tbuckley/cabot-search huggingface dataset:
Interleukin-18 gene promoter polymorphisms and IgE-mediatedallergy in Czech population
Authors: Marcel Schüller, Lydie Izakovičová Hollá, Ondřej Rybníček, Dana Bučková, Jiří Vácha
Journal: Allergy (2003)

Here we present no direct association of the -607C/A and
-137G/C polymorphisms in the IL-18 gene promoter with
IgE-mediated allergic diseases or total IgE serum level in the
Czech population. However, -607A allele was significantly
associated positive skin prick test reactivity to Alternaria.
A phase II trial of neoadjuvant aromatase inhibitor therapy and the mTOR inhibitor everolimus in postmenopausal women with hormone receptor positive/HER2 negative breast cancer and a low/intermediate risk Oncotype Dx Recurrence Score (≤ 25).
Authors: Maysa M. Abu-Khalaf, Sarah Schellhorn Mougalian, Tara Beth Sanft, Erin Wysong Hofstatter, Gina G. Chung, Kerin B. Adelson, Andrea Silber, Debra S. Brandt, Kathleen E. Bober-Sorcinelli, Neal Fishbach, Wajih Zaheer Kidwai, Kert D. Sabbath, Michael DiGiovanna, William M. Sikov, Lajos Pusztai
Journal: Journal of Clinical Oncology (2015)

TPS630 Background: Breast cancer (BC) patients (pts) with low/intermediate Oncotype Dx recurrence scores (RS) ≤ 25 represent a large fraction of BC cases, and a substantial number of distant recurrences occur in this group despite their low to moderate risk and high sensitivity to endocrine therapy. These pts are also the least likely to be sensitive to or benefit from adjuvant chemotherapy. Anatomical risk factors (nodal status, tumor size) continue to define a higher risk group among these endocrine sensitive and molecularly low risk BC pts. The goal of this study is to assess tumor response to a combination of the mTOR inhibitor everolimus and an aromatase inhibitor (AI) in this patient population, utilizing the preoperative endocrine prognostic index (PEPI). Our hypothesis is that everolimus will improve the efficacy of AI in this setting. Methods: This is a phase II study evaluating the efficacy and safety of neoadjuvant AI and everolimus in postmenopausal pts with hormone receptor positive (HR+)/HER...
Detecting prostate cancer in<i> BRCA1</i> and <i>BRCA2 </i>mutation carriers: A role for EN2?
Authors: Emma Killick, Richard Morgan, Francesca Launchbury, Nicola E. Annels, Elizabeth Bancroft, Elizabeth Page, Elena Castro, Zsofia Kote-Jarai, Ros A. Eeles, Hardev S. Pandha
Journal: Journal of Clinical Oncology (2012)

4653 Background: EN2 is part of the HOX gene family and plays a role in foetal development. More recently a potential oncogenic role for the protein has been postulated and its utility as a cancer biomarker has been explored in prostate cancer (PrCa) and breast cancer. Carriers of mutations in the BRCA1 and BRCA2 genes have an increased risk of PrCa (1.8-fold and 5-fold respectively) and their tumours tend to be more aggressive and advanced than sporadic cases. Currently there is no national screening program for BRCA mutation carriers in the UK, and the IMPACT study was set up to evaluate PSA screening in this particular group. Here we analyse the efficacy of the urinary EN2 protein as a marker of early cancer detection within this higher risk group. Methods: First pass urine (without preceding digital rectal examination) was collected as part of the IMPACT screening study which enrolled individuals aged between 40 and 69 who were unaffected by PrCa at time of enrolment into the study (n= 418). All participants were from families harbouring a BRCA1 or BRCA2 mutation and were either BRCA mutation carriers themselves or controls with a negative predictive BRCA genetic test. They underwent annual PSA test with a PSA of &gt; 3.0 ng/ml triggering a diagnostic biopsy. EN2 protein was measured in the urine using an ELISA; (positive = &gt; 42.5ng/ml). Results: Our initial results demonstrated urinary EN2 had a sensitivity of 66.67% and a specificity of 89.29% when discriminating which men had been diagnosed with PrCa; the ROC AUC was 0.816. The difference in EN2 level between those diagnosed with cancer and those who were not was significant (p = &lt;0.001). There was trend towards higher EN2 levels in those with more aggressive tumours (median EN2 84.5ng/mL in Gleason ≤3+4 vs 111ng/mL in Gleason ≥4+3), however this was not statistically significant. In one PrCa case EN2 rise preceded PSA rise by 2 years. Further samples are in the process of being analysed, results from these will be included. Conclusions: Urinary EN2 protein measurement warrants further investigation as a PrCa biomarker in this higher risk group with genetic predisposition to PrCa.
EGFR, KRAS, BRAF, PTEN, and PIK3CA mutation in plasma of small cell lung cancer patients.
Authors: Hongyang Lu, Weimin Mao, Qiao-Yuan Cheng, Hai-Miao Xu, Ju-Fen Cai, Xiaojia Wang, CaiJin Lou, Jing Qin, Wei-Wu Ye, Na Han, Lei Lei, Zhiqiang Ling
Journal: Journal of Clinical Oncology (2014)

