tbuckley/cabot-search huggingface dataset:
Inhibition of tumor cell growth, invasion, and metastasis by SIM-89, a novel inhibitor of HGF receptor tyrosine kinases.
Authors: Jun Pei, Baohui Han, Minhua Shao, Huifang Sha
Journal: Journal of Clinical Oncology (2012)

e13528 Background: The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are overexpressed and/or activated in a wide variety of human malignancies. SIM-89, developed by Simcere Bio-Pharmaceutical Co, Ltd, is a small-molecule kinase inhibitor that targets members of the HGF receptor tyrosine kinase families. Methods: Kinase inhibition was investigated using Z-lyte detection technique(Invitrogen), LanthaScreen Tb-activity technique and LanthaScreen Binding technique. Inhibition of p-Met and Met is validated through Westernblot. IC50 of the compound is determined by CCK-8. HGF level in culture medium is determined by ELISA.Migration and invasion assayare done with Transwell system. A549 and H460(2×10 6 )are implanted subcutaneous in right upper extremity of nude mice.Once daily oral administration of SIM-89/ placebo are given to nude mice for 35d.Tumor growth curve is calculated. B16F10 tumor cells (2 × 10 5 ) were implanted via i.v. tail vein injection into mice on day 0. SIM-89/ placebo administration was initiated 3 days after implantation for 10 days followed by assessment of lung tumor burden. Lung nodule diameters were morphometrically measured on digitally captured images. The results for each treatment group (n = 10 animals) were averaged, and statistical t test analysis was done comparing each treatment group to the placebo treated control. Results: SIM-89 is a small-molecule kinase inhibitor that targets members of the HGF receptor tyrosine kinase families,with additional inhibitory activity toward AMPK (A1/B1/G1) and TRKA. SIM-89 significantly decreases HGF level in culture medium of nsclc cell lines at the IC50 of 625nmol/l. In vivo, these effects produce significant dose-dependent inhibition of tumor burden in an experimental model of lung metastasis. Once daily oral gavage administration of SIM-89 resulted in a dose-dependent reduction in tumor burden, as determined by a reduction in lung wet weights. Conclusions: These data indicate that SIM-89 may prevent tumor growth through a direct effect on tumor cell proliferation and by inhibition of invasion mediated by HGF receptors.
Cancer survivorship in the primary care setting: A new medical school elective.
Authors: Miklos C. Fogarasi, Gerald R Berg, Roy P Eichengreen
Journal: Journal of Clinical Oncology (2017)

15 Background: Responding to calls for education in Cancer Survivorship, the Frank H. Netter MD School of Medicine introduced new content using an interactive student elective for Y2 medical students with the goal of improving medical knowledge and confidence in caring for survivors. Methods: Learning objectives and course content were developed based upon the ASCO curriculum (ASCO Core Curriculum for Cancer Survivorship Education Shapiro, CL et al, Journal of Oncology Practice Feb 2016 Vol. 12 (2) p 145-e117). Seven medical and one biomedical science student enrolled to complete the Sep-Dec 2016 course. Weekly sessions, facilitated by an Oncologist, utilize independent and collaborative learning, small group role playing, concept maps, algorithms and multiple case scenarios to identify and analyze key issues of survivorship. Co-facilitators with varied expertise and cancer survivors are invited weekly. Successful completion requires active participation, reading and discussion of required articles, contributing to a Glossary, and constructing a Survivorship Care Plan after independently interviewing a cancer survivor. A pre/post course questionnaire and reflective writing is used to assess change in knowledge and attitudes. Results: Weekly attendance was excellent, and students remained highly engaged. Sessions involving a geneticist, social worker, hospice nurse or APRN were well received. Students built a Glossary of cancer-terms, and practiced “Skills of the Week”. Pass/fail data and questionnaire data are pending, as the course is ongoing. Conclusions: Teaching cancer survivorship is feasible for Y2 students. Motivation and interest in the topic is high for this self-selected course. Based upon early observations and feedback the small group setting is valuable for interactions with survivors and inter-professional staff. Students recognize complex social factors influencing survivors’ care and combine knowledge from prior molecular biology, genetics, and physiology classes with the humanistic aspects of patient-centered care. If course evaluation data confirms its value, this curriculum may serve as one element of a multi-level graduate/post-graduate curriculum in Survivorship education.
Gene expression profiling (GEP) for the prediction of response to neoadjuvant paclitaxel and gemcitabine in breast cancer (BC). Preliminary results from a Phase II trial
Authors: A. Llombart-Cussac, G. Moreno-Bueno, A. Ruiz, J. Albanell, J. I. Mayordomo, V. Carñana, V. Guillem, R. Diaz-Uriarte, J. Palacios, I. Garcia-Ribas
Journal: Journal of Clinical Oncology (2004)

