tbuckley/cabot-search huggingface dataset:
3D‐Printed Multidrug‐Eluting Stent from Graphene‐Nanoplatelet‐Doped Biodegradable Polymer Composite
Authors: Santosh K. Misra, Fatemeh Ostadhossein, Ramya Babu, Joseph Kus, Divya Tankasala, Andre Sutrisno, Kathleen A. Walsh, Corinne R. Bromfield, Dipanjan Pan
Journal: Advanced Healthcare Materials (2017)

Patients with percutaneous coronary intervention generally receive either bare metal stents or drug-eluting stents to restore the normal blood flow. However, due to the lack of stent production with an individual patient in mind, the same level of effectiveness may not be possible in treating two different clinical scenarios. This study introduces for the first time the feasibility of a patient-specific stenting process constructed from direct 3D segmentation of medical images using direct 3D printing of biodegradable polymer-graphene composite with dual drug incorporation. A biodegradable polymer-carbon composite is prepared doped with graphene nanoplatelets to achieve controlled release of combinatorics as anticoagulation and antirestenosis agents. This study develops a technology prototyped for personalized stenting. An in silico analysis is performed to optimize the stent design for printing and its prediction of sustainability under force exerted by coronary artery or blood flow. A holistic approach covering in silico to in situ-in vivo establishes the structural integrity of the polymer composite, its mechanical properties, drug loading and release control, prototyping, functional activity, safety, and feasibility of placement in coronary artery of swine.
Identification of the functional significance of mutations using the novel Precision Cancer Analysis System.
Authors: Nir Peled, Gabi Tarcic, Naama Barabash-Katzir, Zohar Barabash, Shlomo Yaakobi, Eli Besser, Hani Nevo, Michael Vidne, Yaniv Tocker, Mariusz Adamek, Mordechai R. Kramer, Nikolai Goncharenko, Yakov Fellig, Karen Meir, Keith Mostov, Erez Chimovits, Yoram Altschuler
Journal: Journal of Clinical Oncology (2015)

e22123 Background: As no two tumors share the same molecular mechanism, each cancer patient presents a unique type of disease. Genomic profiling, especially NGS, has armed oncologists with new information leading to major improvements in patient care. The establishment of such tools has raised the bar for the next generation of cancer diagnostics to overcome two challenges 1) Identification of the clinical significance of the mutations in tumors and the interplay within them, most of which are classified as variants of unknown significance (VOUS) 2) assessing the usefulness of targeted therapeutics to the specific patient’s cancer. Methods: 20 cancer patients were sequenced for a panel of 37 genes and analyzed by the Precision Cancer Analysis system (PCAS). This system quantifies oncogenic activity in the majority of the oncogenic signaling pathways altered by the patients’ mutations through a functional assay and does not rely on prior knowledge of the mutations. The system produces a quantitative output enabling grading the different mutants of the same patient, providing prioritization for better drug selection. Results: In 3 tested genes, 16 different mutations were identified- 4 in EGFR, 4 in PIK3CA and 8 in KRAS. Of these 10 were classified as known mutations for which functional annotation exists, and 6 were VOUS. In addition to correctly annotating all known mutations, the PCAS further quantified oncogenic activity in all the VOUS tested. Measuring the functional mechanism behind known mutations and VOUS provides another layer of critical information to the physician. These results clearly demonstrate the value of a functional assay in accurately identifying the optimal course of treatment, particularly by its ability to add actionable information to VOUS. Conclusions: The study produced a comprehensive delineation of the oncogenic activity of each patient’s individual mutations demonstrating the ability of the PCAS to 1) accurately deliver comparable actionable information as found by NGS, 2) functionally characterize mutations annotated as VOUS, and 3) monitor oncogenic activity of signaling pathways induced by different mutations and mutation-combinations enabling informed treatment decisions.
A targeted intervention to improve awareness to molecular testing in NSCLC.
