tbuckley/cabot-search huggingface dataset:
Prevalence of recurrent thrombosis in cancer patients with isolated gonadal vein thrombosis: A retrospective study.
Authors: Suebpong Tanasanvimon, Naveen Garg, Chitra Viswanathan, Milind M. Javle, Mylene Truong, Harmeet Kaur, Chris R. Garrett
Journal: Journal of Clinical Oncology (2012)

e19645 Background: The natural history of isolated gonadal vein thrombosis (GVT) occurring in cancer patients (pts) is not well described in the medical literature. GVT in cancer pts it is of uncertain clinical significance. Methods: Utilizing a software program allowing a searchable database of radiology reports, the computerized tomographic scan (CT) reports of pts at a single cancer center from January 1, 2004 to June 30, 2011, were searched for the term “gonadal vein thrombus”. Pts included in this analysis had a diagnosis of cancer, isolated GVT (i.e. no evidence of thrombosis at another site), and at least six months of follow-up information. Results: 162 cancer pts with GVT were identified for analysis [median age 57.8 ± 12 years, right GVT 89 pts (54.9%), left GVT 59 pts (36.4%), bilateral 14 pts (8.6%)]; the majority of the pts (96, 59.3%) had a non-gynecologic malignancy. At the time of diagnosis of GVT the majority of pts were receiving chemotherapy (84, 51.9%); 70 pts (43.2%) had surgery within the prior six months (the most common being hysterectomy, 127 pts, 78.6%). The majority of pts in this study had metastatic disease (93, 57.4%) as well as active cancer (138, 85.1%, defined as GVT occurring at the time of cancer diagnosis, disease recurrence, metastatic disease, or treatment for cancer within the prior six months); median follow-up time was 22 months. A minority of pts received anticoagulation (28pts, 17.2%). Twenty-two pts (13.6%) developed a recurrent venous thromboembolic event (VTE); these events were pulmonary embolism (12 pts, 7.4%), deep venous thrombosis (5 pts, 3.1%), inferior vena cava thrombosis (4 pts, 2.5%). Median time to development of re-thrombosis was 7 months (range 2-13.5 months). Active cancer was the only risk factor significantly associated with recurrent VTE (p = 0.047); pts with prior hysterectomy had a significantly reduced risk of recurrent VTE (p = 0.036). Conclusions: Incidental isolated GVT identified in cancer pts has a high risk of recurrent VTE (13.6%). Based upon specific pts risk factors for VTE, treatment of an incidentally detected GVT in cancer pts with anticoagulation, as per guidelines for other VTE sites, may be indicated.
Phase III trial of brentuximab vedotin and CHP versus CHOP in the frontline treatment of patients (pts) with CD30+ mature T-cell lymphomas (MTCL).
Authors: Owen A. O'Connor, Barbara Pro, Tim Illidge, Lorenz H. Trumper, Emily K. Larsen, Dana A. Kennedy
Journal: Journal of Clinical Oncology (2013)

TPS8611 Background: MTCL including systemic anaplastic large cell lymphoma (sALCL) are aggressive neoplasms. Anthracycline-based multiagent chemotherapy regimens have demonstrated response rates ranging from 76 to 88%. Five-year overall survival rates range from 12 to 49% depending on the histologic subtype. Brentuximab vedotin is an antibody drug conjugate that has shown efficacy in a pivotal phase 2 study as a single agent in relapsed sALCL (Pro et al., J Clin Oncol, 2012) and evidence of clinical activity in combination with CHP in the frontline treatment of MTCL including sALCL in a phase 1 study (Fanale et al., ASH 2012). Methods: This randomized, double-blind, placebo-controlled, multicenter, phase 3 study (NCT01777152) is evaluating the safety and efficacy of 1.8 mg/kg brentuximab vedotin with CHP (A+CHP) vs CHOP for frontline treatment of CD30+ MTCL. Pts must have FDG-avid disease by PET and measureable disease of at least 1.5 cm by CT. Approximately 300 pts will be randomized 1:1 to receive A+CHP or CHOP for 6–8 cycles (q3wk). Randomization will be stratified by ALK+ sALCL vs other histologic subtypes and IPI score (0–1, 2–3, or 4–5). The target proportion of pts with a diagnosis of sALCL will be 75%. The primary objective is to compare progression-free survival (PFS) between the 2 treatment arms as determined by an independent review facility (IRF). Secondary objectives include comparisons of PFS per IRF in sALCL patients, safety, overall survival, and complete remission rate between the 2 arms. After completion of treatment, pts will be followed for disease progression, medical resource utilization, quality of life, and survival. Post-treatment stem cell transplant is permitted. Efficacy assessments will use the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). CT and PET scans will be performed at baseline, after Cycle 4, and after the completion of treatment. CT scans will also be performed at regular intervals during follow-up until disease progression, death, or analysis of the primary endpoint. Safety assessments will occur throughout the study until 30 days after last dose of study treatment. Enrollment for this global trial began in early 2013. Clinical trial information: NCT01777152.