e18552 Background: Epidermal growth factor receptor (EGFR) exons 18, 19 and 21 mutation in NSCLC is related to response of tumors to EGFR tyrosine kinase inhibitor (TKI), while mutation with EGFR exon 20, KRAS and BRAF is related to resistance. Some case studies reported that gefitinib-responsive small cell lung cancer (SCLC) with EGFR 19 mutation, but other study reported one SCLC patient with EGFR 19 and phosphatidylinositol-3-kinase catalytic α (PIK3CA) mutation which transformed from NSCLC are resistant to EGFR TKIs. Phosphatase and tensin homologue (PTEN) governs a plethora of cellular processes by suppressing the phosphoinositide 3-kinase (PI3K)-v-akt murine thymoma viral oncogene homolog (AKT)-mammalian target of rapamycin (mTOR) pathway. It is important to know the mutation of EGFR, KRAS, BRAF, PTEN and PIK3CA in SCLC. It is difficult to obtain tumor tissues to detect gene mutation in SCLC patients especially from surgery, and plasma can be replacement of tumor for gene detection. Methods: Thirty two SCLC patients were prospective collected from August 2012 to December 2013 in Zhejiang cancer hospital. EGFR exons 18-21, KRAS exon 2, BRAF exon 15, PTEN exons 5, 6 and 8, PIK3CA exons 9 and 20 were analyzed from plasma by high-resolution melting method. Results: EGFR exon 18 mutation was found in one patient and exon 19 mutation was in another patient. EGFR exons 18 and 19 mutation was identified in one patient and EGFR exons 20 and 21 mutation was in another patient. Three patients were with KRAS exon 2 mutation and another patient was with EGFR exon 18, 20 mutation accompanied with KRAS exon 2 mutation. Conclusions: EGFR exon 18 or 20 mutation was also can be detected in SCLC patients from plasma as EGFR 19 or 21. Double mutation of EGFR was existed in SCLC patients as KRAS exon 2 mutation.
A phase I, first-in-human study to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of IMGN853 in patients (Pts) with epithelial ovarian cancer (EOC) and other FOLR1-positive solid tumors.
Authors: Carla Kurkjian, Patricia LoRusso, Kamalesh Kumar Sankhala, Michael J. Birrer, Maurice Kirby, Sharron Ladd, Susan Hawes, Kelli Lynn Running, James J. O'Leary, Kathleen N. Moore
Journal: Journal of Clinical Oncology (2013)

2573 Background: IMGN853 is an antibody-drug conjugate (ADC) comprising a folate receptor 1 (FOLR1)-binding antibody and the potent maytansinoid, DM4. FOLR1 is over-expressed on many solid tumors, particularly EOC, endometrial cancer, non-small cell lung cancer (NSCLC), and clear-cell renal cell cancer. Methods: The primary study objectives are to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary objectives include evaluation of safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy. In dose escalation, patients with any type of FOLR1-expressing, refractory solid tumor may be enrolled. Once the MTD is defined, 3 expansion cohorts will evaluate patients with (1) primary platinum refractory or resistant EOC; (2) relapsed/refractory EOC, amenable to biopsy, and (3) relapsed/refractory NSCLC. Cohorts 2 and 3 will have IMGN853 PD assessment by pre-and post-dose tumor biopsy and by FLT-PET imaging, respectively. IMGN853 is given intravenously (IV) on Day 1 of each 21-day cycle. During dose escalation, an accelerated titration design was used. Responses are assessed using RECIST and GCIG criteria (as appropriate). Results: Eleven patients have been enrolled across 6 dose levels ranging from 0.15 to 5.0 mg/kg: 7 patients with EOC and 4 patients with endometrial cancer. No study drug-related serious adverse events (SAEs) or dose-limiting toxicity (DLT) have been reported. Among these 11 patients, 3 patients reported adverse events (AEs) considered study drug related; these were mild or moderate. At the 3.3 mg/kg dose level, one patient with serous EOC had an 82% reduction in CA125 (confirmation pending). The other 2 patients at this dose level, one with EOC and one with endometrial cancer, have stable disease. Drug exposure has been measured in 8 patients and has been found to generally increase linearly, with a half life at 3.3 mg/kg (3 patients) of approximately 4 days. Conclusions: IMGN853 is well tolerated at doses up to 3.3 mg/kg. Safety evaluation continues at 5 mg/kg and dose escalation is ongoing. Clinical trial information: NCT01609556.
A phase I/II study to evaluate the ability of decitabine and panobinostat to improve temozolomide chemosensitivity in metastatic melanoma.
Authors: Chang Xia, Douglas Earl Laux, Jeremy Michael Deutsch, Melanie Frees, Brian Smith, Raymond J. Hohl, Mohammed M. Milhem
Journal: Journal of Clinical Oncology (2012)

