bluuebunny/crossref_metadata_2025 huggingface dataset:
Choice of therapy and time to first treatment for patients with colon cancer: A National Cancer Database analysis.
Authors: Olson David C. , Abou El-Ezz Khaled Mohamed , Silberstein Peter T.
Published: March 2020

e14642

Background: Insurance status has been shown to affect adherence to guidelines in the treatment of colon cancer1. This study aims to investigate trends in management of colon cancer and time to first treatment in patients with various insurance types using the National Cancer Database (NCDB). Methods: Treatment data for 845,121 patients and time to first treatment data for 497,993 patients diagnosed with colon cancer between 2000 and 2010 were identified using the NCDB. Reported utilization of treatment and time to first treatment were analyzed by insurance status. Results: Among all stages of colon cancer, no treatment was received more often by Veteran Affairs (10.5%) and Medicare (10.9%) patients than uninsured (8.8%), managed care (4.5%), private insurance (4.7%), Medicaid (8.4%) or Medicare with supplement (7.7%). Among stage I colon cancer, surgery was received less often by uninsured (90.9%) than other insurance types. Stage III colon cancer patients enrolled in Medicare with/without supplement received chemotherapy less often than other insurance types (49.9% and 46%). Stage IV Medicare patients with/without supplement also received chemotherapy less than other insurance types (59.5% and 52.9%). Surgery as monotherapy was the most common treatment received among all insurance types and stages. More uninsured patients received treatment within 3 days than any other insurance types (61%). A delay of at least 17days occurred more in Veteran Affairs patients than other insurance types (40.6%). Conclusions: This is the largest study to date to have examined treatment trends and time to first treatment. Among all insurance types, Medicare without supplement and Veteran Affairs patients were most likely to receive no treatment. Uninsured were less likely to receive the standard of care treatment with stage I cancers. Medicare patients were less likely to receive the standard of care for stage III and stage IV cancers than other insurance types. Veteran Affairs patients had treatment delayed significantly more than other insurance types. Future studies are needed to assess factors leading to receipt of substandard care.
Evolving disparities in colorectal cancer control in Texas in the first decade of twenty-first century and implications for cancer control.
Authors: Vugrin Davor
Published: March 2020

e14643

Background: Colorectal cancer (CRC) is the 2nd leading cause of cancer death among Texans although it is potentially one of the most preventable and curable cancers. In 2000, an intensive public education and screening was launched throughout Texas with goal by 2015 to increase up to 75% the number of 50 year and older individuals undergoing screening per the national guidelines, to reduce age-adjusted CRC incidence to 34.8/100,000 and mortality to 12.0/100,000. The purpose of this study is to identify disparities challenging meeting the 2015 objectives. Methods: The Texas Cancer Registry 2000 to 2009 data of the at risk population was queried for CRC cases diagnosed, number of deaths, age-adjusted incidence and mortality rates, and correlation with gender, race and anatomical location and evolving 10 year trend. Results: Incidence: of 91,260 CRC diagnosed 71.8% originated in colon (CoCa), 19.7 in rectum (ReCa) and 8.5 % in Rectosigmoid juction (RSJ). Age-adjusted rates (AAR) declined for CoCa by 6.6/100,000 (18%) and ReCa by 0.8 (8.6%). AAR for Non Hispanic White (NHW) declined by 10.0/100,000 (19.7%), Blacks (B) 9.8/ (15.3%) and Hispanics (H) 5.1/ (12.0%). Males AAR declined by 11.8/100,000 (19.7%) and women 18.1. 10 yr cumulative AAR for Black Males was 74.7/100,000, B female53.6/ with with lower AAR for other groups. Mortality: Of 32,929 death CoCa accounted for 83.5% and ReCa + RSJ for 16.5% cases. CoCa AAR mortality declined but for ReCa +RSJ was insignificant. Decline for NHW was –4.2 (22.0%), B – 5.6 (18.5%) and H – 1.5 (10.4%), males – 4.3 (18.5% and females – 3.7 (22.7%). AAR mortality rate in B males (35.0/100,000 and B females (23.2/) was higher than for other groups. Conclusions: Disparities in CRC control have been evolving over 10 yr study period based on anatomic site, gender, race/etnicity and their combination. Our targeted cancer control activities need to be adjusted to neutralize observed disparities in order to reach 2015 objective.
Preclinical activity of lenalidomide in metastatic colorectal cancer.
Authors: Leuci Valeria , Maione Federica , Todorovic Maja , Giraudo Enrico , Gammaitoni Loretta , Migliardi Giorgia , Aglietta Massimo , Leone Francesco , Trusolino Livio , Bertotti Andrea , Sangiolo Dario
Published: March 2020