Authors: Alona Zer, Jean-Claude Cutz, Harmanjatinder S. Sekhon, David M Hwang, Christina Sit, Matthew Binnie, Anthony M. Brade, TaeBong Chung, Suzanne Kamel-Reid, Paul Narinder, Ming-Sound Tsao, Thomas K. Waddell, Gilda da Cunha Santos, Milan Patel, Ronald F Carter, Natasha B. Leighl
Journal: Journal of Clinical Oncology (2014)

6547 Background: Molecular testing is now standard of care to guide treatment selection in advanced NSCLC. Population-based implementation of testing remains a challenge in Ontario’spublic healthcare system, with ~37% of eligible samples undergoing testing and~12% insufficient for testing. We developed an intervention to improve understanding among Ontario specialists of the importance of molecular testing and appropriate diagnostic sampling in NSCLC. Methods: Based on IASLC guidelines for molecular testing in NSCLC, leaders in lung pathology, respirology, interventional radiology and thoracic surgery identified key messages for each specialty regarding molecular testing and diagnostic sampling in lung cancer. Specialty-specific educational programs (delivered by a multidisciplinary team) were developed and administered at provincial and national specialty meetings. Participants were assessed on their knowledge of targeted therapy, molecular testing and sample requirements Results: Ten educational programs were administered across the country targeting pathologists, thoracic surgeons, respirologists, interventional radiologists, medical and radiation oncologists. 210 pre- and 188 post-intervention surveys were completed.Baseline results demonstrated significant uncertainty: 30% were unsure regarding tissue handling techniques to ensure successful molecular testing, 20% chose an incorrect technique. Half were unfamiliar with how to initiate EGFR and ALKtesting, and 17% were uncertain of whom to test. After the intervention, specialist knowledge increased regardingtissue handling techniques (OR=3.01, p<0.0001), appropriate fixation (OR=2.48,p<0.0001), and the level of uncertainty decreased from 30% to 3% (p<0.0001). Participants understood the importance of initiating testing as soon as possible rather than deferring to the medical oncologist (p<0.0001), and to send samples even if unsure they met technicalrequirements (OR=4.63,p<0.0001). Conclusions: Significant knowledge gaps existabout molecular testing in NSCLC among specialists that diagnose the disease. Specialist education significantly improves knowledge and awareness about molecular testing and its importance in NSCLC.
Updated results of a phase 1 study combining the matrix metalloproteinase 9 inhibitor GS-5745 with gemcitabine and nab-paclitaxel in patients with advanced pancreatic cancer.
Authors: Johanna C. Bendell, Manish R. Patel, Carrie Baker Brachmann, Xi Huang, Julia D. Maltzman, Victoria Smith, Gregory Sumpao Vosganian, Zev A. Wainberg, Alexander Starodub
Journal: Journal of Clinical Oncology (2017)

363 Background: GS-5745 is a monoclonal antibody inhibitor of matrix metalloproteinase 9 (MMP9), an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. We present data from patients (pts) with advanced pancreatic adenocarcinoma enrolled in an ongoing multi-indication phase 1 study (NCT01803282) evaluating GS-5745. Methods: Following a monotherapy dose finding stage, pts with locally advanced or metastatic pancreatic cancer received gemcitabine (G) + nab-paclitaxel (Abraxane, A) and GS-5745 800 mg IV every 2 weeks. Treatment continued until disease progression, unacceptable toxicity or withdrawal of consent. Response was assessed every 8 weeks per RECIST version 1.1 criteria. Results: As of April 2016, 36 pts were enrolled (1 continues to receive GS-5745). The most frequently observed adverse events (AEs) of any grade include fatigue (75%), alopecia (55.6%), peripheral edema (55.6%) and nausea (50%). Grade ≥ 3 AEs observed in ≥ 10% of pts included neutropenia (25%), anemia (19.4%) and fatigue (13.9%). The median progression free survival (PFS) for all pts is 7.8 (90% confidence interval (CI) = [6.1, 11]) months (mos), median duration of response (DOR) is 5.8 mos and the objective response rate (ORR) is 44.4%. Of the 31 pts who were treatment naïve in the metastatic setting, median PFS is 9.2 (90% CI = [6.1, 11]) mos, median DOR 5.8 mos and the ORR 51.6%. Median baseline circulating MMP9 was 44.3 (range 12.4-549.6) ng/mL and 31 of 32 patients with post-baseline samples had undetectable MMP9 levels within 8 weeks. Conclusions: GS-5745+GA demonstrated numerically higher ORR and PFS compared to historical data without additional toxicity. Additionally, reductions in circulating MMP9 levels post treatment suggest target engagement by GS-5745 . These results suggest this combination may warrant additional study in first line metastatic pancreatic adenocarcinoma. Clinical trial information: NCT01803282.