3056 Background: Epigenetic gene regulation is likely a contributing mechanism of cancer initiation and progression. Emerging evidence indicates that epigenetics may also play a key role in the development of chemoresistance in melanoma. We proposed combining the histone deacetylase inhibitor panobinostat (PT) and the demethylator decitabine (D) to overcome the development of epigenetic mediated temozolomide (TMZ) resistance in metastatic melanoma. Methods: Eligible patients must be ≥18, stage IV melanoma, and naïve or previously treated, with good performance status (ECOG ≤ 2) and normal organ functions. Patients with previous exposure to TMZ were allowed on study. The study includes the dose escalation of D and PT followed by expansion cohorts. D (0.1mg/kg SQ, 0.2mg/kg SQ) on days 1, 3, 5, 8, 10,12, PT (10mg PO, 20mg PO, 30mg PO) Q96h starting day 8, and TMZ 150mg/m 2 PO daily on days 9-13 of each 42 day cycle. TMZ was increased to 200mg/m2 in the absence of grade 2 thrombocytopenia. Primary endpoints of phase I study are to determine the toxicity, safety and maximum tolerated dose (MTD) of the D, PT and TMZ combination. Results: To date, the phase I portion of this trial is completed. We report on the safety data for this combination. 17 patients received treatment (1 st cohort: 5; 2 nd cohort: 4; 3 rd cohort: 4; 4 th cohort: 4 ). M:F 11:6. Median age: 56 (32-77); Median ECOG PS: 1; 82% of the patients received at least one cycle (n=14). Median number of cycles given: 2 (0-6). To date, no DLTs have occurred. The MTD was not reached. The only grade (G) 4 adverse event (AE) is neutropenia on a patient in cohort 3 and it resolved within 3 days. G3 AEs included lymphopenia (n=4, 23%), anemia (n=2, 12%), leukopenia (n=2, 12%) and fatigue (n=2, 12%). Common G2 toxicities were leukopenia (n=5, 30%), neutropenia (n=4, 23%), nausea (n=4, 23%) and lymphopenia (n=3, 18%). Conclusions: The combination of D, PT, and TMZ appears to be safe and well-tolerated. The recommended dose for the phase II study remains to be determined.
A phase I study of selective cyclin dependent kinase inhibitor P1446A-05 administered on an intermittent schedule in patients with advanced refractory tumors.
Authors: Sudeep Gupta, Minish Mahendra Jain, Anish Maru, Shona Milon Nag, Naresh Somani, Ajay O. Mehta, Sujay Kulkarni, Shivani Anil Acharya, Poornima Dhobe, Nitin Jadhav
Journal: Journal of Clinical Oncology (2012)