e14654

Background: Metastatic colorectal cancer (mCRC) is currently considered incurable. Recent evidences support the importance of micro-environment and angiogenesis on survival and propagation of mCRC. Lenalidomide is a derivative of thalidomide, effective in several hematologic disorders, whose activity includes modulation on tumor microenvironment and inhibition of angiogenesis. We investigated the preclinical activity of lenalidomide against mCRC in vitro and in vivo. Methods: CRC cell lines and primary mCRC cells were treated with scalar concentrations of lenalidomide (10 to 150 µM). Two cohorts of NOD/SCID mice (n=8) implanted with mCRC xenografts derived from two different patients were treated orally for 21 consecutive days with Lenalidomide (50 mg/Kg/die). Results: In vivo a significant reduction of tumor growth was observed in one cohort compared to untreated controls (n=8), 247±118 mm3 vs. 567±216 mm3 (P=0.02), while no significant differences occurred in the second cohort. Pathology review on tumor samples removed from the mice revealed a trend toward the restoration of normal colon tissue morphology and architecture in lenalidomide treated samples compared to untreated controls. Quantitative evaluation of tumor angiogenesis on the responsive cohort, by immunohistochemistry for factor VIII, revealed a tumor-vessel reduction of 49% with lenalidomide compared to controls. Moreover, necrotic-hypoxic areas were reduced by 6 fold in lenalidomide treated xenografts compared to untreated controls (P<0.001). Treatment in vitro did not result in any direct antitumor effect. The average rate of cell death in treated samples was 15.5±2.1%, 15.3±6.7%, and 11.5±3.4% at lenalidomide doses of 10, 40 and 150 µM respectively, compared to 14.6±2.6% of untreated controls. Conclusions: Our data indicate a potential activity of lenalidomide against mCRC. The beneficial effect was limited in-vivo, supporting the hypothesis that the main activity of lenalidomide is exerted through modulation of tumor microenvironment and angiogenesis rather than a direct antitumor effect. Our findings may be of clinical relevance and support further investigations to explore the benefit of lenalidomide in the challenging setting of mCRC.
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.
Local failure after liver resection for hepatocellular carcinoma.
Authors: Fredman Elisha T. , Kumar Aryavarta M. S. , El-Gazzaz Galal , Aucejo Federico , Coppa Christopher , Abdel-Wahab May
Published: March 2020

e15015

Background: Partial resection is the most common surgical management of primary hepatocellular carcinoma (HCC), yet long-term prognosis remains poor, with 3-year intrahepatic recurrence rates up to 80%. A percentage of these occur within close proximity to the original tumor site. We conducted a retrospective review of liver resections at the Cleveland Clinic to determine rates and patterns of close tumor failure to inform future treatment. Methods: 147 patients, identified from an IRB approved database, underwent partial hepatectomy for definitive treatment of HCC from 1996-2012. All were followed with CT or MRI for indications of recurrence, defined as characteristic or biopsy proven liver lesions absent from previous imaging. Patients were divided into two groups: local recurrence (≤2 cm from surgical margin, A) and non-local intrahepatic recurrence (>2 cm from surgical margin, B). Logistic regression modeling was used for statistical analysis. Results: 73 (49.7%) patients had tumor recurrence, within a median time of 11.9 months (range: 1.6-69.9 months). 5 (6.8%) had extrahepatic recurrences only and were excluded from analysis. Groups A (n=19) and B (n=49) were demographically comparable. Mean tumor size was 8.9 cm (range: 2.6-14.5 cm) and 7.5 cm (range: 1.5-20 cm) respectively. In Group A, 6 (32%) had local lesions exclusively and 13 (68%) had concurrent local and non-local intrahepatic failure. Vascular invasion correlated with overall recurrence (p = 0.01). Patients with local recurrence were more likely to have a single lesion at initial diagnosis (p = 0.02) and had a shorter median time to surgery (p = 0.02). Presence of cirrhosis, tumor size, grade, margin status and tumor rupture were not significant correlates. Conclusions: In our population, 49.7% of patients had HCC recurrence. 26% of these recurrences were local failures. Vascular invasion correlated with overall recurrence. A single lesion and shorter time from diagnosis to surgery were associated specifically with local recurrence. Our findings open the possibility of employing intra-operative and/or adjuvant radiation therapy, which have demonstrated good local control with limited toxicity in other cancers, for patients at increased risk of local failure of HCC.
A prognostic model for early recurrence prediction in hepatocellular carcinoma after liver resection.
Authors: Ruan Dan-Yun , Li Yang , Jiang Nan , Lin Ze-Xiao , Wan XiangBo , Li Xing , Wu Xiang-Yuan , Chen Guihua
Published: March 2020

