, the number of cht. regimens received and addition of Bevacizumab to the treatment.
General epidemiologic colorectal cancer profile in Oncologos del Occidente from Colombia, South America.
Authors: Sanchez Villegas Tomas , Villegas Mejia Carlos Raul , Chacon Cardona Jose Arnoby 
Published: March 2020

e14693 Background: The Colorectal Cancer is one of the most common cancer in the US and the fourth cancer for the developing countries like in our area. Methods: This is a preliminary and partial report of a retrospective analysis from our cancer records in Oncologos del Occidente a Private Oncologic Cancer Center from Colombia. Results: 663 patients (50% of final report) from January 1997 to June 2012 with Colon Cancer 306(46%), Rectal Cancer 309(47%) y Anal Cancer (7%); 51% female; median age 60(range 16-92. sd:13.929); Urban Area 91%. Clinical stage I (7%), IIA (19%), IIB (3%), IIIA (5%), IIIB (13%) and IIIC (10%), IV (11%), Adenocarcinoma 81%, Mucinous (8%); Well differentiated (63%), Poorly differentiated (7%); pretreatment Carcino-embryonic antigen mean 32.778 ng/ml (range 0.18-550.0), Adverse prognostic factors were Obstruction (39%), Ulceration (31%), Lymph Vascular Invasion (10%), T4 Stage (5%), Perforation (4%), Positive Surgical Margin (2%) with two factors 21% and three factors 7%; Low rectal cancer was 90%, Non-Surgical treatment was Chemotherapy (CT) (37%), CT/Radiotherapy (RT) (35%), CT and RT (8%), RT (3%), None (16%); preoperative treatment 37%, First line CT was based on 5FU/LV (52%); 20% relapsed and the main recurrence pattern was Local-marginal (25%), Liver (17%), Pelvic peritoneal (3%), Carcinomatosis (8%) and Lung (23); Rescue treatment was CT (10%), Surgery+CT (1%), CT+RT (1%) and Surgery (1%); the main rescue CT was Folfox 2%, 5FU/LV (3%), Capecitabine (3%), Mixed 6%; Surgical Lymph nodes mean excised was 10.037 (0-38 SD.7.554) and positive nodes mean was 1.972(0-29 SD 3.503); Overall Survival at 5 years for Colon cancer is 63% and 53% to 10 years and Rectal cancer to 5 and 10 years is 45% and 36% respectively (p=0.001). Conclusions: These results reflect the colorectal cancer behavior in a specific area of Colombia and the importance of a multidisciplinary work.
Safety and feasibility of yttrium-90 (Y-90) treatment for primary and metastatic liver tumors at a community hospital.
Authors: Martinez Brandon Keith , Gupta Niraj K. , Flanders Vincent , Natarajan Kannan , Underhill Marc , Cooke Jeff 
Published: March 2020

e14698 Background: Y-90 microspheres administered via hepatic artery is being increasingly utilized in the management of pri/metastatic liver cancers. We report safety/efficacy data on Y-90 therapy performed at a community hospital treating high volume of cancer patients. Methods: Multi-disciplinary tumor conferences were used for appropriate patient selection and pts. were seen on referral in the I/R clinic. Liver/tumor volume calculations were performed on pre-treatment imaging. Prescribed activity was calculated by BSA methods. Fractional tumor, liver-flow characteristics and lung shunt fractions were determined using Tc-99m MAA scan. All pts. recieved Y-90 resin microspheres, SIR-Spheres (Sirtex Medical Inc, Lake Forest, IL). Response to therapy was assessed by imaging studies and/or tumor markers. Results: 27 pts. were treated between Apr 2012 and Jan 2013 with 46 doses delivered. Male 46%/ Female 54%;Median age:58 yrs (29-86). ECOG P.S. of 22 pts. was 0-2, 5 had P.S. of 3. Tumor types; 11 (40%) colon, 2 breast, 2 cholangioca, 3 NET, 2 HCC, 1 ovarian, cervical, gastric, GIST, urothelial, uveal melanoma and pancreatic adenoca. Percent tumor involvement was between 0-25% in 16 (59.25%) and 25-50% in 11 (40.75%). Average whole liver administered activity was 48.33 mCi (33.9-62.9 mCi). Early imaging on 18 patients revealed 84% response rate (PR+SD). 1 patient with cholangiocarcinoma was downstaged to surgical resection.One patient with Childs class-B cirrhosis and multifocal HCC developed liver failure following treatment and died. 5 deaths from progression of disease occurred in hevaily pre-treated pts. with extrahepatic disease. 2 patients had coil migration during mapping angiography, however, microsphere distribution was unaffected due to intrahepatic collaterals. Out of 46 delivered doses, 6 (13%) grade-3 toxicities including, severe fatigue, nausea and vomiting resulted in short term hospitalization. Conclusions: Y-90 can be safely and efficiently delivered in a community setting. Development of a community-based radioembolization program, although challenging, can be successfully accomplished with establishing a dedicated multi-disciplinary team.
Treatment patterns in metastatic colorectal cancer (mCRC) in Slovakia.
Authors: Salek Tomas , Pichna Peter 
Published: March 2020

