tbuckley/cabot-search huggingface dataset:
Phase 1, pharmacokinetic (PK) and pharmacodynamic (PD) study of oral alvespimycin (A; KOS-1022; 17-DMAG): Two different schedules in patients with advanced malignancies
Authors: K. T. Flaherty, L. Gore, A. Avadhani, S. Leong, K. Harlacker, Z. Zhong, R. G. Johnson, A. L. Hannah, P. O’Dwyer, S. G. Eckhardt
Journal: Journal of Clinical Oncology (2007)

14059 Background: A is ∼3–5 fold more potent compared to 17-AAG (the first Hsp90 inhibitor to enter clinical testing), based on in vitro cytotoxicity or the MTD in toxicology studies; it is water-soluble; and oral bioavailability in dogs is estimated at 40%. Toxicity in the dog included kidney, intestinal and liver findings. This study was conducted to determine the toxicity, MTD, recommended phase 2 dose (RP2D), PK and PD of A in pts with solid tumors. Methods: Escalating doses of A were given PO on 2 different schedules: every other day or daily for 4 out of 6 weeks. An initial IV dose was given to calculate absolute bioavailability. PK was evaluated after the IV dose, Day 1 and 21 of oral dosing. PBLs were collected to investigate changes in intracellular signaling proteins by immunoblot (Days 1 and 21 at 1, 3, 24 and 48 hours post-dose). Results: 28 pts were enrolled: 24 on the QOD schedule at doses of 5 (n=4), 10 (n=4), 20 (n=8), 30 (n=5) and 40 mg (n=3); 4 pts received 10mg on the QD schedule. 50% were male, median age/ECOG PS 55 and 0; median prior regimen 3. DLT has not yet been observed. Common drug-related toxicities (n=23): fatigue 43%, nausea 24%, anorexia 19%, proteinuria 19%, and peripheral edema 14%. Of these, fatigue and peripheral edema appear to be possibly dose-related. Drug-related Grade 3–4 toxicity (one patient each) included anemia, neutropenia, peripheral edema, hypokalemia, pain in extremity and hypoxia. For pts with full PK data (n=14), bioavailability equaled 51% and 49% on Day 1 and 21, and was not dose-dependent. Mean Day 21 AUC inf for the 5 to 30 mg/m 2 levels equaled 91, 166, 542 and 1889 ng*h/mL. One pt with 3-fold increase in AUC inf comparing Day 1 and 21 dose had been started on dronabinol, a CYP2C9 inhibitor. One pt with fibrosarcoma (4 prior regimens) had necrotic changes in the tumor in the axilla with improved symptoms (active at 5+ months). Additional pts with SD include hemangioendothelioma (7 months), melanoma (6+ months), and renal cell (5 months). Induction in Hsp70 at the 30 mg dose level was seen pre-dose on Day 21 with maximal induction at 24 hours post-dose. Conclusions: Dose escalation continues on both schedules in order to define a RP2D. Toxicity is acceptable. Early signs of activity have been observed. [Table: see text]
Efficacy and safety of axitinib (AG-013736; AG) in patients (pts) with advanced non-small cell lung cancer (NSCLC): A phase II trial
Authors: J. H. Schiller, T. Larson, S. I. Ou, S. A. Limentani, A. B. Sandler, E. E. Vokes, S. Kim, K. F. Liau, P. W. Bycott, A. J. Olszanski
Journal: Journal of Clinical Oncology (2007)