Competing event risk stratification may improve the design and efficiency of clinical trials: Secondary analysis of SWOG 8794.
Authors: Brent Shane Rose, Kaveh Zakeri, Sachin Gulaya, Anthony Victor D'Amico, Loren K. Mell
Journal: Journal of Clinical Oncology (2012)

6121 Background: Efficiency of clinical trials may be improved by stratifying according to competing event risk. We aimed to test whether effect and sample size estimates would be altered when adjusting for competing event risk, using data from the SWOG 8794 trial of adjuvant radiation therapy (RT) for high-risk post-operative prostate cancer. Methods: The primary outcome was metastasis-free survival (MFS), defined as time to first occurrence of metastasis or death from any cause (i.e., competing mortality (CM)). We developed separate risk scores for time to metastasis and CM using backward stepwise competing risks regression. Risk factors for metastasis were PSA, Gleason score, and seminal vesicle invasion, and for CM were age, performance status, and Charlson comorbidity index. Treatment effects were estimated using Cox models adjusted for risk scores. We identified an enriched subgroup of 75 patients at high risk of metastasis and low risk of CM, based on risk score cutoffs. Sample size estimates assumed type I and II error of 0.10 and 0.20, and accrual and follow-up times of 6 and 6 years. Results: The mean CM risk score was significantly lower in the RT vs. control arm (p=0.001). The effect of RT on MFS (HR 0.70; 95% CI, 0.53-0.92; p=0.010) was attenuated when controlling for metastasis and CM risk (HR 0.76; 95% CI, 0.58-1.00; p=0.049). The hazard for CM was reduced by RT (HR 0.82; 95% CI, 0.59-1.14; p=0.24), but this effect was attenuated when controlling for CM risk (HR 0.94; 95% CI, 0.67-1.31; p=0.71). In contrast, there was no difference in the adjusted and unadjusted HRs for metastasis (0.50; 95% CI, 0.31-0.81; p=0.005 and 0.49; 95% CI, 0.30-0.81; p=0.005). Compared to the whole cohort, the enriched subgroup had the same baseline 10-year incidence of MFS (40%; 95% CI 22-57%), but a higher incidence of metastasis (30% (95% CI, 15-47%) vs. 20% (95% CI, 15-26%)). A randomized trial in an enriched population could have achieved 80% power with 44% less patients (313 vs. 709 patients, respectively), due to the differing event composition. Conclusions: Stratification based on competing event risk may improve the design and efficiency of clinical trials. These findings should be externally validated.
Sequential high-dose chemotherapy (HDCT) for relapsed or refractory germ cell cancer (rGCC): Results of a unicentric standardized approach.
