tbuckley/cabot-search huggingface dataset:
Individual KRAS mutations modulate response to targeted agents in colorectal cancer.
Authors: A. Bardelli, S. Lamba, F. Di Nicolantonio
Journal: Journal of Clinical Oncology (2011)

e14123 Background: Personalized cancer medicine has become a reality thanks to the identification of the genetic bases of this disease and the development of drugs inhibiting oncogenic proteins to which cancer cells are dependent upon. Up until now, the paradigm has been of a binary correlation between a mutated cancer gene and the response to a given therapy. We hypothesized that mutations in different codons of a single cancer gene may affect differently the response to targeted therapies. As a test case we evaluated whether individual KRAS mutations may have divergent impact on sensitivity and resistance to cetuximab, a monoclonal antibody targeting EGFR. KRAS mutations are present in approximately 35-40% of CRC samples. Of these, over 70% consist of alterations affecting codon 12 (with G12D and G12V variants representing approximately 34% and 23%, respectively) and about 20% are found at codon 13 (with G13D changes being by far the most prevalent). Methods: We exploited tumor samples, an innovative cell based approach and mouse preclinical models to assess the role of individual KRAS mutations on response to targeted agents in colorectal cancers. Results: We found that patients with G13D mutated tumors treated with cetuximab had a longer overall and progression-free survival than patients with other KRAS mutated tumors (De Roock, et al. JAMA, 2010). We observed that cetuximab impairs proliferation and tumorigenicity of G13D mutated cells, while G12V or G12D cells are not affected. All mutant cells displayed activated Ras, as shown by the levels of GTP-bound Ras. However, differences in the phosphorylation status of KRAS effectors, such as MEK, ERK and AKT were observed. Interestingly, we found that not only the G13D variant but also other KRAS mutants differentially affect sensitivity and resistance to cetuximab and, importantly, to other targeted agents currently undergoing phase I clinical trials. Conclusions: Current paradigms for personalized cancer medicine are based on the assumption that a binary relationship exists between a mutant or deregulated cancer gene and response to the therapy. Our findings indicate that individual mutations within a single cancer gene can have distinct roles on the response to therapeutic regimens.
Clinical utility of circulating tumor DNA (ctDNA) in resectable pancreatic ductal adenocarcinoma (PDAC).
Authors: Hui-Li Wong, Kevin Bushell, Joanna Karasinska, Sarah Arthur, Ryan Morin, David F. Schaeffer, Daniel John Renouf
Journal: Journal of Clinical Oncology (2016)

247 Background: ctDNA is emerging as a promising biomarker, with potential utility in screening, detecting minimal residual disease after curative resection and monitoring treatment response or resistance in advanced disease. Most PDAC studies to date have focused on identifying mutant KRAS ctDNA in metastatic disease. Here we perform sequential ctDNA quantification in patients (pts) with resectable PDAC using a novel and highly sensitive multiplex technology to explore the clinical utility of ctDNA as a diagnostic and prognostic biomarker. Methods: Banked plasma and tumor samples from 18 pts with resected PDAC were retrieved. Plasma samples were collected 0-28 days before, and 28-70 days after surgery. DNA was extracted using standard protocols and analyzed using the OnTarget system, which enriches for DNA molecules containing hot spot mutations prior to sequencing. A 96-plex panel that includes the most prevalent mutations in KRAS, PIK3CA and TP53 was used. Results: 16 pts (89%) had at least 1 mutation detected by OnTarget in the tumor sample, most frequently in KRAS codon 12 (n = 14). ctDNA was detected in the pre-operative blood sample in 7/16 pts with tumor mutations (sensitivity 44%) and 0/2 pts without detectable tumor mutations (specificity 100%). Of the 10 pts with available post-operative blood samples, 1 did not have a tumor mutation. 4 pts had detectable ctDNA, 3 of whom have recurred. In contrast, 0 of the 5 pts without detectable post-operative ctDNA have recurred. At median follow-up of 37 weeks, recurrence-free survival (RFS) was significantly longer in pts without detectable ctDNA after surgery (median not reached vs 9 weeks, p = 0.022). Of 11 plasma samples with detectable ctDNA, 3 harbored mutations that were not detected in the primary tumor, including 2 non-KRAS mutations (GNAS R201H and PIK3CA E542K). Conclusions: Pre-operative ctDNA has low sensitivity, suggesting limited utility in PDAC screening. RFS was significantly longer in pts without detectable post-operative ctDNA; however this analysis is limited by small numbers and short follow-up. Discordance in hot spot mutations detected in tumor and matched plasma was observed in 27% of samples, possibly related to intratumoral heterogeneity.
Subcutaneous administration of cefepime: An option when the IV route is problematic
Authors: P. Walker, M. N. Neuhauser, V. H. Tam, J. Willey, E. Bruera, J. L. Palmer, R. A. Prince
Journal: Journal of Clinical Oncology (2005)