e14700 Background: CRC is one of the most frequent malignant diseases in Slovakia. Slovakia with approximately 5 million inhabitants is country with the highest incidence of CRC in Europe, and there is a focus on CRC treatment within Slovak healthcare system. Methods: Between March 2012 and June 2012 we made a survey in the vast majority of hospital medical oncology departments and outpatient cancer clinics /93 facilities- it comprises approximately 95 % of Slovak departments and clinics treating metastatic CRC/. Data obtained during this 4months period were then multiplied by 3, and that gave us the approximate yearly data. (We reviewed data from 532 patients during four months period.) Results: 670 newly diagnosed mCRC patients (pts) (38%) were treated with chemotherapy alone in the first line, 867 pts (48%) with chemotherapy plus biologics and 231 pts (13%) were treated with best supportive care only. 87% of our newly diagnosed mCRC pts were treated with first line therapy, 37% with second line therapy and 25% with third and later lines of treatment. 42% of pts had KRAS status examined with following results: 44% KRAS wild type, 50.4% KRAS mutated and 5.6% status unknown. Conclusions: We conclude that in Slovakia we have similar patterns of mCRC treatment like in other Middle European countries and high percentage of pts in the first line is treated with biologic therapy.
Third line chemotherapy in metastatic colorectal cancer: A single institution experience.
Authors: Carbonel Luyo Wilver Federico , Carranza Montenegro Zoila Elizabeth , Cousillas Castineiras Antia , Constenla Figueiras Manuel , Garcia Arroyo Francisco Ramon , Fernandez Ribeiro Francisca , Gallardo Martin Elena , Lorenzo Lorenzo Isabel , Vazquez Tunas Lidia Maria 
Published: March 2020

e14706 Background: The median overall survival for metastatic colorectal cancer (mCRC) has been increasing over the past two decades and is very common to see longer survivals with a good performance status. They may benefit from treatment after progression to second line chemotherapy. In this context, raltitrexed is an active and simple-administration drug that appears to be a convenient treatment. Our objetive was to determine if there is benefit in patient retreated with oxaliplatin based chemotherapy (OBCT), CPT 11 based-chemotherapy (CBCT) or raltitrexed every 21 days in a third line chemotherapy (3L CT) setting. Methods: We conducted an analytical epidemiological study, using descriptive analysis and Long Rank test. Between 2009 and 2012, were treated 28 mCRC with a 3L CT and 11 of which recieved adyuvant chemotherapy. All were treated previously with OBCT and CBCT. Treatment consisted in OBCT, CBCT or raltitrexed in monotherapy. Results: Male predominance in proportion of cases (67.9%) with a median of 62 years old (range 27-79 and 90% between 45-75) and 78.6% had aceptable clinical condition (ECOG 0-1). Median CEA level before 3L CT was 61.1 ng/dL. Sixteen patient had rectal cáncer, mostly male (75%). In our sample, the mCRC overall survival was 30.4 months (95% confidence interval(CI), 14.3 to 46.4) . Patients retreated with OBCT or CBCT had the same survival than treated with a particular sequence that includes OBCT, CBCT and raltitrexed in monotherapy (7.5 months (CI, 5.81 to 9.2) vs 7.4 months (CI, 2.5 to 12.3); p<,598). Raltitrexed in monotherapy tends to have better survival in comparison with OBCT or CBCT, no reaching statistical significance (14.3 months (CI, 3.6 to 24.9) vs 7.5 months (CI, 5.9 to 9.1) vs 7.4 months (CI, 0.0 to 18.1); p<,755). The most common toxicity with raltitrexed was asthenia grade 1 (32,1%), with OBCT was neurotoxicity grade 1 (75%) and with CBCT was abdominal pain grade 1 (55.5%). Conclusions: In our serie, there was a male predominance and median mCRC survival is better than reported in the literature. There is a trend for a better survival with raltitrexed in monotherapy with a good toxicity profile in a 3L CT setting. Future studies are needed to verify these findings.
Phase I expansion trial of an oral TORC1/TORC2 inhibitor (CC-223) in nonpancreatic neuroendocrine tumors (NET).
Authors: Mita Monica M. , Wolin Edward M. , Meyer Tim , Nemunaitis John J. , Bergsland Emily K. , Mahipal Amit , Wong Lilly , Wu Xiaoling , Carmichael James , Chopra Rajesh , Hege Kristen , Bendell Johanna C. 
Published: March 2020