Authors: Guenter Niegisch, Alina Henn, Martin Zaum, Guido Kobbe, Rainer Haas, Joachim Schirren, Peter Albers, Anja Lorch
Journal: Journal of Clinical Oncology (2015)

e15551 Background: HDCT with carboplatin and etoposide (CE) followed by residual tumor resection (RTR) is a routine regimen for patients (pts) with rGCC. We evaluated the results of a unicentric approach with one oncology, one urologic and one thoracic surgeon. Methods: All 25 pts who underwent HDCT for rGCC between 03/12 and 12/14 were analyzed. Mobilization chemotherapy (paclitaxel/ifosfamide [TI] or VIP) was followed by 3 cycles of high-dose CE (500 mg/m² each, d 1 – 3). Whenever feasible, all residual tumors were resected immediately after HDCT. Kaplan-Meier method was used to estimate progression-free (PFS) and overall survival (OS). Results: Median age of pts was 41 [range 20-57] years. Histology was non-seminoma in 20/25 pts, 23/25 pts had gonadal primaries. HDCT as 1st salvage was performed in 18/25 pts (prognostic score: 4/18 very low/low, 9/18 intermediate, 5/18 high/very high risk) and as 2ndsalvage in 7/25 pts TI for mobilization was used in 23/25 pts, VIP in 2/25 pts. Median time from mobilization to d1 HDCT was 14 [range 8-27] days. Stem cell harvest was sufficient for 3 cycles in all pts. All HDCT cycles were administered in 21/25 pts. Dose-adjustment due to upfront impaired renal function was required in 4/25 pts. Median time between HDCT cycles was 28 [range 21-36] days. Neither treatment-related deaths nor renal failure requiring hemodialysis was observed. Major toxicities occurred in 5/25 pts (4x sepsis, 1x ileus). Complete response by HDCT alone was achieved in 5/25 pts, 13/25 pts got one or more RTRs. Median time to first RTR was 41 [range 27-72] days. Major surgical complications were observed in 2/13 pts (1x urinoma, 1x wound dehiscence). Histologically 7/13 pts had viable cancer, 2/13 teratoma only and 4/13 necrosis. Conclusions: A unicentric approach in a high-volume center of expertise provides low complication rates both during HDCT and perioperatively and enables salvage treatment in an optimal timely manner. Even limited by a short follow up outcomes of our series emphasizes the efficacy of HDCT.
Cisplatin with dose-dense paclitaxel before and after radical hysterectomy for locally advanced cervical cancer: Final results of a multicenter phase II study (Sankai Gynecology Study Group 013).
Authors: Satoshi Yamaguchi, Kiyoshi Fujiwara, Shinya Sato, Shoji Nagao, Kazuhiro Takehara, Masato Nishimura, Muneaki Shimada, Junzo Kigawa, Maki Tanioka
Journal: Journal of Clinical Oncology (2014)

5526 Background: The primary objective of the study was to investigate survival after cisplatin plus dose-dense paclitaxel (ddTP) before and after radical hysterectomy (RH) without radiotherapy of patients for locally advanced cervical cancer. Methods: Patients with stage IB2, IIA2, or IIB cervical cancer received 3 cycles of cisplatin (75 mg/m2, day 1) with paclitaxel (80 mg/m2, days 1, 8, and 15) every 21 days, RH, and another 2 cycles of the same regimen. Primary endpoint was 2-year recurrence-free survival (RFS). Secondary endpoints were 2-year overall survival (OS), safety, response, and pathologic complete response (pCR), defined as no evidence of malignancy in all surgical specimens. Results: Fifty one patients were enrolled from 2010 to 2012 (41 with squamous cell carcinoma [SCC], 9 with adeno/adenosquamous carcinoma, and 1 with small cell carcinoma). Median age was 52 years (range 30-70). The FIGO stage was IB2 in 14 patients, IIA2 in 3, and IIB in 34. All but 1 non-responsive patient underwent RH. At the median follow-up time of 27 months, 2-year RFS and OS were 88.2% and 94.1%, respectively. Six recurrences occurred within 1 year from last treatment. Five patients died. Except 1 patient with grade 4 hypersensitivity during the first paclitaxel infusion, 18 patients achieved complete response and 29 achieved partial response, with response rate of 94% (47/50). Fourteen patients (28%; 13 with SCC, 1 with adenocarinoma) achieved pCR. Eight good responders refused to receive adjuvant ddTP, with no recurrence. Grade 3/4 adverse events were neutropenia (34%), nausea (12%), appetite loss (10%), fatigue (6%), and anemia (6%). Febrile neutropenia was uncommon (2%). No serious long-term adverse events occurred. Conclusions: Administering with ddTP before and after RH for locally advanced cervical cancer achieves good survival and is feasible, evidenced by the acceptable toxicity. Phase III studies should compare this with concurrent chemoradiation. Clinical trial information: UMIN000006440.