580
TBCRC-010: Phase I/II study of dasatinib in combination with zoledronic acid (ZA) for the treatment of breast cancer bone metastasis (MBC-bone).
Authors: Zahi Ibrahim Mitri, Rita Nanda, Kimberly L. Blackwell, Colleen Costelloe, Ilona Hood, Abenaa M. Brewster, Nuhad K. Ibrahim, Kimberly Higginbotham Koenig, Gabriel N. Hortobagyi, Catherine H. Van Poznak, Mothaffar F. Rimawi, Stacy L. Moulder
Journal: Journal of Clinical Oncology (2015)

11080 Background: Osteoclast activation and subsequent bone resorption release growth factors that promote tumor growth. These events are blocked by the Src/PDGF inhibitor dasatinib. The tyrosine kinase Src phosphorylates and activates the ER in ligand-independent manner. Dasatinib, by inhibiting Src, may facilitate the antitumor effect of endocrine therapy. Methods: A phase I/II study was completed by the TBCRC at three institutions: MD Anderson Cancer Center, Duke University, and University of Chicago. Pts with HER2-negative, MBC-bone received standard dose ZA IV on day 1 and Dasatinib 100 mg QD, days 1-28 of each 28 day cycle. Prior therapy with bone-modifying agents was allowed. Response was assessed by RECIST (non-bone disease) and MDACC criteria for bone. Pts progressing on endocrine therapy continued this therapy to determine dasatinib’s effect. Change in urine n-terminal telopeptide levels (NTX) was correlated with response. Results: 25 pts were enrolled, 7 in phase I and 18 in phase II. An initial pt developed pleural and pericardial effusions in cycle 1 on dasatinib 70 mg BID, prompting change to 100mg/day for the MTD/RP2D (recommended phase 2 dose) 6 pt run-in cohort (0/6 developed DLT). Most adverse events (AEs) were grade 1-2: rash (32%), fatigue (28%), and nausea (20%). Grade 3 AEs: anemia (4%) and pain (4%). In pts treated at RP2D (n = 24, Table 1), RR (CR, PR) in bone was 5/24 (21%), all PRs. Clinical benefit rate (CR, PR, SD > 6months) in bone was 8/24 (33%). Median TTF was 2.69 months (1.77 - 5.45), 3.61 months (1.84 - 5.71) in ER+ disease and 0.67 months (0.26 – 1.73) in ER- disease. Response was associated with low grade, ER+ disease, and high baseline NTX levels. In ER+ disease pts who had progressed on, but continued their previous endocrine therapy (n = 14), 29% had PR in bone. In pts with metastatic sites outside the bone (n = 12), RR was 3/12 (25%) and CBR 4/12 (33%) for non-bone metastasis. Conclusions: Dasatinib and ZA were well tolerated, and may have benefit in a subset of pts. Clinical trial information: NCT00566618.Characteristics of patients treated at RP2D. Patients (N) 24 Median Age, (Range) 45, (36-74) Hormone receptor Positive 21 Negative 3 NTX at baseline Low 16 Moderate 3 High 4 Reason for discontinuation PD 22 AE 2
Comparison of sleep variables between healthy participants and hospitalized acute myeloid leukemia patients treated with decitabine, followed by cytarabine.
Authors: Dana H. Bovbjerg, Tonia Peters, Jessica Manculich, Amy Lowery, Donna M. Posluszny, John E. Schmidt, Martica Hall, Daniel Buysse, Michael Boyiadzis, Annie P. Im
Journal: Journal of Clinical Oncology (2014)