e15021

Background: Recurrence resulting in high morbidity of hepatocellular carcinoma (HCC) patients received radical liver resection, the majority of which occur within 1 to 3 years. The study aims to find risk factors and set up a prognostic model predicting early recurrence of HCC. Methods: From 2003 to 2010, 196 HCC patients underwent liver resection were retrospectively analyzed. Univariate and multivariate analyses were used to assess variables. A recurrence risk model was developed with independent prognostic factors. Area under the ROC curve (AUC) was carried out to evaluate its predictive value. Results: The median follow-up time was 33 months (1-103M), median RFS was 22 months. Total tumor volume (TTV), hepatitis B, Child-Pugh score, and portal vein tumor thrombus were independent factors of recurrence. Patients with TTV>115cm3 had worse RFS (28.9% vs 51.7%, p<0.000) and OS (64.4% vs 80.1%, p=0.032) than those TTV≤115cm3. We established a risk model consisted of the 4 parameters, and classified patients into four stages. There were significant differences between each stage, especially for the 1st year. (1-yr RFS: 80.1% vs 47.8% vs 28.6% vs 0%, p=0.000, AUC 0.682). Compared to four currently used staging systems (BCLC, TNM, CLIP, and Okuda), the new model could well predict patient’s survival with the largest AUC in both RFS and OS (Table). Conclusions: TTV has been found a preferable description of tumor burden and a prognostic factor in HCC. This prognostic model predicts early tumor recurrence and survival of patients received radical liver resection and might contributes to the selection of patients who may benefit from surgery. [Table: see text]
Association of AREG exon 1 polymorphism with worse prognosis in Japanese and U.S. patients with gastric cancer.
Authors: Wakatsuki Takeru , Zhang Wu , Yang Dongyun , Azuma Mizutomo , Ning Yan , Volz Nico Benjamin , Stintzing Sebastian , El-Khoueiry Rita Elie , Li Joseph Ethan , Wilson Peter M. D. , Labonte Melissa Janae , Maus Martin K. H. , Sunakawa Yu , Koizumi Wasaburo , Watanabe Masahiko , Iqbal Syma , Barzi Afsaneh , El-Khoueiry Anthony B. , Shah Manish A. , Lenz Heinz-Josef
Published: March 2020

