tbuckley/cabot-search huggingface dataset:
Enhancement in sensitivity of detection of clinically actionable tumor gene mutations by DNA sequencing employing QClamp enrichment PCR.
Authors: Michael Joseph Powell, Madhuri Ganta, Elena Peletskaya
Journal: Journal of Clinical Oncology (2015)

e22130 Background: Next Generation Sequencing (NGS) has offered a powerful alternative for mutation detection. However, all bench-top sequencers generate some inaccuracies due to the chemistry used. NGS can accurately detecting single nucleotide variations (SNV) but is not suitable for the detection of indels. In addition, the bioinformatics pipelines used for calling mutations needs to be extensively validated to ensure the right calls are made. Several studies have shown that the accuracy of mutation detection needs to be improved in order for NGS to become a good option for clinical genetic testing. Digital PCR offers highly precise, direct quantification without requiring a calibration curve. However, the instrumentation is expensive and required highly skilled operators. It is really critical that ddPCR assays perform so well that even if a single molecule is present it can be detected. Not all assays are that good and mutations can be missed. Specificity is also an issue. Many assays will amplify products other than the sequence of interest, particularly if pseudo genes are present. Understanding rates of false positives is crucial when hunting for rare alleles. Methods: DiaCarta's QClamp mutation tests was employed to amplify DNA obtained from patients plasma QClamp is a real-time PCR assay that uses a xenonucleic acid (XNA) clamping probes to suppress amplification of wild type DNA, allowing selective amplification of mutants during the PCR process thus enhancing the number of copies of mutant templates available for detection and Sequencing. Results: 30 plasma DNA samples from melanoma patients were analyzed for BRAF mutations by NGS and ddPCR. NGS and ddPCR detected mutations in 29 samples. QClamp BRAF Mutation Test (CE)detected mutations in all 30 samples. The mutation deleted by QClamp was further confirmed by Sanger sequencing of the QClamp PCR product. Conclusions: This data indicates that NGS and ddPCR yield false negative results. Thus QClamp PCR is more sensitive than ddPCR or NGS for detection of actionable tumor somatic mutations in DNA obtained by minimally invasive procedures from cancer patients
Dose-ranging randomized pharmacokinetic (PK) and pharmacodynamic (PD) study of vorinostat in patients with advanced solid tumors.
Authors: Tara C. Gangadhar, Jan Hendrik Beumer, Igor Espinoza-Delgado, Bean N. Anyang, Sanja Karovic, Manish Sharma, Yujia Wen, Linda A. Janisch, Hedy Lee Kindler, Rita Nanda, Theodore Karrison, Mark J. Ratain, Michael L. Maitland
Journal: Journal of Clinical Oncology (2013)

2571 Background: Continuous 400 mg daily vorinostat (V) is effective treatment for cutaneous T-cell lymphoma, but has displayed erratic activity in combination therapy for solid tumors. Short-course high-dose vorinostat may have a better therapeutic index for solid tumors, but dose/exposure/PD relationships have not been tested in sufficiently powered studies. Methods: Patients (pts) were randomized to either V 1600 mg daily, days (d) 1-3 then 400 mg d8-10 or 400 mg d1-3 then 1600 mg d8-10 with complete PK sampling on d3 and d10 to determine the increase in Cmax upon increasing V from 400 to1600 mg. To assess safety and tolerability of high dose V added to carboplatin, pts then received high dose V d15-17 with carboplatin AUC 5 on d17; this combination was repeated every 21d thereafter. Platelet counts were determined weekly. To detect with 80% power a difference in vorinostat Cmax between 400 and 1600 mg required at least 10 pts in each sequence. In vitro studies of gene expression in solid tumors suggested as a secondary endpoint the frequency of pts achieving Cmax &gt; 1000 ng/mL. Results: 24 pts (11 men/13 women) enrolled between April 2011 and March 2012 and were evaluable for study endpoints. No sequence dependence of change in Cmax was detected. Cmax for V 1600 mg was nearly double that for 400 mg (1184+/-631 vs. 616+/-442 ng/mL, p &lt; 0.001). The PD effect on platelets (d10) was greater for the higher dose (median -76 vs. -14 K/µL, p= 0.02). There were no dose limiting toxicities. Of 24 pts, 11 achieved Cmax &gt; 1000 ng/mL. Conclusions: The 1600 mg dose of vorinostat results in a higher Cmax than 400 mg and greater PD effect than 400 mg and is tolerable in combination with carboplatin. The carboplatin/vorinostat doublet serves as a DNA-damaging/epigenetic modifier module to be combined in more complex regimens. Clinical trial information: NCT01281176.
Clinical benefits of sequential administration of docetaxel and intermittent erlotinib as a second-line therapy for advanced non-small cell lung cancer (NSCLC): A phase II randomized study.
Authors: Francisco Aparisi, Alfredo Sanchez-Hernandez, Vicente Giner, José Muñoz-Langa, Gaspar Esquerdo, Antonio López Jiménez, Javier Garde, Jose Garcia Sanchez, Oscar Juan Vidal
Journal: Journal of Clinical Oncology (2012)