Phase I study of sirolimus plus gemcitabine in patients with advanced solid tumors: A Spanish Group for Research on Sarcomas (GEIS) study.
Authors: Juan Martin Liberal, Marta Gil, Laura Jimenez, Maria Ochoa de Olza, Carmen Munoz, Nuria Gonzalo, Raul Rigo, Helena Colom, Miguel Sainz Jaspeado, Oscar M. Tirado, Xavier Garcia del Muro
Journal: Journal of Clinical Oncology (2012)

3096 Background: In preclinical studies, combination of sirolimus with gemcitabine enhances apoptosis in vitro and increases anti-tumor efficacy in vivo. Methods: Patients with advanced solid tumors, age 18-70 years, no prior mTOR inhibitor or gemcitabine, ECOG PS 0-1, and adequate hematological, renal and hepatic function, were enrolled in this phase I study to assess safety, tolerability, pharmacokinetics (PK), and to identify the dose limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended dose (RD) of the combination of sirolimus and gemcitabine. A 3+3 dose escalation design with cohorts of 3-6 patients was used. Sirolimus was given po continuously. Gemcitabine was given iv 10mg/m 2 /minute on days 1 and 8 every 3 weeks. Dose levels 1, 2 and 3 corresponded to sirolimus 2, 2 and 5mg/24h plus gemcitabine 800, 1000 and 1000mg/m 2 respectively. After observing DLTs at higher dose level and poorer mTOR signaling inhibition at lower doses, a new cohort of sirolimus 5mg/24h plus gemcitabine 800 mg/m 2 was added. Skin biopsies pre and post treatment were performed to assess the inhibition of mTOR pathway. Results: 19 patients were enrolled: median age 51 years (36-70); gender 12M, 7F. Median number of cycles was 4. Patients were treated at 4 dose levels, the MTD was reached at level 3 and the RD was: sirolimus 5mg/24h and gemcitabine 800mg/m 2 . 3 DLTs were observed, 1 at dose level 2 and 2 at dose level 3: transaminitis grade 3, thrombocytopenia grade 3 and thrombocytopenia grade 4. Other toxicities grade 1-2 included anemia, neutropenia, asthenia, mucositis and high cholesterol levels. 2 patients achieved partial response (1 uterine cervix cancer and 1 colon cancer). Immunohistochemistry of pS6 in skin biopsies showed significative inhibition of mTOR pathway at RD. PK parameters estimated were in agreement with those previously reported in the literature. No influence of sirolimus administration on gemcitabine clearance was found. Conclusions: Combination of sirolimus and gemcitabine is feasible and safe, allowing administration of active doses of both agents and achieving mTOR signaling inhibition. A phase II study to assess the activity of this combination in sarcomas is ongoing.