Mitigating functional performance decrement in cancer patients undergoing treatment
Authors: P. M. Anton, C. A. Dennehy
Journal: Journal of Clinical Oncology (2007)

9105 Background: It is well-documented that treatment side-effects cause physical and psychosocial de-conditioning in cancer patient. Decrease in functional performance (FP), as measured by activities of daily living (ADL), is a major contributor to a decline in patient quality of life (QOL). Relatively little information is available on the effects of a specific exercise regimen targeting muscle groups/energy systems involved in FP. Methods: 30 male and female cancer patients receiving treatment were randomly assigned to either the experimental (EX) or control (C) groups. EX participated in two exercise sessions per week for 17 weeks. Sessions included a combination of aerobic, resistance, flexibility, and balance training. C did not participate in any structured exercise. Data were collected post-diagnosis (1), post- surgery (2), at 9 weeks post-diagnosis (3), and at 17 weeks post-diagnosis (4). Measurements included resting heart rate (RHR), fatigue, physical activity level (PA), QOL, and the FP tasks of: treadmill walking (TRED), stair climb/descent (STAIR), lifting/carrying (CARRY), sit to stand (STAND), and balance (REACH). Results: Factor analysis yielded four variables: FP1 = [(0.5 × TRED) - (0.5 × RHR)]; FP2 = [(STAIR) + (CARRY) + (STAND)]/3]; FP3 = [(0.333 × QOL) + (0.333 × PA) - (0.333 × FT)]; FP4 = REACH. Repeated-measures ANOVA with within-subjects contrasts detected significant differences between groups. No significant differences existed at 1 or from 1 to 2. Significant differences were found on all variables from 1 to 4, 1 to 3 and 3 to 4 (p &lt; 0.001) (significant improvement for experimental group vs. significant decline for control group). Mean changes for the experimental vs. control groups from 1 to 4 are as follows: FP1 (+65.5 vs. -29.5); FP2 (-5.3 vs. +3.6); FP3 (+1.8 vs. -3.4); FP4 (+1.7 vs. -0.81). Conclusions: Specifically-designed exercise interventions promote positive adaptations that elicit significant improvement in ADL, QOL, and decrease fatigue. Prescriptive exercise is a viable therapy during treatment for mitigating side effects and avoiding de-conditioning. No significant financial relationships to disclose.