e18049 Background: Patients (p) with advanced NSCLC have few treatment options after progressing to 1st-line platinum doublet chemotherapy. Several preclinical and phase I studies have suggested that sequential administration of erlotinib (E) and docetaxel could avoid possible negative interactions and optimize the benefit obtained against NSCLC. This randomized phase II was designed to address the clinical benefit obtained with the use of sequential administration of docetaxel and intermittent E. Methods: 70 p with advanced NSCLC progressing to previous PDC for advanced disease were randomized (1:1): Group A (n = 34): Docetaxel 75 mg/m 2 day 1 and intermittent E (day 2-16), up to 4 cycles, followed by E in monotherapy; and Group B (n = 36): E in monotherapy. Treatment was administered until unacceptable toxicity or disease progression. Primary endpoint: rate of p free of progression at 6 months; secondary endpoints: progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. The study has completed enrolment. At the date of cut-off for this communication, data of 60 patients were available: 30 in Group A/30 in Group B. Results: Baseline characteristics: non-adenocarcinoma (60.3%), current/former smokers (95%), male (90%) and stage IV (87.9%). 6 months PFS: 13.5% in the sequential arm. PFS: 2.7 months (m) in Group A (95% CI 2.1 – 3.8) and 2 m in Group B (95% CI 1.7 – 2.4) p value 0.08. Median OS: 11.0 m (95% CI 4.5 – 13.4) in group A and 4.7m (95% CI 2.5 – 6.6) in Group B with a p value 0.02. DCR: 44.4% in the experimental group whereas in the E one was 30.8%. Adverse events (AEs), including skin rash and diarrhea, were all generally tolerable. Of interest, the low number of p developing neutropenia in the D + E arm. Conclusions: Although the primary objective has not been met, an encouraging benefit on survival has been shown in the exploratory analysis, with a median overall survival of 11 months for patients treated with the sequential regimen (p value 0.02). Final data will be presented during the meeting.
Screening for Osteoporosis: An Update for the U.S. Preventive Services Task Force
Authors: Heidi D. Nelson
Journal: Annals of Internal Medicine (2010)