3011 Background: Cyclin-dependent kinases (Cdks) have emerged as important targets in anticancer drug development. P1446A-05 is a potent and specific inhibitor of Cdk4-D1 (IC 50 -0.09µM), Cdk1-B (IC 50 -0.025µM), and Cdk9-T (IC 50 -0.022µM). This study was designed to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT), safety profile, pharmacokinetics, and antitumor activity of orally administered P1446A-05 in patients with advanced refractory tumors. Methods: This study was conducted at 5 centers in India. P1446A-05 was administered in escalating doses across 5 cohorts of eligible pts starting with a dose of 75 mg once a day (OD) for 14 days in a 21 day cycle utilizing a modified Fibonacci scheme for dose escalation. 10 pts positive for cyclin D1 expression in the tumor were enrolled at MTD. Treatment was continued until unacceptable toxicity or disease progression. For pharmacokinetic analysis, blood samples were collected on days 1 and 13/14 of cycle 1 at multiple time points. In consenting pts, skin and tumor tissue biopsies were collected on days 1 (pre-dose), 8 and 15 of cycle 1. Results: A total of 29 patients were dosed. Two DLTs (abdominal pain and acute renal failure) were reported at 850 mg/d. The MTD was 600 mg/d and diarrhea was reported as 1 DLT at this dose level. Six SAEs including one death related to study drug were reported. Pharmacokinetic analysis demonstrated a median half-life of 16 to 26 h and linear increase in exposure at steady state across tested doses. Plasma concentration at 300 mg/d dose level crossed efficacy exposure of 100mg/kg of five day dosing in SCID mice. The recommended phase II dose is 600 mg OD on this schedule. Stable disease for 4 to 6 cycles was reported in 5 pts. Of them, one patient each with breast cancer, spindle cell sarcoma in neck, and nasopharyngeal carcinoma had cyclin D1 over expression. No objective responses were observed in this group of heavily pretreated patients. Conclusions: The safety profile of P1446A-05 is considered acceptable. On this dosing schedule, the MTD is determined as 600 mg/day. Further testing of P1446A-05 in phase II studies is planned.
Evaluation of the prognostic significance of RACGAP1, Ki67, and TOP2A mRNA expression in high-risk early breast cancer.
Authors: Kyriaki Pliarchopoulou, Helen Gogas, Christos A. Papadimitriou, Ralph M Wirtz, George Kouvatseas, Eleni Timotheadou, Flora Stavridi, Christos Christodoulou, Angelos Koutras, Nikolaos Pisanidis, George E. Pentheroudakis, Dimitris Bafaloukos, Epaminontas Samantas, Konstantine T. Kalogeras, Meletios A. Dimopoulos, Dimitrios G. Pectasides, George Fountzilas
Journal: Journal of Clinical Oncology (2013)

582 Background: Proliferation is a major process in carcinogenesis. RACGAP1 is a protein involved in cell growth regulation and metastasis, Ki67 is a known proliferation marker and TOP2A has a key role in DNA replication and remodeling. The aim of the present study was to explore the prognostic significance of a signature of proliferation markers, such as RACGAP1, Ki67 and TOP2A on disease-free survival (DFS) and overall survival (OS) in high-risk early breast cancer patients. Methods: A total of 1681high-risk breast cancer patients, enrolled in two consecutive phase III trials, were treated with anthracycline-based adjuvant chemotherapy. Formalin-fixed paraffin-embedded tumor tissue samples from 963 of these patients were extracted using a standardized fully automated isolation method for total RNA based on silica-coated magnetic beads, followed by multiplex RT-qPCR for assessing RACGAP1, Ki67 and TOP2A mRNA expression. CALM2 was included in the same reaction, as a reference gene. Results: After a median follow-up of 107 months, 289 patients (30.0%) demonstrated disease progression and 261 (27.1%) patients died. Univariate analysis revealed that poor OS was associated with high RACGAP1 mRNA expression (p=0.0185, log-rank), high Ki67 (p=0.0219), as well as high TOP2A (p=0.0019) mRNA expression, while in multivariate analysis only TOP2A retained significance (Wald’s p=0.008). In an effort to improve prognostic significance, combinations of the expression of two or all three genes were tested, with low mRNA expression of the three genes being associated with improved DFS (HR=0.74, CI=0.56-0.98, p=0.035) and OS (HR=0.60, CI=0.42-0.85, p=0.004). However, in multivariate analysis, none of the combinations retained prognostic significance, except the combination of high RACGAP1 and TOP2A mRNA expression, which was found to be associated with decreased DFS (HR=1.26, CI=0.96-1.63, p=0.092) and OS (HR=1.49, CI=1.10-2.03, p=0.009). Conclusions: High RACGAP1 and TOP2A mRNA expression was found, in multivariate analysis, to be of adverse prognostic significance in high-risk early breast cancer patients treated with anthracycline-containing adjuvant chemotherapy.
Association of clofarabine (Clo)-associated GFR decline (GFRd) with dose and AUC.
Authors: Peter H. O'Donnell, Federico Innocenti, Amittha Wickrema, Wendy Stock, Marjie Hardj, Andrew S. Artz, Koen van Besien
Journal: Journal of Clinical Oncology (2012)