8197 Background: Management of symptomatic infections can aid in palliation. We investigated the pharmacokinetics and tolerability of cefepime given as a subcutaneous infusion. This novel route of administration is proposed as an alternative to intravenous and intramuscular administration for patients treated outside an institutional setting, such as home hospice. Methods: Ten healthy adult volunteers received 1g of cefepime infused subcutaneously over 30 minutes. Serial serum samples (0.5, 1, 1.5, 2, 4, 6, 9, and 12 hours) were obtained after the end of infusion, and cefepime concentrations were determined by a HPLC. All serum concentration profiles were modeled by a population pharmacokinetic analysis using the Non-Parametric Adaptive Grid (NPAG) program. Acceptability of administration was evaluated using subjective sensation grading, observation of the subcutaneous site, and a final global evaluation. Results: The mean (median) Cmax, β-t ½, AUC 0-oo and total clearance were found to be 36.1 (30.9) mg/L, 2.34 (2.56) hours, 134.8 (125.3) h·mg/L, and 7.42 (7.98) L/h, respectively. All infusions were completed without difficulty or discomfort. No drug side effects occurred. The global acceptability was “strongly agreeable” with all the subjects. Conclusions: Subcutaneous infusion of cefepime appeared to result in a pharmacokinetic profile similar to that of an intramuscular injection. Our evaluations showed excellent tolerability and acceptability. These favorable results warrant further clinical evaluation. No significant financial relationships to disclose.
The First Trimester Human Placenta Is An Embryonic Hematopoietic Organ with An Unexpected Function in Primitive Erythroid Maturation.
Authors: Ben Van Handel, Sacha Prashad, Andy Huang, Nargess Hassanzedeh-Kiabi, Mattias Magnusson, Boriana Atanassova, Eija Hamalainen, Angela Chen, Hanna Mikkola
Journal: Blood (2009)
Pharmacy inventory control ordering web application.
Authors: Dalia Sumaida
Journal: Journal of Clinical Oncology (2012)

330 Background: Many departments within the hospital system were complaining of errors in the carousel system and the quantity of drugs ordered vs. received. Methods: Development of a communication tool between purchasing, inventory control, materials management, finance and accounts payable to streamline the process of ordering and receiving throughout the hospital system. Results: Communication between the departments in ordering and receiving. Reduction in errors of drug quantities ordered vs drug quantity received. Automating the receiving log system and the packing slip process. The web app cut down the time to process a drug by 50%. Conclusions: The use of IT to reduce waste, increase productivity, and improve quality of the system.
Effect of preoperative hepatic and regional arterial chemotherapy on metachronous liver metastasis after curative colorectal cancer resection: A prospective, multicenter, randomized controlled trial.
Authors: Jianmin Xu, Jianguo Xia, Yan Gu, Jianjiang Lin, Kefeng Ding, Ye Wei, Chunzhi Qin, Dexiang Zhu, Li Ren, Xinyu Qin
Journal: Journal of Clinical Oncology (2015)