Background: This review updates evidence since the 2002 U.S. Preventive Services Task Force recommendation on osteoporosis screening. Purpose: To determine the effectiveness and harms of osteoporosis screening in reducing fractures for men and postmenopausal women without known previous fractures; the performance of risk-assessment instruments and bone measurement tests in identifying persons with osteoporosis; optimal screening intervals; and the efficacy and harms of medications to reduce primary fractures. Data Sources: Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the fourth quarter of 2009), MEDLINE (January 2001 to December 2009), reference lists, and Web of Science. Study Selection: Randomized, controlled trials of screening or medications with fracture outcomes published in English; performance studies of validated risk-assessment instruments; and systematic reviews and population-based studies of bone measurement tests or medication harms. Data Extraction: Data on patient populations, study design, analysis, follow-up, and results were abstracted, and study quality was rated by using established criteria. Data Synthesis: Risk-assessment instruments are modest predictors of low bone density (area under the curve, 0.13 to 0.87; 14 instruments) and fractures (area under the curve, 0.48 to 0.89; 11 instruments); simple and complex instruments perform similarly. Dual-energy x-ray absorptiometry predicts fractures similarly for men and women; calcaneal quantitative ultrasonography also predicts fractures, but correlation with dual-energy x-ray absorptiometry is low. For postmenopausal women, bisphosphonates, parathyroid hormone, raloxifene, and estrogen reduce primary vertebral fractures. Trials are lacking for men. Bisphosphonates are not consistently associated with serious adverse events; raloxifene and estrogen increase thromboembolic events; and estrogen causes additional adverse events. Limitation: Trials of screening with fracture outcomes, screening intervals, and medications to reduce primary fractures, particularly those enrolling men, are lacking. Conclusion: Although methods to identify risk for osteoporotic fractures are available and medications to reduce fractures are effective, no trials directly evaluate screening effectiveness, harms, and intervals. Primary Funding Source: Agency for Healthcare Research and Quality.
Phase I trial of temsirolimus (TEM), irinotecan (IRN), and temozolomide (TMZ) in children with refractory solid tumors: A Children's Oncology Group study.
Authors: Rochelle Bagatell, Robin Elizabeth Norris, Ashish M Ingle, Charlotte H Ahern, Jennifer Saggio, Anthony Little, Brenda Weigel, Susan Blaney
Journal: Journal of Clinical Oncology (2012)

9540 Background: Inhibitors of mTOR have demonstrated activity in preclinical pediatric solid tumor models. A phase I trial to define the dose limiting toxicities (DLTs) associated with the mTOR inhibitor TEM in combination with IRN and TMZ was conducted in patients (pts) with refractory solid tumors. Methods: Escalating doses of TEM were administered intravenously on days (d) 1 and 8 of a 21-d cycle for a maximum of 1 year (y). IRN (50 mg/m 2 /dose) was administered orally on d1-5. TMZ (100 mg/m 2 /dose) was administered orally on d1-5. When the maximum planned dose of TEM was reached (35 mg/m 2 /dose), IRN was escalated stepwise from 50 to 90 mg/m 2 /dose. Pts were enrolled on 6 dose levels using the rolling-six design. Results: 46 eligible pts (30 male, median age 11y, range 1 – 21) were enrolled; 37 were fully evaluable for toxicity [neuroblastoma (9), osteosarcoma (4), Ewing sarcoma (3), rhabdomyosarcoma (3), CNS (10) or other (8) tumors]. 173 cycles, median 2 (range 1 – 17) have been delivered. Dose-limiting hyperlipidemia was observed during cycle 1 in 2 pts at dose level 3 (TEM 25 mg/m 2 , IRN 50 mg/m 2 , TMZ 100 mg/m 2 ); both pts were on chronic corticosteroids. The protocol was amended to preclude chronic systemic steroid use and modify hyperlipidemia management. Dose-limiting hyperlipidemia was not observed in subsequent pts. Cycle 1 DLT (elevated GGT) was observed in 1 pt treated with TEM 35 mg/m 2 , IRN 65 mg/m 2 , TMZ 100 mg/m 2 . DLT has not been observed in 4 of the first 6 pts treated at the highest planned dose level (TEM 35 mg/m 2 , IRN 90 mg/m 2 , TMZ 100 mg/m 2 ). Additional ≥Grade 3 regimen-related toxicities occurring in &gt;1 evaluable pt include neutropenia (12), lymphopenia (10), leukopenia (6), thrombocytopenia (4), anemia (2), nausea or vomiting (5), hypokalemia (4), hypophosphatemia (2), diarrhea (2), elevated transaminases (2), and infection (2). 1 pt had a Grade 3 allergic reaction to TEM. 1 pt had a confirmed partial response and 4 have remained on protocol therapy for ≥1 year. Conclusions: The combination of TEM (35 mg/m 2 /dose) d 1 and 8, IRN (90 mg/m 2 /dose) d 1-5, and TMZ (100 mg/m 2 /dose) d 1-5 of a 21-d cycle appears to be well tolerated in children with refractory solid tumors.
Stereotactic body radiation therapy for early-stage non-small-cell lung cancer utilizing a helical intensity modulated image-guided approach.
Authors: Lane R Rosen, Benjamin W Fischer-Valuck, Sanford R. Katz, Michael Durci, Terry Wu, Joseph Syh, Bijal Patel, Jarron Syh
Journal: Journal of Clinical Oncology (2012)