7507 Background: A correlation between vascular endothelial growth factor (VEGF), microvessel density, and prognosis has been reported in pts with NSCLC. AG is a small molecule inhibitor of the receptor tyrosine kinases, with picomolar potency against VEGFR 1, 2 and 3 and nanomolar potency against PDGFR-β and KIT. This is an open-label, multicenter phase II study examining the efficacy and safety of AG in pts with advanced NSCLC. Methods: Pts with stage IIIB or metastatic NSCLC received AG 5 mg BID. Eligibility criteria included measurable disease and ECOG performance status of 0 or 1. A Simon 2-stage minimax design was used with 18 pts in the first stage plus an additional 14 in the second stage if 1/18 pts responded. The primary endpoint was response rate (RR) according to RECIST. Results: A total of 32 pts were enrolled: median age was 66 yrs (39–80); histologies were adenocarcinoma (75%), squamous cell carcinoma (9%), and not otherwise specified (16%); 56% male/44% female; 72% received prior chemotherapy, 47% prior surgery, 47% prior radiotherapy, 9% investigational therapy, 3% immunotherapy, and 13% were treatment-naïve. Mean duration of treatment was 93 days (1–271). Three (9.4%) investigator confirmed responses were reported with a 95% confidence interval (CI) of 2, 25. Median duration of response was 9.4 months (mo). Median survival was 12.8 mo (95% CI: 9.9 mo, undefined) and progression-free survival was 5.8 mo (95% CI: 3.8 mo, 10.2 mo). 26 (81%) pts discontinued treatment: lack of efficacy 19 pts (59%), adverse events 5 pts (16%), death 1 pt (3%), and withdrawal of consent 1 pt (3%). Grade 3/4 toxicities (=5%) were fatigue (22%), diarrhea (6%), hypertension (6%) and hyponatremia (6%). Conclusions: AG demonstrates single- agent activity in pts with advanced NSCLC. Therapy is well tolerated with manageable toxicity in this population. Further investigation in this setting is warranted. [Table: see text]
Dose intensive administration of carboplatin and paclitaxel with pegfilgrastim and whole blood support
Authors: P. J. Woll, D. W. Fyfe, F. Willis, S. D. Pledge, W. P. Steward, C. Gallagher, N. Davidson, P. Barker, N. Baker, R. Pettengell
Journal: Journal of Clinical Oncology (2005)

6674 Background: Optimising cytotoxic dose intensity is critical to achieving the best outcomes for patients with solid tumours. Chemotherapy dose intensification can be achieved by reducing cycle length or increasing doses of cytotoxic agents. In this study we explored the feasibility of delivering carboplatin/paclitaxel at a reduced cycle interval (10–11 days) supported by pegfilgrastim and autologous whole blood infusions. Methods: Patients with solid tumours received carboplatin AUC 6 (1 hour IV infusion) and paclitaxel 175mg/m2 (3 hour IV infusion) for a total of 6 cycles. Cycle 1 was 21 days, cycles 2–6 were administered every 10–11 days. Patients were randomised to receive pegfilgrastim 6mg, 12mg or 18mg on day 2 or filgrastim 5μg/kg from day 2 to an ANC ≥10x109/L. Prior to chemotherapy on day 1 of cycles 3–6, 750ml of whole blood was collected by venesection for re-infusion on day 2. The primary endpoint of the cycle 2–6 analysis was proportion of patients receiving cycles 2–6 at full dose (i.e. >75% of planned dose) and on schedule (i.e. every 11 days ± 3 days). Results: Fifty-three patients (37 [70%] with lung or ovarian cancer) started cycle 2 chemotherapy. A total of 39 (74%) patients completed 4 cycles of chemotherapy and 27 (51%) completed 6 cycles. Of 265 planned cycles of study chemotherapy, 201 (76%) were given on schedule. Only 8 (3%) were delayed due to slow ANC or platelet recovery. The most frequently reported serious adverse events (reported by 5 patients) were thrombocytopenia, abdominal pain and nausea. Other adverse events including bone pain were similar in incidence across the groups. Conclusions: It is feasible to administer full dose carboplatin/paclitaxel every 10–11 days with pegfilgrastim and whole blood support. There was no significant difference between filgrastim and pegfilgrastim 6, 12 and 18 mg with respect to enabling full dose on schedule and no increase in SAEs or bone pain at the higher doses. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Amgen Ltd. Amgen Amgen, Amgen Ltd. Amgen
Clinical efficacy of accelerated partial-breast irradiation in treatment of ER-negative breast cancer: Results of a matched pair analysis.
Authors: Peter Y. Chen, Jessica Wobb, Michelle Wallace, Inga S. Grills, Maha Saada Jawad, Arielle Pietron, Joshua T. Dilworth, Nayana Dekhne, Donald S. Brabbins
Journal: Journal of Clinical Oncology (2014)