e15022

Background: Recent data suggest that Amphiregulin (AREG) and Epiregulin (EREG), ligand of EGFR pathway, is possibly a prognostic and predictive marker in gastrointestinal cancer. Previous data have shown that higher AREG and EREG gene expression levels are associated with better survival in metastatic colorectal cancer as well as gastric cancer (GC). Since polymorphisms in AREG and EREG may affect their gene expression levels or change their functions, we tested the hypothesis whether these polymorphisms could predict outcome in two ethnically and epidemiologically different GC cohorts from Japan and the US. Methods: One-hundred and sixty-nine Japanese (n=169), as a training set, and one-hundred and thirty-seven (n=137) the US patients, as a validation set, with histopathologically-confirmed localized (stage Ib to IV; AJCC-6th) GC were enrolled between 2002 and 2010. Four functional SNPs in AREG and five SNPs in EREG were selected. Genomic DNA was extracted from blood or tissue, and all samples were analyzed by PCR-based direct DNA-sequencing. Results: The median follow-up periods were 4.0 years in the Japanese cohort and 3.3 years in the US cohort, respectively. The median DFS and OS in the Japanese cohort were 4.8 and 5.8 years, whereas the median TTR and OS in the US cohort were 2.8 and 4.7 years, respectively. Only exon 1 polymorphism rs1615111 G/A was associated with outcome in Japanese cohort. Patients heterozygous G/A (n=23) showed a median OS of 2.7 years vs. 20.1 years for patients homozygous G/G (n=146) (HR: 1.83 [95%CI: 1.02-3.30], p=0.039). This result was successfully validated in the US cohort. Patients harboring at least one-A allele (n=14) showed a median OS of 2.8 years vs. 5.4 years for patients homozygous G/G (n=111) (HR: 2.54 [95%CI: 1.09-5.89], p=0.018). In the pooled multivariate analysis, these results were still conserved (HR=2.24 [95%CI: 1.36- 3.67], p=0.0015). Conclusions: AREG exon 1 polymorphism rs161511 may be negative prognostic factor in GC regardless ethnicity and regional differences in gastric cancer. Further clinical validation of SNPs in EGFR ligands are warranted.
Trans-catheter arterial p53-gene-embolization using gelatin sponge particles in treatment of patients with advanced hepatocellular carcinoma.
Authors: Zhang Yuewei
Published: March 2020

e15024

Background: Treatment options for advanced hepatocellular carcinoma (HCC) are limited due to patients’ poor condition, and resistance to both chemo- and radio-therapy. Trans-catheter embolization (TAE) or Trans-catheter chemo-embolization (TACE) is the most widely used locoregional treatment for advanced HCC. But no solid evidences support the beneficial effect of the chemotherapy in TACE. Many advanced HCC patients also can’t tolerate the locoregional chemotherapy. The p53 gene has multiple anticancer functions and does not have any of the immune-inhibitory effects of chemo- or radio-therapy. The objectives of this study are to investigate TAE plus recombinant adenoviral human p53 gene (rAd-p53) in treatment of advanced HCC. Methods: Fifty-eight patients with advanced, unresectable HCC were randomly to two groups: TAE plus p53 group (TAE-p53G), or TAE group (TAEG). The study patients included 56 males and 2 females with an average age of 62.5 (53-89) years old and with Child-Pugh score A or B (42 or 16, respectively). The patients received 3 times of TAE plus rAd-p53 for TAE-p53G or TAE only for TAEG, once in a month for 3 months. The TAE materials consist of gelatin sponge particles (GSP) alone or plus 2-4 x 1012viral particles of rAd-p53, mixed into 30 ml suspension. The study endpoints included response rate, one-year survival, liver function, and adverse effects. Results: After 3-5 days of the first treatment, CT scan showed deceased tumor density in all the study cases. At 6 months after the first treatment, based on the RECIST standard, 31.0% (9/29) and 51.7% (15/29) patients in TAE-p53G achieved a complete response (CR) and partial response (PR), respectively, versus 17.2% (5/29) and 37.9% (11/29) of CR and PR in TAEG, respectively. One-year survival rates were 79.4% and 60.7% with median survival time of 11.7 and 8.3 months for TAE-p53G and TAEG, respectively. There are no significant changes of liver functions in both groups after treatment. Mild or median fever was observed in all the patients in TAE-p53G. No serious adverse events or complications observed. Conclusions: TAE using GSPs plus rAd-p53 is effective and safe treatments for advanced HCC.
Synergistic killing in pancreatic cancer cell lines of the combination of a MEK inhibitor and DNA methylation inhibitor.
Authors: Jeffries Matlock Arizona , Kurkjian Carla
Published: March 2020