e18022 Background: A recent survey study of patients with acute leukemia (93% inpatient) found that difficulty sleeping was one of the most prevalent patient complaints (55%), exceeded only by lack of energy (79%) and feeling drowsy (56%) on the 32-item scale. To date however, studies of sleep difficulties in leukemia patients using objective measures of sleep (e.g., actigraphy) are lacking. A better understanding of sleep problems in these patients is important since poor sleep, particularly in the elderly, is associated with a host of negative health effects, including premature mortality. Methods: We conducted a preliminary study comparing objective sleep measures in newly diagnosed older patients with AML (n=13, mean age=74) (all participating in a phase II study of an induction regimen using decitabine [days 1-5] as an epigenetic primer followed by cytarabine [days 6-10], followed by recovery [days 11-15]) to sleep measures collected from an age-matched sample (n=13) of healthy older individuals. All participants wore an actigraphy device (Actiwatch) providing objective, validated measures of sleep duration and disruption. Nightly sleep results for patients were averaged across days in each treatment interval, which were compared separately to comparable means for the comparison group. Results: With regard to length of sleep, the inpatient AML patients slept longer (range 512-536 min) than the comparison group (range 431-455 min) in each of the three treatment intervals (t-tests, p’s <0.05). With regard to sleep disruption, patients evidenced more disrupted sleep. During their sleep periods they had significantly (<0.05) higher levels of: a) wake time after sleep onset; b) mean wake bout duration; and c) percentage of time awake. Conclusions: Results suggest that while sleep length would suggest no deficits in the AML patients, the measures of sleep disruption revealed substantial decrements for the AML patients. Future research with larger patient samples should explore the impact of high levels of sleep disruption on patient reported outcomes and response to treatment.
CHEK2 mutation in renal cell carcinoma (RCC): Single center experience.
Authors: Joanna Huszno, Magdalena Mazur, Elzbieta Nowara, Ewa Grzybowska
Journal: Journal of Clinical Oncology (2017)

480 Background: Renal cell cancer (RCC) accounts for about 4% of all the adult malignancies. RCC occurs in both sporadic and heritable forms. Genetic mutations have been identified as the cause of inherited cancer risk in 1% to 2% of RCC cases overall. In some studies, variant I157T of CHEK2 gene were found to be associated with increased risk of clear cell renal cancer. The aim of this study was to evaluate the association between CHEK2 mutation and RCC in our centre. Methods: We reviewed the medical records of 43 clear cell renal cancer patients (pts) who were diagnosed and treated in COI in Gliwice. Mutation profile was assessed by RFLP-PCR technique. In Poland, there are three polymorphic variants of CHEK2 1100delC, IVS2+1G →A (premature protein truncation), and a common missense variant (I157T) (substitution of an isoleucine for a threonine). We evaluated the presence of CHEK2 mutation in clear cell carcinoma. Results: In our study CHEK2 mutation (variant I157T) was detected in 7% pts. The median age of pts was 57 years (range from 34 to 74). Most of the patients were women (87%). All CHEK2 mutation carriers were women and were &gt;65 years old. Cancer in family history were reported in 80% pts. Most frequently were: breast cancer (33%), gynecological cancers (33%), gastrointestinal cancers (27%), and renal cell carcinoma (20%). There was also described lung cancer in family history (7%). The most frequent cancers in family history in CHEK2 mutation carriers were: breast cancer and gynecological cancers. 20% of pts had other cancers in their history (breast cancer, ovarian cancer, and contralateral renal cell carcinoma). Contralateral renal cell carcinoma was reported in CHEK2 mutation carrier. All pts had nephrectomy due to RCC and all had clear cell renal cancer in histopathologic examination. All CHEK2 mutation carriers had higher grade (grade 3) and capsular invasion. 5% of CHEK2 mutation carriers had TP53 (c.[215G&gt;C])polymorphism. Conclusions: Variant I157T of CHEK2 gene were found to be associated with increased risk of cancer in family history (breast cancer, gynecological cancer), and renal cancer of contralateral kidney. Factors associated with CHEK2 mutation carriers were higher histologic grade (G3) and elderly age.
Implementation and Evaluation of a Large-Scale Teleretinal Diabetic Retinopathy Screening Program in the Los Angeles County Department of Health Services
Authors: Lauren P. Daskivich, Carolina Vasquez, Carlos Martinez, Chi-Hong Tseng, Carol M. Mangione
Journal: JAMA Internal Medicine (2017)