Use of computerized tomography (CT) as an early prognostic indicator of response to imatinib mesylate (IM) in patients with gastrointestinal stromal tumors (GIST)
Authors: C. H. Holdsworth, J. Manola, R. D. Badawi, D. A. Israel, C. Blanke, M. Von Mehren, H. T. Joensuu, S. Dimitrijevic, G. D. Demetri, A. D. Van Den Abbeele
Journal: Journal of Clinical Oncology (2004)

3011 Background: We report results from a pilot study aimed at optimizing the use of CT bi-dimensional measurements (CT-BDM) as a prognostic indicator of response to IM (Gleevec) in patients with advanced GIST. Methods: 52 patients enrolled from a single center enrolled in a multi-center trial evaluating IM in advanced GIST patients had CTs performed at baseline and 1 month (range 21–40 days) after initiation of treatment. CT-BDM were performed using axial plane measurements of the maximum diameter of each lesion and its maximal perpendicular dimension. Up to 12 lesions were evaluated per patient per scan, and the products of the bi-dimensional measurements were summed for each scan. Patients were followed for up to 36 months. The measurements were correlated with time-to-treatment failure (TTF), defined as the earliest of time to progression by Southwest Oncology Group (SWOG) criteria, death, or cessation of therapy for any other medical reason. The maximally selected chi-square statistic and recursive partitioning methodology of Breiman was used to determine the % change in CT-BDM that best distinguished failures from patients who were failure free, using a time-to-event model. Results: SWOG criteria for partial response (i.e., 50% reduction in CT-BDM) at 1 month were not predictive of TTF (logrank p=0.63). The optimal change in CT-BDM from the baseline scan to the 1-month scan was found to be 8.25% reduction in this patient group (see table). A logrank p-value is not quoted for this threshold as all thresholds were tested. Conclusion: The results support the hypothesis that only a small reduction in CT-BDM 1 month after therapy initiation is sufficient to predict freedom from failure in patients with advanced GIST treated with IM. Future work is aimed at validating this hypothesis with independent data. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharma AG Astra-Zeneca; Bristol-Myers Squibb Oncology; Novartis; Novartis Pharma AG Novartis Pharma AG Novartis Novartis
Integrated genomic analysis by whole exome and transcriptome sequencing of tumor samples from EGFR-mutant non-small-cell lung cancer (NSCLC) patients (p) with acquired resistance to erlotinib.
Authors: Jonathan S. Weissman, Petros Giannikopoulos, John St. John, Andrew V. Uzilov, Carlota Costa, Niki Karachaliou, Irene Sansano, Eloisa Jantus-Lewintre, Rolf A. Stahel, Alain Vergnenegre, Radj Gervais, Jose Luis Perez-Gracia, Maria D. Lozano, Anne S. Wellde, Rodolfo Bordoni, Andres Felipe Cardona Zorrilla, William Reilly Polkinghorn, George W. Wellde, Rafael Rosell, Trever Grant Bivona
Journal: Journal of Clinical Oncology (2013)

11010 Background: NSCLC p with EGFR mutations initially respond to EGFR tyrosine kinase inhibitors (TKIs) but ultimately relapse. Sub-genomic molecular studies indicate that the EGFR T790M mutation and the activation of MET, PI3K, AXL, HER2 and MAPK can lead to acquired resistance to EGFR TKIs. To date, no integrated comprehensive genomic investigation of EGFR TKI resistance has been performed. Methods: FFPE biopsies of erlotinib-sensitive and erlotinib-resistant tumors were obtained from 11 EGFR mutant NSCLC p. DNA was extracted from all tumor and corresponding normal tissue samples and underwent whole exome sequencing using the Illumina HiSeq2500. RNA was extracted from all tumor samples and analyzed by whole transcriptome sequencing, also using the Illumina HiSeq2500. Results: Erlotinib resistant NSCLC specimens harbored upregulation of known resistance drivers including MET and AXL and novel alterations including upregulation of genes that are: 1) recurrently mutated in NSCLC, including ALK, STK11; 2) components of established embryonic stem cell signatures, including targets of Nanog, Oct4, Sox2, c-Myc, 3) neuronal lineage specific regulators, including NTRK3, NRCAM, ALK, LRP4. The analysis also revealed downregulation of several genes that are: 1) components of innate and acquired immunity, including HLA-A, -B, DQ, CD40; 2) phosphatases regulating survival signaling pathways, including PTEN, PTPRD, 3) proapoptotic components, including BNIP3L, IKIP. Conclusions: This study demonstrated the feasibility and utility of comprehensive genomic analysis in the clinical management of NSCLC p receiving targeted therapy. We identified known and novel molecular biomarkers of erlotinib acquired resistance in NSCLC p, and uncovered a previously unappreciated role for genetic events governing stem cell and neuronal phenotypes as well as immune evasion in erlotinib acquired resistance in NSCLC p. Together, our data provide unprecedented insight into the molecular pathogenesis of escape from EGFR oncogene inhibition in NSCLC. We are now conducting a prospective observational study in additional NSCLC p.