e15025

Background: A growing body of evidence implicates aberrant DNA methylation in the etiology of a number of cancers, including pancreatic. Previous reports link defective ERK signaling with reduced DNA methylation via DNMT1. Here, we examined the ability of the MEK inhibitor U0126 to alter expression of DNMTs in k-RAS mutant and wild type pancreatic cancer cell lines and assess additive cytotoxicity of U0126, the hypomethylating agent 5-Azacytidine and two HDAC inhibitors. Methods: DNMT levels were quantified in AsPC1 and BxPC3 lines 2 days after adding 25 umolar U0126 using real-time RT-PCR. Significance was calculated using a Student t-test. For survival, agents were added singly and in combination: U0126, 25 umol; 5-Aza, 10 umol; Valproic acid 1 mmol and Trichostatin-A 5 umol. Survival was assessed using a colorimetric MTS method at 1, 2, 3, and 4 days. Expected cell survival and synergism were calculated via relative risk ratios, and significance via a Student t-test. Results: U0126 treatment reduced expression of DNMT1 significantly in AsPC1: 2.06 ± 0.3 vs. 1.09 ± 0.08, p = 0.004 (mean ± S.D., arbitrary units). No change was seen in BxPC3. Increased expression of de novo DNMT3a and DNMT3b was seen: AsPC1 1.28 ± 0.3 vs. 3.13 ± 0.8, p = 0.02; BxPC3 1.78 ± 0.3 vs. 4.14 ± 1, p = 0.02; AsPC1 1.26 ± 0.3 vs. 2.66 ± 0.4, p = 0.006, respectively. DNMT3b in BxPC3 was not altered significantly. U0126 and 5-Aza were individually cytotoxic in both cell lines, and synergism was observed in combination. In AsPC1, the observed vs. expected combination survival was 13% ± 3% vs. 29% ± 2%, p = 0.001; for BxPC3, 7% ± 2% vs. 62% ± 3%, p = 0.002, both at 4d. No synergism was found when adding Valproic acid or Trichostatin-A. Conclusions:Treatment of k-RAS mutant pancreatic cancer cell lines with the MEK inhibitor U0126 results in significantly reduced expression of DNMT1 and increased DNMT3a and DNMT3b. U0126 combined with 5-Aza produced synergistic cytotoxicity, which may be due to enhanced hypomethylation activity. Although no significant change in expression of DNMT1 was found in the BxPC3 cells, we noted synergistic cytotoxicity when treated with both U0126 and 5-Aza.
Cetuximab combined with concurrent chemoradiotheray in Chinese patients with unresectable, locally advanced esophageal squamous cell carcinoma: A prospective, multicenter phase II trial.
Authors: Meng Xue , Wang Jianhua , Sun Xindong , Wang Lvhua , Ye Ming , Feng Ping bo , Zhu Guangying , Lu You , Han Chun , Zhu Shu chai , Liao Zhongxing X. , Yu Jinming
Published: March 2020

e15030

Background: This multicenter phase II trial investigated cetuximab add to concurrent chemoradiotherapy for Chinese patients with esophageal squamous cell carcinoma (ESCC). Methods: Patients with unresectable locally advanced cervical, thoracic upper or mid-ESCC were eligible for this phase II trial. All patients received cetuximab (400 mg/m2 day 1 before chemoradiotherapy and 250 mg/m2 q1w × 7 weeks), paclitaxel (45 mg/m2 q1w × 7 weeks) and cisplatin (20 mg/m2 q1w × 7 weeks) with 59.4 Gy of radiation (1.8Gy/33f). The primary end point was response rate. Second end points included toxicity, overall survival (OS), progression-free survival (PFS), and KRAS mutation status. Results: Forty-five previously untreated patients (36 men, 9 women; median age, 59 year; performance status 0 or 1) with ESCC were treated and evaluated for clinical and radiographic response. After therapy, 29 patients (65%) achieved a complete response, and 15 (33%) patients achieved a partial response, the response rate was 97.7%. Non-hematological adverse events were generally grade 1 or 2, and were most often rash (94.5%), mucositis (58.2%), fatigue (45.5%), nausea (41.8%) and hepatic dyfunction (40%). Hematologic adverse events included grade 3 neutropenia (32.7%) and grade 3 anemia (1.82%). The 1-year PFS and OS rates were 87.3% and 91.1%, 2-year OS were 83.02%, respectively. No mutations were detected at KRAS codons 12 or 13 in all specimens. Conclusions: Cetuximab can be safely administered with chemoradiation for Chinese patients with esophageal cancer and may improve the clinical response rate. KRAS mutations were too rare to be analyzed as a predictor of response. Clinical trial information: NCT00815308.
A pilot study for cellular detection of circulating tumor cells and disseminated tumor cells of patients with hepatocellular carcinoma.
Authors: Minagawa Nozomi , Sakihama Hideyasu , Kobayashi Nozomi , Wakayama Kenji , Kakisaka Tatsuhiko , Tsuruga Yousuke , Shimokuni Tatsushi , Homma Shigenori , Yokoo Hideki , Kamachi Hirofumi , Takahashi Norihiko , Kamiyama Toshiya , Taketomi Akinobu
Published: March 2020