70 Background: To assess outcomes of ER-negative breast CA pts treated with APBI, a matched-pair analysis was performed to determine efficacy of APBI vs whole breast RT (WBRT) from a single institution. Methods: From over 1650 pts treated with BCT from 1980-2013, a cohort of ER[-] pts treated with APBI or WBRT were investigated. Matched-pair analysis with a 1:1 ratio paired 79 APBI with 79 WBRT pts, all ER[-] (total:158). Match criteria included follow-up (FU) &gt; 1.0 yr, stage, &amp; age +/- 5 yrs. Outcomes analyzed included local recurrence (LR), true recurrence/marginal miss (TRMM), regional recurrence (RR), distant metastases (DM), disease-free (DFS), cause-specific (CSS), and overall survivals (OS). Results: As for clinical-pathological traits, no significant differences were noted for age (p=0.302), T-stage (p=1.000), tumor size (p=0.721), N-stage (p=0.062), use of chemoRx (p=0.747), endocrine Rx(p=0.408) or Herceptin (p=1.00). Per ASTRO Guidelines, no differences were seen in cautionary or unsuitable [UnS] groups between APBI &amp; WBRT (p=0.333). With a mean FU of 8.0 yrs (10.1 yrs APBI; 8.4 yrs WBRT p&lt;0.001), no differences were seen in the 10-yr actuarial rates of LR (9.3% vs 22.1% p=0.094), RR (1.3% vs 8.1% p=0.299), DM (7.1% vs 13.0% p=0.429), DFS (83.9% vs. 72.5% p=0.214), CSS (93.5% vs. 89.0 % p=0.677), or OS (79.6% vs. 80.1% p=0.573) between APBI &amp; WBRT. Only TRMM was significantly different (0% APBI vs 12.5% p=0.011). In stratifying patients based on ER% (0%, 1-3%, 4-8%) no outcome differences were noted. Of the 158 ER[-] pts, 124 were cautionary with similar 10-yr outcomes except for TRMM (0% APBI;WBRT 14.4% p=0.017) &amp; CLBF (0% APBI;WBRT17.1% p=0.019). For the 34 UnS patients, no endpoint differences were seen APBI vs WBRT. But, when the entire 158 ER[-] patients were analyzed for # of UnS factors, increasing UnS factors led to significant risk of RR (p&lt;0.001) &amp; DM (p=0.002). Conclusions: With 10-year FU of APBI for ER[-], the clinical results were equivalent to WBRT. No differences were noted based on ER%. Increasing number of unsuitable factors had more RR and DM. Maturation of randomized trial data will be needed to provide Class I evidence for equivalence of APBI to WBRT in ER[-] patients.
Surrogate markers of antiangiogenic therapy in patients with locally advanced breast cancer with lymphangitic spread to the chest wall: Results from a phase II randomized study of bevacizumab with sequential versus concurrent oral vinorelbine plus capecitabine
Authors: M. Locatelli, G. Curigliano, P. Mancuso, F. Bertolini, G. Peruzzotti, M. Scicchitano, S. Dellapasqua, L. Lunghi, A. Goldhirsch
Journal: Journal of Clinical Oncology (2008)

14649 Background: As most of antiangiogenic agents are extremely expensive there is a compelling need to monitor biological activity and select the patients who are most likely to benefit from treatment according to surrogate markers that are able to predict clinical benefit. Methods: We evaluated the activity and biological effects of Bevacizumab (B) (15 mg/Kg Q 3 weeks) in a phase II randomized study in patients with locally advanced breast cancer with lymphangitic spread to the chest wall. We assessed the activity and toxicity of B administered alone (arm A) and with concurrent or sequential oral vinorelbine (V) plus capecitabine (C) (arm B). We collected blood samples of all patients at baseline, after 12 days and at every disease evaluation in order to assess circulating endothelial cells (CECs) and circulating progenitors cells (CEPs) levels. Results: Out of 43 planned patients, 11 patients have been enrolled in the study (5 pts in arm A/ 6 pts in arm B). 8 pts are evaluable for response (3 are too early) and all pts are evaluable for toxicity. Out of 8 patients evaluable for response, we observed 4 PR (50%) and 2 SD (25%) in arm B; and 2 PD (40%) in arm A. Crossover was planned for patients in PD. By six-colors flow-cytometry we evaluated CECs and CEPs at baseline, at +12 and at +42. The mean number of CECs was 220+137/ml (n=11) at baseline (versus 150±51/mL in healthy subjects (n=12), 123+74/ml at +12 and 283+190/ml at +42, while CEPs were 330+ 329 at baseline (versus 129+178), 295+309/ml at+12 and 68+107/ml at +42. The fraction of apoptotic/necrotic CECs was 85±4% in healthy subjects and 56±22% in cancer patients at baseline, 64±20 at+12, and 39±13 at+42. Conclusions: Development of cellular and molecular pharmacodynamic surrogate markers of antiangiogenic activity is a key point for treatment schedules including antiangiogenic agents. Our preliminary data demonstrated CECs and CEPs as potentially useful surrogate markers of antiangiogenic activity of B in BC patients. An updated report will be presented. No significant financial relationships to disclose.
Criteria for monitoring carcinoembryonic antigen: variability of sequential assays at elevated levels.
Authors: J J Lokich, S Ellenberg, B Gerson
Journal: Journal of Clinical Oncology (1984)