Improvement of pharmacokinetic, pharmacodynamic and thrombopoietic activities of human interleukin-11 mutein by PEGylation.
Authors: Seong-Hyun Ho, Seung Shin Yu, Jong-Mook Kim, Sunyoung Kim, Suyong Ma, Dong-Sik Kim, Hwang-Jae Lee
Journal: Journal of Clinical Oncology (2012)

e19574 Background: Chemical modification of recombinant human interleukin-11 (rhIL-11) by polyethylene glycol improved the pharmacokinetics (PK), but not remaining biological activity. Human interleukin-11 mutein (mIL-11) has been shown the improved safety and equivalent efficacy at one-third of the clinical dose of rhIL-11 in chemotherapy-induced thrombocytopenia (CIT) patients. Methods: To evaluate whether PEGylated mIL-11 (PEG-mIL-11) could reduce the toxicity and the frequency of administration without compromising biological activities, comparative preclinical studies on PEG-mIL-11 and mIL-11 in normal and myelosuppressed animals were performed. Results: In vitro biological assay showed that the ED 50 value of purified mono-PEG-mIL11 was comparable to that of mIL-11. The PK parameters such as AUC of PEG-mIL-11 were at least 4-fold larger than those of mIL-11 at the same dosage. The thrombopoietic activity resulting from a single PEG-mIL-11 administration was almost similar to that achieved from multiple administrations of mIL-11 in normal rodents and monkeys. In myelosuppressed model, PEG-mIL-11 was s.c. administered twice at doses of 200, 420 or 900 μg/kg and the platelet number of each group was compared with that of control group injected with 200 μg/kg of mIL-11 once daily for 9 days. The high dose group of PEG-mIL-11 showed 2-fold increase in the nadir platelet count and the mean time to platelet recovery of PEG-mIL-11 groups was shortened up to a maximum of 7 days as compared with mIL-11 or untreated group. PEG-mIL-11 also significantly prevented the reduction of WBC and RBC counts which was considered a major hematological AE of chemotherapy and radiotherapy for cancer as compared with mIL-11 or naïve group. Conclusions: These results suggest that the PEG-mIL-11 show improved PK profile without compromising biological activities and prevent CIT more effectively with better safety profile than mIL-11.
Phase (Ph) 1/2 study of TSR-011, a potent inhibitor of ALK and TRK, including crizotinib-resistant ALK mutations.