e13120^ Background: Clo, a nucleoside analog, is approved for pediatric ALL, but also has activity in AML. We conducted a ph I-II trial of clo-melphalan-alemtuzumab for allo transplant and found grade 3-5 renal toxicity in 16 of 74 patients, despite prolonging infusion time to reduce Cmax (BBMT 2011, Epub). Methods: Clo pharmacokinetics were analyzed in 65 pts (Clo doses 10-40 mg/m 2 , infusion time 1 or 3 hrs) of 74 pts; baseline GFR estimated by modified MDRD equation. Clo levels were drawn at 1, 1.5, 2, 3, 5, 7, 9 and 24 hrs following the 1st and 3rd (or 4 th ) dose. GFRd (in ml/min/m 2 ) between start of Clo (d-7) and day of transplant constituted the outcome of interest. Results: Median age 53 (21-73), median baseline GFR 94 ml/min/m 2 (46-120). Mean (range) Cmax, clearance (CL) and AUC were 531 ng/ml (119-1010), 42002 ml/min (13979-88020) and 2052 ng*hr/ml (471-5835), respectively. Mean AUC per dose was 32.0 ng*hr/ml/mg (14-32). Systemic exposure was similar between d1 and d3. Further analyses used the highest AUC and Cmax. Decreases in GFR ranging from 10-100 ml/min/m 2 (average 44 ml/min/m 2 ) occurred in 30 of 65 patients. There was no correlation between Clo dose and GFRd (r=-0.02,p=0.87). There was a significant correlation between Clo AUC and GFRd (r=0.53, p &lt;0.0001), Clo AUC per dose and GFRd (r=0.62, p&lt;0.001) and between Clo CL and GRFd (r=-0.38, p=0.0001). There was a weaker correlation between Clo Cmax and GFRd (r=0.22, p=0.07). Clo CL was highly correlated with baseline GFR (r=0.4, p=0.0009). Of interest baseline GFR was inversely correlated with pt age (r=-0.46, p=0.0001) and age was significantly correlated with AUC (r=0.4, p=0.001), AUC per dose (r=0.36, p=0.003) and with GFRd (r=0.34, p=0.005). Conclusions: Decline in GFR is associated with inter-patient variability in exposure to Clo. Baseline GFR affects Clo CL and thus AUC, and potentially increases risk for renal toxicity. Older age is associated with decreased baseline GFR and risk for toxicity. Clo may require dose adjustment based upon renal function and/or age. These data require confirmation in further studies.
Patterns of care for synchronous rectal cancer with liver-only metastasis: Results from the South Australian registry of metastatic colorectal cancer.
Authors: Amitesh Chandra Roy, Christos Stelios Karapetis, Cynthia Piantadosi, Amanda Rose Townsend, Rob Padbury, Scott Carruthers, Guy Maddern, David Roder, James Moore, Timothy Jay Price
Journal: Journal of Clinical Oncology (2017)

701 Background: Management of rectal cancer with synchronous liver metastasis is not clear. Optimal timing of radiotherapy, chemotherapy, resection of primary and liver metastasis is debated. Methods: The South Australian Registry for metastatic colorectal cancer has entered all patients with mCRC since 1st February 2006. Registry data were analyzed to assess patient characteristics, therapy received and outcomes for patients with liver only metastasis and synchronous rectal or colon primary. KM analysis was used for survival outcomes. Results: 2677 patents had synchronous mCRC. 42% (n = 1125) had liver only metastasis (primary: 275 rectal/850 colon). The main differences between rectal/liver vs. colon/liver were: more males (68.7% v 57.8%, p = 0.001), younger age (65.8 v 73.3 years, p &lt; 0.001) and less poorly differentiated histology (14.2% v 24.1%, p = 0.003). The rate of no surgery on the primary was 21.4% for rectal cancers v. 36% for colon (p ≤ 0.001). Liver surgery rates in both groups was similar (28.4% v 23.0% (p = 0.075). Out of the 275 rectal cancer patients, 100 (36.3%) had rectal surgery, 83 (30%) had chemo-RT and 47 (17%) had chemotherapy +/- targeted therapy as initial treatment, 45 (16%) patients had no treatment. Median OS of rectal cancer patients based on their initial treatment was 33.2m (Chemo-RT) vs. 22.2m (surgery) vs. 19.2m (chemotherapy +/- targeted therapy, p &lt; 0.001). The mOS for rectal group was 22.8m v. 14.8m (p = 0.001) for colon group. For patients who had liver surgery mOS was 60.7m vs. 67.1m respectively. Survival was better if primary was rectum or left colon vs. right colon (mOS 18.3m vs 18.8m vs 10.2m respectively p &lt; 0.001). Resection of the primary occurred first in all patients who had liver resection. Conclusions: Patients with synchronous rectal cancer with liver only metastases have better survival compared to those with colon cancer and liver only metastases. Where surgery is possible, OS is equivalent between the two groups and in our registry population surgery on the rectal primary or chemo-RT were found to be the preferred initial treatment for rectal cancer patients with synchronous liver metastases.