Fifty-five patients with advanced cancer and elevated plasma carcinoembryonic antigen (CEA) levels greater than 20 ng/mL (Roche assay) were monitored by clinical parameters for disease activity and a daily plasma specimen was obtained and stored frozen. In 45 patients with evaluable metastatic lesions, 35 were stable; five had progressive disease; and five had regressive disease. Plasma CEA in patients with stable disease showed an overall coefficient of variation of 13%. The CV did not differ according to various quantitative CEA levels from less than 100 ng/mL to greater than 1,000 ng/mL. The coefficient of variation in responding and progressive disease patients ranged from 13% to 63%. An analysis of CEA variability relative to the baseline CEA level was possible using the formula square root 2 times the variability about the mean; this yields a value of +/- 36% representing the range within which approximately 95% of sequential CEA levels would lie in the absence of a clinical change in disease. In 225 CEA determinations in stable disease patients, 6% demonstrated an increase beyond this level (36%) and none demonstrated a decrease of 36% or more from the baseline level. This study establishes guidelines for the boundaries of change in plasma CEA that may be applied as a criterion (in conjunction with standard objective disease parameters) for determination of tumor response to therapy.
Covariates of efficacy and safety in four trials of pemetrexed gemcitabine (PG) in advanced stage IIIB (with pleural effusion) or stage IV non-small cell lung cancer (NSCLC)
Authors: B. A. Van Doren, Z. Ye, J. A. Treat
Journal: Journal of Clinical Oncology (2007)

18076 Background: P and G have demonstrated antitumor activity as a first-line treatment in pts with locally advanced or metastatic NSCLC. The impact of covariates such as age and gender on the activity and toxicity of this doublet has not been elucidated. Methods: A total of 220 pts with Stage IIIB (with pleural effusion) or IV NSCLC were treated with PG in four Phase 2 clinical trials. Three trials used G 1250 mg/m 2 D 1,8 and P 500 mg/m 2 on D 1 or D 8, and one used a 14-d regimen of G 1500 mg/m 2 D 1 and P 500 mg/m 2 D 1. Two types of analyses were performed to determine covariates’ relationship to variables of response (CR+PR), disease control (CR+PR+SD), and toxicity. Using logistic regression, odds ratios (ORs) were calculated by comparing pt covariates to outcomes. In a separate analysis, pt populations were stratified by baseline covariates, which were treated as categorical variables. Results: Conclusions: Neither age nor gender were statistically significant prognostic factors for activity or toxicity using either analysis, although older pts may have had a slightly better response rate and disease control rate when compared with younger pts. Complete analyses will be presented at the meeting. [Table: see text] No significant financial relationships to disclose.
MicroRNA 21 in tissue injury and inflammation: AUTHORS' RETROSPECTIVE
Authors: C. K. Sen, S. Roy
Journal: Cardiovascular Research (2012)

This editorial refers to an article by S. Roy et al .[1][1] published in Cardiovascular Research in 2009. It is accompanied by an editorial by J. Bauersachs (doi:10.1093/cvr/cvs200) as part of this Spotlight on Landmark Papers in Cardiovascular Research. 

This editorial celebrates the extraordinary citation of our recent publication1 in Cardiovascular Research highlighting the emerging significance of miR-21 in the heart, particularly in the context of tissue injury, inflammation, and remodelling. The work was first submitted to a leading cardiovascular journal in January 2008. The submission was summarily rejected, citing ‘paucity of novel mechanistic insight’. The work went on to be published in Cardiovascular Research and has now been cited 150 times in 3 years, being recognized as one of the most highly cited articles in the journal. Had the work been published in the original journal it would have been published almost a year in advance and would have today ranked third in citation score among all of nearly 300 articles published in that journal in 2009. Here, we briefly review the progress in the field since our original work was published.⇓ 



Box 1 
Title page including abstract from the original 2009 publication in Cardiovascular Research .1 Used with permission of Oxford University Press on behalf of the European Society of Cardiology.