511 Background: To evaluate the addition of preoperative hepatic and regional arterial chemotherapy (PHRAC) on prognosis for stage II and III colorectal cancer in a multicenter setting. Methods: Patients with clinical stage II or stage III colorectal cancer (CRC) were randomly assigned to receive PHRAC plus adjuvant therapy (PHRAC arm) or adjuvant therapy alone (control arm). The primary end point was disease free survival (DFS). Second end points were incidence of metachronous liver metastasis, overall survival (OS) and safety. Results: A total of 688 patients from 5 centers of China were randomly assigned to each arm. Five-year DFS were 75% for PHRAC arm and 61% for control arm (HR 0.60; 95% CI, 0.45 to 0.80; p&lt;0.001). Five-year liver-metastasis rate was 8% and 18% in PHRAC arm and control arm, respectively (HR 0.39; 95% CI, 0.24 to 0.64; p&lt;0.001). Five-year OS was 81% in PHRAC arm and 72% in control arm (HR 0.59; 95% CI, 0.42 to 0.84; p=0.003). There were no significant differences in morbidity or mortality between two arms. The results of eligible patients were barely changed. Subgroup analysis shows differences of DFS, liver-metastasis rate and OS were significant in stage III patients, but not in stage II patients. Conclusions: Additional PHRAC could reduce the incidence of metachronous liver metastasis and improve DFS and OS in patients with stage III CRC, without compromising patient safety. Clinical trial information: NCT00643877.
Phase II study of S-1 plus leucovorin (1-week treatment regimen followed by 1-week rest period) in patients with untreated metastatic colorectal cancer in Japan and China: Comparing results of each country and updating overall survival.
Authors: Ruihua Xu, Jin Li, Jianming Xu, Tadamichi Denda, Koji Ikejiri, Lin Shen, Hideo Baba, Yasushi Toh, Ken Shimada, Takeshi Kato, Kenji Sakai, Ayumi Matsuyama, Hideyuki Mishima, Jin-Wan Wang
Journal: Journal of Clinical Oncology (2013)

528 Background: We previously reported results of a phase II study of the S-1 plus oral Leucovorin(LV) (1 week on/ 1 week off) for patients (pts) with metastatic Colorectal Cancer (mCRC) (Denda et al. Gastrointestinal Cancers Symposium 2012). This study showed promising activity in pts with mCRC. We report here the comparison of efficacy and safety data of each country, and updated Overall Survival (OS). Methods: Pts were eligible as follows: histologically confirmed adenocarcinoma, age ≥20, ECOG PS 0-1, no prior chemotherapy, at least one measurable lesion by RECIST ver1.0 criteria, adequate organ function, and written informed consent. S-1 (40-60 mg bid) and LV (25 mg bid) were orally administered for 1 week, followed by 1 week rest period. The treatment was repeated until disease progression or unacceptable adverse events. The primary endpoint was the response rate (RR), and the secondary endpoints were efficacy and safety. This trial was supported by Taiho Pharmaceutical CO., LTD. ClinicalTrials.gov Identifier: NCT00891332 Results: From October 2008 to June 2009, 73 pts were enrolled in Japan and China. Of the eligible 71 pts, Japan/China was 32/39; median age was 60 (range 27-84); Male/Female was 38/33, and PS:0/1 was 39/32. RR as primary endpoint was 53.5% (95% CI, 41.3-65.5), and 59.4% in Japan and 48.7%in China; Progression Free Survival(PFS) in Japan and China was 6.3 and 6.8 months; median OS was 29.0 and 20.8 months, respectively. The incidences of grade 3 adverse drug reactions were diarrhea 8.3% (3.1% in Japan, 12.5% in China), stomatitis 8.3% (12.5% and 5.0%), anorexia 2.8% (6.3% and 0.0%), neutropenia 9.7%(9.4% and 10.0%), and there was no treatment-related death. Conclusions: This S-1 plus LV (1week on/ 1 week off) treatment regimen showed promising activity in pts with untreated mCRC without the concurrent use of irinotecan, oxaliplatin, or molecular-targeted drugs in both Japan and China. Clinical trial information: NCT00891332.
A systematic review of end of life cancer care in the elderly population in Qatar: A retrospective cohort study.
Authors: Azza Adel Hassan, Ayman Allam, Cicy Mary Jacob
Journal: Journal of Clinical Oncology (2015)