Authors: Glen J. Weiss, Jasgit C. Sachdev, Jeffrey R. Infante, Monica M. Mita, Ronald B. Natale, Hendrik-Tobias Arkenau, Keith Wilcoxen, Vikram Kansra, Haley Laken, Lorraine Hughes, David G. Brooks, Robert E. Martell, Stephen Patrick Anthony
Journal: Journal of Clinical Oncology (2014)

e19005 Background: Ultimately, the majority of anaplastic lymphoma kinase (ALK) rearranged (+) non-small cell lung cancers (NSCLC) are either unresponsive to crizotinib or develop resistance mutations. Similarly, gene rearrangements in NTRK1 have been identified as a potentially actionable oncogenic aberration. TSR-011 inhibits ALK and tropomyosin-related kinase (TRK) A, B, and C receptor activity with IC50 values < 3 nM and exhibits inhibition of oncogenic echinoderm microtubule associated protein like 4 (EML4)-ALK and tropomyosin (TPM)-TRKA dependent tumor growth in mice. Methods: A Ph 1-2a dose escalation and cohort expansion study is underway to evaluate safety, tolerability, PK, and preliminary efficacy of TSR-011. Ph 1 is evaluating unselected patients with advanced solid tumors and lymphomas. The recommended Ph 2 dose will be evaluated in Ph 2a in patients with ALK+ or TRK ligand/receptor + tumors (defined by immunohistochemistry or fluorescent in-situ hybridization) including those with NSCLC progressing on, or naïve to, ALK inhibitor therapy. Results: Twenty-three patients with advanced cancer have been enrolled at oral total daily doses between 30 and 480 mg, including NSCLC (n=10, including 5 ALK+), pancreatic (3), ovarian (2), salivary gland (2) and 1 each with papillary thyroid, cholangiocarcinoma, bladder, carcinoid, colon & leiomyosarcoma. Bi-exponential PK was observed, with dose proportional Cmax and AUC and t1/2 of 12-24 h. Dose-limiting toxicities included dysaesthesia and QTc prolongation; MTD has been defined. PK modeling revealed that a fractionated dose of 60 mg daily (dose expansion cohort) minimizes peak exposure and achieves sustained trough concentrations well above the IC50 for ALK inhibition. Of 5 patients with ALK+ NSCLC, 3 (all crizotinib-resistant) achieved PR (1 met RECIST criteria and 2 had non-measurable disease, so not formally RECIST-classified) 1 is early (not imaged yet), and 1 discontinued for DLT. Stable disease was observed in ALK- papillary thyroid, pancreatic and colorectal patients. Conclusions: TSR-011 is a well-tolerated promising second-generation agent for ALK-dependent and crizotinib resistant NSCLC, and is being explored in ALK+ and TRK+ tumors. Clinical trial information: NCT02048488.
Effect of microRNA-206 on G1 arrest by inhibition of CDK4, cyclin C, and cyclin D in melanoma cells.
Authors: Robert W Georgantas, Katie Streicher, Xiaobing Luo, Wei Zhu, Zheng Liu, Philip Brohawn, Chris Morehouse, Brandon W Higgs, Laura Richman, Bahija Jallal, Yihong Yao, Koustubh Ranade
Journal: Journal of Clinical Oncology (2013)

e20047 Background: MiR-206 has been implicated in a large number of cancers. However, its role in tumor biology is unknown and its biological function has yet to be fully characterized. To examine the role of miR-206 in cancer, we examined the expression of miR-206 in melanoma and identified potential target transcriptss that could be important for the progression of this disease. Methods: Using quantitative RT-PCR we compared expression of 364 microRNAs in melanoma skin biopsies skin from normal donors, melanoma cell lines, and normal melanocytes. The effects of miR-206 on cell growth, apoptosis, and cellular migration/invasion were determined using in vitro assays comparing melanoma cell lines to normal melanocytes. Putative mRNA targets of miR-206 were bioinfomatically identified, and empirically tested by luciferase-3’UTR reporter assays. The effect of miR-206 on the cell cycle of melanoma cells was assayed by flow cytometry. Results: Expression profiling of microRNAs in melanoma lesional skin biopsies compared to normal donor skin biopsies revealed numerous differentially regulated miRs. One such microRNA, miR-206, was significantly highly down-regulated in melanoma biopsies (-75.4-fold, p=1.7x10 -4 ) compared to normal skin and normal melanocytes. Functional analysis showed that miR-206 substantially reduced growth and migration/invasion of multiple melanoma cell lines. Bioinformatic analysis identified the cell cycle genes CDK2, CDK4, Cyclin C, and Cyclin D1 as strong candidate mRNA targets of miR-206. Luciferase reporter gene assays revealed that miR-206 inhibits translation of CDK4, Cyclin D1, and Cyclin C. Consistent with this inhibition of CDK4 and Cyclin D1, miR-206 transfection induced robust G1 arrest in multiple melanoma cell lines. Conclusions: MiR-206 expression was decreased in melanoma tissue and cell lines compared to normal skin and melanocytes, respectively. Inhibition of Cyclin C, Cyclin D1 and CDK4 by miR-206 highlights its role in regulating cell cycle progression, a key aspect of melanoma progression. These observations support miR-206 as a potential tumor suppressor in melanoma, and possibly other cancers.