Diabetic retinopathy (DR) is the leading cause of blindness in adults of working age in the United States. In the Los Angeles County safety net, a nonvertically integrated system serving underinsured and uninsured patients, the prevalence of DR is approximately 50%, and owing to limited specialty care resources, the average wait times for screening for DR have been 8 months or more.
Customized first-line chemotherapy according to ERCC1 and RRM1 SNPs in advanced NSCLC patients: A phase II study.
Authors: Francesca Mazzoni, Fabiana Letizia Cecere, Giulia Meoni, Costanza Giuliani, Andrea Camerini, Giacomo Allegrini, Domenico Amoroso, Luca Boni, Francesca Martella, Prabha Ranchicchio, Elisa Giommoni, Francesca Torricelli, Francesco Di Costanzo
Journal: Journal of Clinical Oncology (2012)

e18074 Background: Excision repair cross complementing group 1 (ERCC1) and ribonucleotide reductase1 (RRM1) expression levels are predictive of CT efficacy in some malignancies. “Customized” CT has several advantages: (1) pts are more likely to be treated with agents that they will respond to, (2) pts can be spared the toxicity of agents that they are resistant to, (3) effective treatment can be delivered early in the course of disease. Methods: We planned a phase II multicentric open label study in two steps (based on Simon design) to evaluate ERCC1 SNPs (T118C and C8092A) and RRM1 SNPs (-37C&gt;A and -524T&gt;C) in advanced NSCLC pts. Here we report the first step for futility. Pts received first line CT according to the assessed ERCC1 and RRM1 SNPs status and the correlated expression levels: treatment A (low ERCC1 and low RRM1) Cisplatin plus Gemcitabine; treatment B (low ERCC1 and high RRM1) Cisplatin plus Docetaxel; treatment C (high ERCC1 and low RRM1) Gemcitabine plus Docetaxel; treatment D (high ERCC1 and high RRM1) Docetaxel plus Vinorelbine. Results: 42 pts were enrolled from Jan. 2010 to Oct. 201, 40 pts received at least 1 cycle of CT; median age was 66 yrs (range 47-73); 33 pts were males; 23(55%) pts were ECOG PS 0, 19(45%) PS 1; all pts had stage IV; 23(55%) pts had adenoca, 13(31%) squamous, 6(14%) other types; 25(62%) pts received treatment A, 3(8%) treatment B, 11(27%) treatment C, 1(3%) treatment D. As primary end-point we assessed the overall best response: 18(45%) pts achieved PR, 12(30%) SD, 8(20%) PD, 2(5%) pts were not evaluable. Updated information on OS and PFS will be presented. CT was well tolerated, there were no treatment related deaths. Conclusions: We observed an improved RR in this setting of NSCLC pts treated with CT according to ERCC1 and RRM1 SNPs status. We are planning to continue the second step of this trial (total 110 pts).
Biomarker correlation to clinical response in phase I/II trials of the adjuvant breast cancer vaccine neuvax (nelipepimut-S or E75).
Authors: John S. Berry, Alfred F Trappey, Alan K. Sears, Timothy J Vreeland, Guy T. Clifton, Diane F. Hale, Ritesh Patil, Jarrod P. Holmes, Sathibalan Ponniah, Elizabeth Ann Mittendorf, George Earl Peoples, David C. Van Echo
Journal: Journal of Clinical Oncology (2013)