e17524 Background: To report the techniques and results of a large cohort of patients treated with stereotactic body radiotherapy (SBRT) for early-stage non-small-cell lung cancer (NSCLC) using image-guided helical intensity modulated radiation therapy (IMRT) and FDG-PET assisted targeting. Methods: Between February 2005 and August 2010, 79 patients with stage 1 NSCLC were treated with SBRT. 59 patients had T1 tumors and 20 patients had T2 tumors. 62 patients had biopsy proven malignancies and 17 patients were treated empirically based on strong clinical indications. Central tumor location did not disqualify patients. All patients underwent FDG-PET or FDG-PET/CT scanning in the treatment position for planned fusion with a separate kilovoltage (KV) CT simulation. Rigid immobilization was achieved during CT simulation using a double vacuum cast device with abdominal compression. SBRT was delivered via 12 Gy x 4 or 12 Gy x 5 fractionation scheme (48-60 Gy total). Megavoltage CT images were obtained on the treatment unit prior to therapy and repeated mid-fraction with comparison to the KV CT simulation planning images to assure set-up accuracy. Serial follow-up with FDG-PET or FDG-PET/CT studies were performed at 3 months and every 6 months thereafter on all surviving patients. Results: Median patient age was 73 years. Mean tumor size was 2.3 cm (range 0.5 – 6 cm). Median follow-up was 24 months (range 4-78 months). Overall local control rate (LCR) was 94% (95% confidence interval (CI), 86-97%) based on serial FDG-PET. LCR for T1 tumors was 95% vs. 90% for T2 tumors (p = 0.60). Entire cohort overall survival rate (OSR) was 87% (CI, 78-93%) at 1 year and 58% (CI, 47-68%) at 3 years. T1 patients had a 3-year OSR of 71% vs. 43% OSR for T2 patients (p = 0.04). No patients developed life threatening radiation pneumonitis or pulmonary complications. Chest wall pain or rib fracture was reported in 8 patients (10%; CI, 5-19%). Conclusions: Image-guided SBRT with helical IMRT delivered in 4 or 5 fractions of 12 Gy with rigid immobilization and FDG-PET assisted targeting is an effective treatment for early NSCLC and is associated with excellent local control rates and acceptable treatment-related morbidity.
A multicenter, phase III randomized trial for stage IIIB/IV NSCLC of weekly paclitaxel and carboplatin vs. standard paclitaxel and carboplatin given every three weeks, followed by weekly paclitaxel
Authors: C. P. Belani, R. V. Larocca, D. A. Rinaldi, W. J. Tester, P. S. Gable, M. C. Perry
Journal: Journal of Clinical Oncology (2004)