e15004 Background: Clinical activity of everolimus, an allosteric TORC1-selective inhibitor, has been established in pancreatic NET. CC-223 is an ATP-competitive inhibitor of the mTOR kinase, inhibiting both TORC1 and TORC2 complexes. Methods: Following establishment of the MTD (reported at ASCO 2012), subjects with non-pancreatic NET and selected other tumors were enrolled in expansion cohorts of up to 20 evaluable subjects. CC-223 was dosed at 45 mg once daily in 28 day cycles until disease progression. Results: As of 09 January, 2013, 101 solid tumor subjects have been treated. Preliminary results from the NET cohort (n=23) are reported here. Subjects with non-pancreatic tumors of gut origin with progression within 12 months and receiving ongoing treatment with somatostatin analogs (SSA) were eligible. The majority of tumors were of midgut origin with liver metastases; 9 subjects had refractory carcinoid syndrome despite SSA use. The most common (> 20%) related adverse events (all grades) were stomatitis, diarrhea, fatigue, anorexia, nausea and rash. In addition, related serious adverse events included one case of transient dehydration/renal insufficiency (1). CC-223 dose reduction to 30 or 15 mg was required in 57% of subjects, usually during cycle 1 or 2, but thereafter treatment was well tolerated. Inhibition of TORC1 (p4EBP1) and TORC2 (pAKT) biomarkers was confirmed in blood cells. Reduction in glucose uptake (> 25% change in SUV) on PET imaging at day 15 was observed in 54% (7/13) subjects. All evaluable subjects (n=10) reported stable disease (SD) with treatment ongoing at up to 9 cycles (median 6; range 4 – 9). Although not prospectively collected, 6 subjects with refractory carcinoid syndrome reported complete resolution of flushing (5) or improvement in diarrhea (1). Symptom improvement generally occurred within the first week of dosing and persisted despite dose reduction in 5 subjects. Conclusions: Encouraging signals of biomarker and clinical activity were observed in NET including prolonged SD and symptomatic improvement in subjects with refractory carcinoid syndrome. Due to the frequency of early dose reductions, the NET cohort will be explored further at a starting dose of 30 mg QD. Clinical trial information: NCT01177397.
Preclinical study of cytotoxicity and predictive markers of response to dual inhibition of PI3K and mTORC1/2 signaling by NVP-BEZ235 with or without paclitaxel or nab-paclitaxel as a new therapeutic strategy in pancreatic cancer cell lines.
Authors: Loaiza-Bonilla Arturo , Kittaneh Muaiad , Guardiola Amado Victor Daniel , Kovacs Krisztina , Merchan Jaime R. 
Published: March 2020

e15007 Background: Targeting the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) (PI3K-AKT-mTOR) pathway could arrest tumor growth and induce cell death in cancers that are resistant to currently available therapies. NVP-BEZ235 is an oral, targeted anticancer agent which exerts its potential activity through PI3K/mTOR dual inhibition. The paradoxical feedback activation of the PI3K/Akt pathway may compromise the efficacy of TORC1 inhibitors and provide the rationale for generating dual inhibitors in human pancreatic cancer. Methods: Kras mutant and wild-type human pancreatic cell lines were treated in vitro with BEZ235 and its combination with nab-paclitaxel. Antiproliferative effect per WST-1 assay was measured. Western blot analysis of S235/S236P-RPS6 and Akt (S473P-Akt, T308P-Akt) after exposure to BEZ235 was also performed. The potential synergistic and time-dependent effect at different concentrations of experimental agents was measured at different intervals. Results: BEZ235 reduced S473P-Akt, T308P-Akt and S235/S236P-RPS6 levels in a dose-dependent manner. Nab-paclitaxel at higher concentration exerts significant antiproliferative effects in a time-dependent fashion in pancreatic cell lines irrespective of Kras mutation status. BEZ235 in combination with nab-paclitaxel showed significant synergistic effect in a time and dose-dependent manner compared with the corresponding single drug treatments in pancreatic cancer cell lines with wild-type Kras (BxPC-3) but not in cell lines with mutant Kras (MIA PaCa-2 and PANC-1), the latter leading to a paradoxical increase in proliferation in comparison with controls, suggesting an escape pathway. Conclusions: These results provide the preclinical rationale for studies examining the synthetic lethality and escape pathways of PI3K/mTOR dual inhibition in particular subtypes of pancreatic cancer cell lines. Kras may be studied as a potential predictive biomarker of response to these agents and their combination with standard chemotherapy.