TPS3126 Background: We completed phase I/II clinical trials with NeuVax (nelipepimut-S), a HLA-A2/A3-restricted, HER2-derived peptide vaccine. The vaccine was administered in the adjuvant setting to prevent recurrence in breast cancer patients rendered disease-free with standard-of-care therapy. Here, we examine the relationship between in vitro immunologic response (IR) and clinical recurrence (CR) after 5-year follow-up. Methods: The phase I/II trials were performed as dose-escalation/schedule-optimization trials enrolling node positive and high-risk, node-negative patients (pts) with tumors expressing any level of HER2 (IHC 1+,2+,or 3+). HLA-A2/A3+ pts were enrolled in the vaccine group (VG) while HLA-A2/A3- pts were followed prospectively as an untreated control group (CG). The VG was given 4-6 monthly intradermal inoculations of nelipepimut-S+GMCSF (immunoadjuvant) during the primary vaccine series (PVS). In vitro IR was assessed for E75-specific, cytotoxic T lymphocyte clonal expansion by HLA-A2:IgG dimer assay and expressed as mean dimer index (mdi) at baseline, after PVS (R6), and six months after the PVS. HER2 under-expression was defined as an IHC 1/2, and a FISH &lt; 2.2. VG and CG pts were followed for CR over 60 months. P-values were calculated using the Fisher’s exact test. Results: Of the 195 pts enrolled, 8 withdrew, leaving 187 evaluable pts; 108 in the VG and 79 in the CG. R6 dimer assays were available for 86 pts in the VG. The mean R6 dimer in the VG is 0.63 mdi+.08. Of the 30 pts with an R6 dimer above the mean, only one recurred, compared to eight of the 56 below the mean (p=.09). The difference between baseline and maximum mdi was available in 56 HER2 under-expressing VG pts. Of the 26 pts above the mean difference (1.08 mdi +.17), one recurred, compared to six CR in the 30 pts below the mean (p=.06). There were no CR in pts with HER2 under expression with a mean difference ranked in the top third. Conclusions: In prospective, completed phase I/II trials of NeuVax (nelipepimut-S), patients who exhibit robust in vitro IR have lower recurrence rates. This finding suggests that nelipepimut-specific CTL clonal expansion is a valid biomarker for CR in pts treated with NeuVax. Clinical trial information: NCT00841399.
Interim safety analysis of a randomized phase II trial comparing alternate-day oral therapy using S-1 with the standard regimen as a first-line treatment for patients with advanced pancreatic cancer
Authors: Hiroaki Yanagimoto, Takuji Okusaka, Hiroshi Ishii, Junji Furuse, Shinichi Ohkawa, Akira Fukutomi, Tatsuya Ioka, Masayuki Sho, Shoji Nakamori, Masayuki Kitano, Kazuya Sugimori, Hiroyuki Maguchi, Hiroshi Imaoka, Hideo Baba, Atsushi Shimizu, Isao Yokota, Yasuo Ohashi, Hiroki Yamaue
Journal: Journal of Clinical Oncology (2015)