Surgery (S) and radiotherapy (RT) plus adjuvant chemotherapy (CT) versus surgery and radiotherapy in non-small cell lung cancer (NSCLC): A meta-analysis using individual patient data (IPD) from randomised clinical trials (RCTs)
Authors: C. Le Pechoux, H. Tribodet, J. P. Pignon, S. Burdett
Journal: Journal of Clinical Oncology (2007)

7521 Background: Our previous IPD meta-analysis of CT (BMJ 1995;311:899) suggested that CT may have a role in the treatment of various stages of NSCLC. However, the results in the S + RT setting were uncertain because of the small number of patients in this setting. We have updated this meta-analysis, including trials and outcomes not available in 1995. We report here on the effectiveness of S+RT+CT compared to S+RT. Methods: Systematic searches for RCTs were followed by the central collection, checking and re-analysis of updated IPD. Results from individual trials were combined using the stratified (by trial) log rank test to calculate pooled hazard ratios (HRs). Previously included old trials using long-term alkylating agents were excluded from this analysis. Results: IPD were obtained from 2,626 patients (12% with incomplete resection) from 11 RCTs. This represents 86% of all known randomised patients and adds a further 5 trials and 1,956 patients to the 1995 analyses. Median follow-up is 6.3 years. Ten trials used sequential RT-CT. 8 RCTs used cisplatin + vinca alkaloid/ etoposide, 1 used cisplatin + tegafur and 2 used other platinum regimens. There is a significant benefit of CT on survival (HR=0.88, 95% CI=[0.80–0.96], p=0.0062), with an absolute benefit of 4.7% (from 29% to 34%) at 5 years. The HRs for older (0.93 [0.79–1.10]) and more recent trials (0.89 [0.81–0.97]) were comparable (test for interaction p=0.49). Results were similar for recurrence-free survival (0.84, [0.77–0.93], p=0.0006), local (0.79 [0.67–0.94], p=0.0075) and distant recurrence-free interval (0.75 [0.66–0.87], p&lt;0.0001) (data available for 7 trials). There was no clear evidence of a difference in effect by type of CT given. Also, there was no clear evidence that any patient subgroup defined by age, sex or stage benefited more or less from CT. Conclusion: These results demonstrate now a benefit of adjuvant chemotherapy in resected lung cancer associated with radiotherapy. These results are very similar to those of the meta-analysis without radiotherapy. They provides robust estimates for future policy and research. Unrestricted grants from PHRC, LNCC and sanofi-aventis. [Table: see text]
Effect of small inhibitors of nuclear export (SINE) on growth inhibition and apoptosis of human melanoma cells.
Authors: Gregory B. Lesinski, Jennifer Yang, Matthew A Bill, Yosef Landesman, Sharon Shacham, Michael Kauffman, William Senapedis, Trinayan Kashyap, Jean-Richard Saint-Martin, Kari Lynn Kendra
Journal: Journal of Clinical Oncology (2012)

e13549 Background: Inhibition of nuclear export can promote re-activation of tumor suppressor pathways. CRM1 (chromosomal regional maintenance 1) or XPO1 (exportin 1) is the major protein that mediates nuclear export. We hypothesized that CRM1 mediated nuclear export represents a novel therapeutic target that can be manipulated to inhibit melanoma cell survival. Methods: The growth inhibitory and pro-apoptotic effects of KPT-185, KPT-276 and KPT-330, small molecules selective inhibitor of nuclear export (SINE) were evaluated in human melanoma cell lines using an MTT assay and Annexin V/PI staining, respectively. Fluorescence microscopy and immunoblots were used to assess nuclear accumulation of tumor suppressor proteins. The trans-isomer of KPT-185 and DMSO (vehicle) were used as a negative controls in all assays. The pharmacokinetic (PK) profile of all compounds was evaluated in mice. Results: CRM1 protein was highly expressed in human melanoma cell lines with diverse molecular profiles (i.e., B-Raf, NRAS, p53). KPT-SINE inhibited melanoma cell growth in a concentration-dependent manner and induced apoptosis at nanomolar concentrations. Importantly, there was no evidence that B-Raf V600 mutational status influenced melanoma cell response to these agents. Nuclear accumulation and/or induction of p53, p21, FOXO3a, STAT1 and BAD, and reduction of MCL-1 occurred in melanoma cells at time points prior to apoptosis as shown by increase in cleaved PARP and caspase 3 levels. PK studies were conducted in mice following oral administration of 10 mg/kg, to guide drug selection for our ongoing efficacy studies in murine melanoma models. KPT-185 showed limited bioavailability and systemic exposure, while KPT-276 and KPT-330 showed &gt;50% bioavailability reaching Cmax &gt;5µM. Conclusions: This study represents the first report of CRM1 inhibition in melanoma. These data indicate that the novel SINE compounds can effectively inhibit CRM1-mediated nuclear export and induce apoptosis in melanoma cells. KPT-330 is currently under development as orally bioavailable, small molecule inhibitors for a human clinical trial.