Randomized, double-blind study of sonidegib (LDE225) in patients (pts) with locally advanced (La) or metastatic (m) basal-cell carcinoma (BCC)
Authors: Michael Robert Migden, Alexander David Guminski, Ralf Gutzmer, Luc Yves Dirix, Karl D. Lewis, Patrick Combemale, Robert Herd, Sven Gogov, Tingting Yi, Manisha Mone, Ragini Reiney Kudchadkar, Uwe Trefzer, John Lear, Dalila B. Sellami, Reinhard Dummer
Journal: Journal of Clinical Oncology (2014)

9009a^ Background: Pts with advanced BCC have limited treatment options. Sonidegib blocks the hedgehog pathway (overexpressed in ≥ 95% of BCCs) by selective inhibition of smoothened. Methods: In this ph 2 study (BOLT; NCT01327053), pts with LaBCC, not amenable to curative surgery or radiation, or mBCC were randomized 1:2 to receive sonidegib 200 or 800 mg daily. The primary endpoint, objective response rate (ORR—histopathologically confirmed complete response [CR] + partial response [PR]—achieved if point estimate ≥ 30% and 95% CI lower bound > 20% [either arm]), and secondary endpoints duration of response (DoR), CR rate, time to tumor response (TTR), and PFS were assessed according to modified RECIST (mRECIST; LaBCC) or RECIST 1.1 (mBCC) by central review. Statistical comparison of arms was not planned. Safety was assessed up to ≈30 days post-last dose. Results: Pts (194 LaBCC; 36 mBCC) were enrolled from Jul 2011-Jan 2013. The primary endpoint was met for both arms (Table; median follow-up 13.9 mo). Median exposure was 8.9 (200 mg) and 6.5 mo (800 mg). AEs were less frequent at 200 mg. AEs leading to discontinuation (200/800 mg) included muscle spasms (3.8%/8.7%), dysgeusia (2.5%/4.7%), weight decreased (2.5%/4.7%), and nausea (2.5%/4.0%). Conclusions: Meaningfuldisease control with sustained DoR and prolonged PFS were achieved with both doses of sonidegib, with a more favorable benefit-risk profile for 200 mg. Clinical trial information: NCT01327053. Sonidegib (daily) 200 mg 800 mg LaBCCn=66 mBCCn=13 LaBCCn=128 mBCCn=23 % ORRa 47.0 15.4 35.2 17.4 95% CI 34.6-59.7 1.9-45.4 26.9-44.1 5.0-38.8 % CR 3.0 0 0 0 % PR 43.9 15.4 35.2 17.4 % Disease control rate (CR+PR+SD) 90.9 92.3 78.2 82.6 % ORRb 42.9 15.4 37.6 17.4 95% CI 27.7-59.0 1.9-45.4 27.8-48.3 5.0-38.8 % ORR,a per investigator 65.2 23.1 57.0 34.8 95% CI 52.4-76.5 5.0-53.8 48.0-65.7 16.4-57.3 TTRa Median, mo 3.9 4.6 3.7 1.0 95% CI 3.6-4.2 1.8-7.4 2.6-3.8 1.0-2.1 DoRa n/Nc 4/31 0/2 3/45 1/4 Median, mo NE NE NE 8.3 95% CI NE PFSa nc 7 4 10 10 Median, mo NE 13.1 NE 7.6 95% CI 5.6-13.1 6.2-11.1 a Full analysis set (intent-to-treat population) b Subset of pts (LaBCC w/tumor fully assessable per mRECIST [n=42, 200 mg; n=93, 800 mg] + mBCC per RECIST 1.1) c n=PFS events; N=responders NE, not estimable