e15038

Background: Circulating tumor cells (CTC) in peripheral blood (PB) and disseminated tumor cells (DTC) in bone marrow (BM) have been recently focused as predictive and prognostic markers in solid tumors. But hepatocellular carcinoma (HCC) usually lacks epithelial antigens, only a few reports described CTC or DTC at a cellular level. The aim of this study is to establish methodology for detecting CTC and DTC in HCC at a cellular level, and to determine to what degree DTC match the phenotype criterion of putative cancer stem cells. Methods: PB (n-17) and BM samples (n-12) were preoperatively collected from patients with HCC between October 2011 and December 2012. Mononuclear cells were collected by Ficoll gradient separation. CD45+ cell population was deleted through magnetic activated cell sorting system. Subsequently, double immunofluorescence for AFP, Arginase-1 or Hep-Par1 and CD45 was performed. PB samples from 20 healthy volunteers and BM samples from 3 patients with benign disease were used as controls. Our protocol has been approved by the ethical committee of Hokkaido University Hospital and written informed consent was obtained from all enrolled patients. Results: Positive rates of CTC and DTC were 70.5% (12/17) and 75.0% (9/12), respectively. No CTC or DTC was found in the control groups. Poorly differentiated HCC were found in 50.0% of CTC+ patients and 66.6% of DTC+ patients, whereas, 20% in CTC- patients and 0% of DTC- patients. There’re higher risk of recurrence in CTC+ or DTC+ patients, compared with that of CTC- or DTC- patients (33.3%, 55.5% vs 20%, 0%). Over 40% of DTC expressed putative stem cell marker CD133, although the median positive rate of CD133 in primary HCC was reported to be less than 1%. Conclusions: Our protocol might provide highly specific detection of CTC, DTC from HCC patients. Detection of CTC and DTC might closely correlate with histological grade of differentiation and recurrence rate.
Evaluation of EORTC QLQ-C30 and QLQ-STO22 in a phase II, placebo-controlled trial of rilotumumab (R) plus epirubicin, cisplatin, and capecitabine (ECX) in patients (pts) with locally advanced (LA) or metastatic (m) gastric (G) or esophagogastric junction (EGJ) cancer.
Authors: Tzivelekis Spiros , Loh Elwyn , Gallagher Meghan , Barlev Arie , Iveson Timothy
Published: March 2020

e15046

Background: To select a patient-reported outcomes (PRO) instrument for use in a pivotal G/EGJ cancer study, we evaluated the characteristics of two quality of life (QoL) questionnaires in a phase II trial of R (a fully human monoclonal antibody that neutralizes HGF, the MET receptor ligand) or placebo + ECX in the first-line treatment of 121 pts with LA or mG/EGJ cancer. The trial showed trends for improved survival in the R arms, especially in pts with METHigh(> 50% cells +ve). Methods: Discriminant validity of EORTC QLQ-C30 and QLQ-STO22 was assessed by mean baseline (BL) scores grouped by ECOG PS 0 or ≥1. Responsiveness was assessed by longitudinal analyses of mean PRO score changes from BL by change in ECOG PS (better, no change, or worse). Results: Questionnaire completion was ≥ 60% for cycles 1-5. QLQ-C30 scores at BL had good discriminant validity by ECOG PS: ≥1 corresponded to lower QoL. QLQ-C30 was responsive to change from BL: higher mean QLQ-C30 scores were associated with improved ECOG PS. In contrast, QLQ-STO22 scores had poor discriminant validity and poor responsiveness to change from BL. Results were consistent across treatment arms, the intent-to-treat population, and MET expression groups. Conclusions: EORTC QLQ-C30, a global measure of QoL, correlates well with ECOG PS and is a valid and responsive QoL measure in this pt population. QLQ-STO22 is more specific for stomach-related symptoms and did not correlate with ECOG PS. QLQ-C30 will be included in a phase III, randomized, placebo-controlled trial of R + ECX for the first-line treatment of MET+ve LA or mG/EGJ cancer (NCT01697072). Clinical trial information: NCT00719550. [Table: see text]