Identified as one of the first mammalian microRNAs (miRs), the miR-21 sequence is strongly conserved throughout evolution. During the early phase of development of miR-21 biology, most of the target coding genes reported were tumour suppressors. Thus, miR-21 represents one of the first ‘oncomirs’ named. Two concurrent works1,2 published by the Engelhardt laboratory2 and us1 markedly changed the landscape by introducing the cardiac fibroblast as a major hub for miR-21 action. Taken together, these studies drew attention to the role of miR-21 …

 [1]: #ref-1
Development of a gene signature for earlier detection and diagnosis of ovarian cancer
Authors: G. Vansant, P. Pezzoli, W. Goldstein, J. Monforte, M. Birrer
Journal: Journal of Clinical Oncology (2007)

5573 Background: Ovarian cancer is the 5 th leading cause of death from cancer among women and is the most fatal cancer among the gynecological malignancies. One of the major reasons for poor prognosis among ovarian cancer patients is the disease is often detected at stages III and IV, where survival rates are very low. For patients at these stages, less than 25% will survive 5 years and ultimately 75% of women diagnosed at these late stages will die. The current biomarker predominantly used for detection of ovarian cancer and monitoring of patients for relapse during therapy is the mucin 16 gene product CA125. The utility of this biomarker is limited because its expression is not always isolated to tumor tissue and in fact its expression is not associated with 40% of stage I tumors. Methods: Genes were selected that have been shown to have significant expression differences in primary ovarian tumors versus normal surface ovarian epithelium and were used to develop a multiplex RT-PCR assay for monitoring the expression of these genes. We extracted RNA from samples representative of patients with cancers of various stages (1A through 4B) and diagnoses as well as disease free subjects and monitored the expression of the potential genetic biomarkers in these samples with the developed multiplex assay. Results: Cluster analysis of the gene expression data successfully grouped the different stages together with very high specificity including the samples from the stage I patients. One stage I sample clustered with the stage III and IVs. This was from a patient with a poorly differentiated serous adenocarcinoma, a characteristically aggressive tumor which may be physiologically more similar to the later stage tumors. Conclusions: In these experiments we sought to identify and evaluate potential biomarkers that could be used in parallel for early detection and for monitoring patients during treatment. Initial results from this study revealed genes that have the potential to be part of a gene signature assay panel for early detection and patient treatment monitoring for ovarian cancer. No significant financial relationships to disclose.
Colon cancer disparities: A SEER-based analysis of epidemiologic data on Asian and Pakistani immigrants in the United States.
Authors: R. N. Rahman, A. M. Hossain, J. Abraham
Journal: Journal of Clinical Oncology (2010)

1603 Background: Asian Indian and Pakistani population living in the US (US-AIP) comprises 1.5% of total US population and is a rapidly growing minority group. Colorectal (CRC) is the third most common cancer in US-AIP reported in SEER database from 1988-2006. This is the first study reporting different epidemiologic and survival parameters of CRC in this population. Methods: Since 1988, SEER has been collecting and reporting data of US-AIP as a separate ethnic and race group. Using the SEER database including patients diagnosed with CRC from 1988-2006, we performed frequency analysis on demographics and treatment, comparing US-AIP, Caucasian (USW), Hispanic, and African- American (AA). Multivariate analyses and survival sessions (Kaplan-Meier, age-adjusted) were undertaken. Results: CRC accounts about 8% (859) of all cancers (10,833) in US-AIP reported in SEER database; is more common in male (59% vs. 41%, p < 0.001) with incidence rate of 39 per 100,000 (less common than USW, Hispanic and AA, p < 0.001). CRC is the fifth and seventh leading cancer in India and Pakistan respectively according to 2009 World Health Organization's data. Median age of diagnosis is significantly less in US-AIP (62 vs. 71 yrs, p < 0.001), more patients less than 50 yrs of age at diagnosis (26% vs. 11%, p < 0.001) with advanced stages (p < 0.001) and grades (p < 0.001) in comparison to other major US ethnicities. But overall, stage and gender specific 1-5 year survival is significantly better (p < 0.01 – 0.03) in US-AIP than other ethnicities in the USA. Cox regression analysis showed that age at diagnosis, stages, grades, marital status, and year of diagnosis were predictors of death. Relative risk (RR) of death increased with higher grades, stages and older ages. Conclusions: This is the first study analyzing the epidemiologic, biological and survival data of US-AIP. US-AIP change their demographics of CRC with migration. It shows clearly and identifies some unique age, stage and biological features of CRC in US-AIP. The difference in survival is intriguing. It could be due to differences in tumor biology, access to care and other factors. This study has potential implication in screening and therapeutic recommendation in US-AIP population. No significant financial relationships to disclose.