e15267 Background: Based on the results of the GEST study, S-1 was confirmed to be non-inferior to gemcitabine. However, the recommended standard regimen frequently causes adverse events(AEs). On the other hand, a multi-center prospective phase II study showed that the alternate-day administration of S-1 reduced AEs and was tolerable for unresectable advanced pancreatic ductal adenocarcinoma (PDAC) patients. Accordingly, we conducted a multi-center randomized phase II study to investigate the non-inferiority of S-1 using alternate-day administration, compared with the standard regimen for unresectable PDAC. Herein, we report the interim safety analysis results of this study. Methods: Patients who met the study criteria (histologically-confirmed PDAC, age > 20, ECOG Performance Status of 0 or 1, no prior chemotherapy or radiotherapy, and adequate organ functions) were randomly assigned at a ratio of 1:2 to standard daily S-1 administration (Arm A: 4 weeks of administration followed by 2 weeks of rest) or alternate-day administration (Arm B). The primary end point was overall survival (OS). Secondary end points were safety, response rate (RR), progression-free survival (PFS), and time to treatment failure (TTF). Results: A total of 187 patients were treated (Arm A: 65, Arm B: 122). The median age in the two study groups was 67 (38-78) and 66 (40-79) years old, respectively. The two groups were balanced with respect to baseline characteristics. No treatment-related serious AEs or unexpected toxicities were observed. The most frequent toxicities were anemia, hypoalbuminemia, anorexia and fatigue. Anorexia (all grade AEs :Arm A vs Arm B (%): 64.6 vs 51.2, p = 0.014), fatigue (63.1 vs 43.8, p = 0.008), pigmentation (23.1 vs 7.4, p < 0.001) and neutropenia (35.4 vs 21.3%, p = 0.014) were more common in daily administration than alternate-day administration. Conclusions: Our data indicates that alternate-day S-1 administration might reduce AEs in use as a first-line chemotherapy in unresectable PDAC. The follow-up phase of the study is ongoing (UMIN000008604). Final analysis will be conducted in July 2015. Clinical trial information: UMIN000008604.
Cyclooxygenase-2 and epidermal growth factor receptor inhibition in an orthotopic murine model of human lung adenocarcinoma
Authors: E. M. Sievers, R. D. Bart, L. M. Backhus, C. A. Diperna, V. A. Starnes, R. M. Bremner
Journal: Journal of Clinical Oncology (2004)

7362 Background: Activated epidermal growth factor receptors (EGFR) and cyclooxygenase-2 (COX-2) enzyme play a related role in growth, apoptosis, angiogenesis, and metastatic spread of lung cancer. Inhibition of these targets using orally available agents is a potential therapeutic strategy for non-small cell lung cancer (NSCLC). We aim to establish the effect of EGFR and COX-2 blockade on growth and metastatic spread in an orthotopic murine model of lung adenocarcinoma. Methods: Human lung adenocarcinoma cells expressing EGFR and COX-2 (ATCC-CRL5908) were implanted in the left upper lobe of SCID mice (2×106 cells/25uL). Mice were randomly assigned to one of 3 treatments at the time of implantation (n=10/group); normal chow, celecoxib (25mg/kg body weight/day), erlotinib (OSI-774) (15mg/kg body weight/day). At 3 weeks mice were killed and a blinded observer measured primary tumor volume and mediastinal metastatic disease. Primary and mediastinal tumor was confirmed histologically and EGFR and COX-2 expression was established by immunohistochemistry and PCR. Results: All 30 mice survived 3 weeks with no observed toxicities. Primary tumor inhibition occurred in both treatment groups. The mean primary tumor volume was 47mm3 ± 31 SD in the control group. The mean primary tumor volume was 6.8mm3 ± 9.1 SD, and 5.1mm3 ± 7.1 SD in the erlotinib and celecoxib treated groups respectively (p<0.0001; ANOVA). The median number of mediastinal nodal metastasis decreased from 17 lymph nodes (LN) in the control group to 10 LN in the erlotinib group and 8 LN in the celecoxib treated group. Conclusions: Targeted therapy inhibiting EGFR or COX-2 decreases primary tumor burden in an orthotopic model of lung adenocarcinoma. Combination therapy is being studied further. Given the details of each pathway and the potential for cross-talk, an increased benefit with combined treatment is expected. No significant financial relationships to disclose.