87 Background: Managing cancer in the elderly ( ≥ 65 years of age) is quite challenging as a result of associated comorbidities, poor performance status and the expected lower tolerance to treatment. The aim of the present study is to report on the demographics of cancer in the elderly population at NCCCR, also to analyze different indicators constituting End of Life (EoL) care in this subgroup of patients. Methods: Elderly patients ( ≥ 65 years of age) presenting with cancer diagnosis to NCCCR between January 01, 2009 till December 31, 2013 constituted the cohort study group. Their medical records were reviewed for the following items: Diagnosis, Performance status, age, comorbidities, treatment received, place of death, Length of Stay (LOS) during last hospitalizations as well as aggressiveness of care at EoL. Patients were then subdivided into 3 age groups: 65-74 years (n = 175), 75-79 years (n = 63) and ≥ 80 years (n = 54). Results: The most common diagnosis was colorectal cancer (42%, 35% and 46% in the 3 age groups respectively). The palliative ward was the most common place of death (43%, 46% and 36% respectively) followed by Medical ICU (26%, 14% and 20% respectively). The median survival from the date of admission in last hospitalization was not different in the 3 age groups (9.4 days vs 9.11 days vs 8.8 days respectively). There was no statisticallly significant differences between the 3 age groups as regards any of the 6 indicators of aggressive care. However, a high percentage of ICU admissions (ranging between 20% - 29%) was reported across all age groups. Conclusions: Colorectal cancer is the most common type of cancer in elderly population in Qatar. Admission to ICU in the last month of life was high, ranging between 20-29%. The mean LOS of last hospitalization was short ranging between 8.8 - 9.4 days. These findings would warrant the development of a needed community palliative care service that would allow this group of patients to receive their EOL care at home, rather than in hospital.
Phase II study of sorafenib and capecitabine (SorCape) in previously treated metastatic colorectal cancer (mCRC): NCT01471353.
Authors: Thomas J. George, Alison Marguerite Ivey, Long H. Dang, Karen Colleen Daily, Wei Hou, Dana Lynn Viviano, Scott Watson, Renee Granicz, Margaret A. McEwan, Hui Yan, Carmen Joseph Allegra
Journal: Journal of Clinical Oncology (2013)

489 Background: Sorafenib (Sor) is an oral multi-tyrosine kinase inhibitor (TKI) affecting tumor proliferation and angiogenesis through inhibition of the Ras/Raf/MEK/ERK, VEGF and PDGF pathways. Inhibition of the MEK/ERK pathway through Raf has been shown to resensitize tumor cells resistant to chemotherapy. A similar TKI, regorafenib, has recently demonstrated efficacy as monotherapy in advanced mCRC. Demonstrating activity of this class of compounds with standard cytotoxic therapy represents a clinical unmet need for patients (pts) with mCRC. Methods: Eligible pts had progressive mCRC after prior oxaliplatin and irinotecan, at least 1 measurable target lesion by RECIST, ECOG PS 0-1, and adequate organ function. Pts received Cape (1000mg/m 2 PO BID D1-14) and Sor (400mg PO BID max via dose escalation per cycle). Cycles were q21d with tumor assessments q9w. Endpoints included progression-free survival (PFS), objective and biochemical response rates, overall survival (OS), toxicity, and quality of life. Sample size was based on a 50% improved median PFS from 3 (historical) to 4.5 months (m). Results: 24 of 43 planned pts have received therapy. 19 were white and 17 male. Median age 61y (37-79). 14 (58%) were KRAS-mut. Median prior lines of therapy for mCRC was 3 (1-5). All but one had liver and/or lung metastases. Most frequently observed adverse events (AEs) included fatigue (29%), HTN (38%), and HFS (91%). 18 pts (75%) had a grade 3 AE (11/18 were HFS). There were no grade 4 or 5 toxicities. Preliminary PFS is 4.1m. 5/16 (31%) evaluable pts have radiographic stable disease. Conclusions: Enrollment continues with manageable AEs, despite the overlapping toxicity of HFS. Preliminary PFS data appears promising in this refractory mCRC population. Clinical trial information: NCT01471353.
Comparison of docetaxel and cabazitaxel efficacy on prostate cancer cells both in vitro and in vivo.
Authors: Thomas Nelius, Courtney Jarvis, Dalia Martinez-Marin, Stephanie Filleur
Journal: Journal of Clinical Oncology (2016)

351 Background: Despite recently approved novel agents, taxane-based chemotherapy remains the major therapeutic strategy for metastatic castration-refractory prostate cancer/mCRPC. Still mCRPC continues to be incurable. Besides, patients often experience severe side effects, prompting a re-evaluation of standard regimen. Past studies have demonstrated promise for Low-Dose Metronomic/LDM chemotherapy, defined as the frequent administration of low doses of chemotherapeutic drugs with no prolonged drug-free breaks. Yet relative activities of LDM taxanes and combinations with known anti-neoplasic agents have to be investigated. Methods: PC3, Du145 and LNCaP-derivative CL1cell lines were used to compare the effect of increasing doses of taxanes on cell proliferation, cell cycle distribution and apoptosis by crystal violet, propidium iodide and AnnexinV stainings, respectively. Autophagy was assessed by western blotting against Beclin1. In vivotumor growth was measured using CL1 control and CL1-PEDF xenografts. Phagocytosis was determined by cytotoxicity assay in CL1-macrophages co-cultures. Results: Our data showed that cabazitaxel/cbz-treated cells had a significantly lower EC50 compared to docetaxel/doc, with Du145 cells presenting the greatest differences. Both low-dose taxanes increased the sub-G 0 cells population. However, the sub-G 0 increase was significantly greater in cbz- than doc-treated Du145 cells, but not in PC3 and CL1. Accordingly, plasma membrane Annexin V elevation occurred in Du145 cells at lower doses of cbz than doc validating a higher efficacy due to increased apoptosis. Although Beclin1 levels remain unchanged in PC3 and CL1 cells, it was found up-regulated for all doses of cbz in Du145. In vivo, LDM cbz was significantly more efficient in curbing tumor growth than doc. This effect was markedly increased when cbz was combined with the angio-inhibitor and anti-tumor Pigment Epithelium-Derived Factor (PEDF); an effect that could be explained by increased phagocytosis. Conclusions: Our data demonstrate a higher efficacy of cbz on CRPC both in vitro and in vivo, and suggest that LDM taxane chemotherapy/PEDF combination could be used as a novel therapeutic strategy for CRPC.
Molecular profiling of TOPO1: A way to evaluate irinotecan treatment in colorectal cancer?
Authors: Julia Marie Cunningham, Petra Prins, Brian Conkright, Simina Boca, Shruti Rao, Andrew Gabrielson, Andrew Oseran, Robert Beckman, Marwan Al-hajeili, Subha Madhaven, John Marshall
Journal: Journal of Clinical Oncology (2016)

546 Background: Front-line chemotherapy for metastatic colorectal cancer (mCRC) consists of a fluoropyrimidine backbone plus either oxaliplatin (FOLFOX or XELOX) or irinotecan (FOLFIRI or XELIRI). Large, prospective trials enrolling chemotherapy-naïve patients (pts) show FOLFOX and FOLFIRI treatment to be equivalent with similar response rates. Methods: Irinotecan inhibits TOPO1, which is now a candidate marker for irinotecan treatment benefit. Thus, we retrospectively analyzed TOPO1 expression level in 49 pts with mCRC who were treated with irinotecan-containing regimens at the Lombardi Comprehensive Cancer Center between 2009 and 2014. Patient characteristics and outcomes were compiled through chart review and the effect of TOPO1 expression on clinical outcomes was assessed. TOPO1 expression in tumor tissue from each pt was analyzed using a commercially available molecular profiling (MP) service (Caris Life Sciences). Results: The median overall survival (OS) for all pts was 33.9 months (mo), defined as the time from metastasis to death or censorship. When grouped by “high” or “low” TOPO1 expression, as defined by Caris at the time of the testing, 29 pts were high-expressers and 20 were low-expressers. High TOPO1 expressers receiving irinotecan (n = 22) had a median OS of 27.2 mo, compared with median 41.5 mo for low-expressers (n = 14) (p = 0.27). Irinotecan is conventionally given as second-line therapy. The median OS of pts receiving second-line irinotecan was 38.2 mo for high-expressers [n = 11] vs. 68.5 mo for low-expressers [n = 5]) (p = 0.32). Conclusions: Our limited data do not support the use of TOPO1 expression levels as a predictive marker for irinotecan therapy in mCRC. However, our conclusions are limited by small sample size, lack of a control group to distinguish prognostic from predictive markers, and timing of TOPO1 measurement, which in many cases was after irinotecan therapy. Physicians currently lack an evidence-based way to choose between potentially efficacious regimens for mCRC. More rigorous studies are needed to assess the benefit of MP in mCRC care. We are currently planning a prospective study with the hope of validating the use of TOPO1 expression as a predictive marker for treatment of this disease.
Assessment of PML-RARa Real-Time Quantitative PCR for Definition of Molecular Relapse in APL Patients (Results of the APL Study Group).
Authors: Bruno Cassinat, Stephane De Botton, Lionel Ades, Emmanuel Raffoux, Martine Escoffre-Barbe, Andre Baruchel, Jean-Michel Miclea, Oumedaly Reman, Martine Gardembas, Philippe Brault, Noel Milpied, Olivier Legrand, Herve Dombret, Pierre Fenaux, Christine Chomienne
Journal: Blood (2005)