7017 Background: This Phase III study was designed to compare the best weekly regimen of paclitaxel (P) (3 out of 4 wks.) in combination with full doses of carboplatin (C) administered on Day 1 every 4 wks. to the standard regimen of P and C administered every 3 weeks for pts. with advanced stage IIIB/IV NSCLC. Methods: On Arm 1, pts. received P 100 mg/m2 Days 1, 8, 15 and C AUC 6 Day 1 every 28 days for 4 cycles (16 weeks). On Arm 2, pts. received P 225 mg/m2 and C AUC 6 Day 1 every 21 days for 4 cycles (12 weeks). Following initial therapy, all pts.who achieved complete response, partial response or stable disease received maintenance weekly P 70 mg/m2/wk. (3 out of 4 wks.) until disease progression or unacceptable toxicity. Four hundred and forty-four pts. were randomized to the study, 223 on Arm 1 and 221 on Arm 2. Preliminary results are summarized in the table below. Results: Conclusions: Both schedules of P and C were associated with a comparable toxicity profile. Response rate was not statistically different between Arm 1 and Arm 2. Patient survival data will be available at the time of presentation. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Oncology
Effect of nanosecond pulsed electric fields in combination with everolimus on melanoma.
Authors: Jie Dai, Shan Wu, Yan Kong, Zhihong Chi, Lu Si, Chuanliang Cui, Xi Nan Sheng, Jue Zhang, Jing Fang, Jun Guo
Journal: Journal of Clinical Oncology (2015)

e20102 Background: Nanosecond pulsed electric field (nsPEF) is a bioelectrical technology generated high voltage electric field in nanosecond duration to destroy tumor cells with non-thermal effect. It is a potential technique for cancer therapy. PI3K/mTOR/AKT pathway is activated in most melanomas, but single agent activity of mTOR inhibitors is limited in advanced melanomas. The aim of the study is to evaluate the anti-growth efficacy of nsPEF in combination with everolimus in melanoma. Methods: Human A375 melanoma cells were exposed to everolimus for 48 hours, followed by 25 pulses of nsPEF with 100 ns duration at the electric field strength of 15 and 20 kV/cm. Cell viability was measured by CellTilter-Glo luminescent cell viability assay 24 hours later. Cell apoptosis and cell cycle were analyzed by flow cytometry. BALB/c mice were inoculated subcutaneously with A375 cells, and randomly divided into four groups: group I as control, group II treated with nsPEF in a single treatment (30 kV/cm, 100 ns, 100 pulses), group III given everolimus (4 mg/kg) by oral gavage daily for 2 weeks, and group IV treated with nsPEF plus everolimus. Results: With the combination of nsPEF, cell growth was decreased gradually according to the nsPEF intensity. nsPEF could induce melanoma cell apoptosis, and the ratio of apoptotic cells was correlated with nsPEF intensity. Cell cycle analysis showed that both everolimus and nsPEF alone could induce G2/M phase arrest, and combination of everolimus with nsPEF could further increase the percentages of G2/M-arrested cells. In vivo experiments showed that the skin lesions caused by nsPEF all healed in one week, and no adverse effect were observed. When compared to control group, the everolimus group, the nsPEF group and the combination group suppressed tumor growth to 32%, 44% and 10%, respectively. Conclusions: nsPEF and everolimus have synergistic anti-tumor effect on melanoma cells through inducing G2/M phase arrest and apoptosis. Our findings indicate that nsPEF in combination with mTOR inhibitor could be used as a potential treatment for advanced melanoma.
Phase II trial of combination docetaxel and cisplatin in patients with locally advanced nasopharyngeal carcinoma
Authors: M. Yamouni, K. A. Benhadji, Y. Beldjilali, I. Lahfa, H. Khellafi, A. Abdelaoui, L. Djellali, K. Bouzid
Journal: Journal of Clinical Oncology (2009)

6044 Background: The standard treatment of locally advanced nasopharyngeal carcinoma is cisplatin-based chemotherapy followed by locoregional radiotherapy. The purpose of this study is to assess the antitumor activity and toxicity of a new neoadjuvant chemotherapy regimen combining docetaxel (D) and cisplatin (C). Methods: Previously untreated patients (pts) with histologically diagnosed locally advanced nasopharyngeal carcinoma (stages IVA and IVB, TNM/UICC 1997) received D 75 mg/m 2 and C 75 mg/m 2 both on day 1, with cycles repeated every 21 days. All pts received three cycles in a neoadjuvant setting before radiotherapy (4 to 6 weeks after the third cycle of DC, 65–70 Gy 5 fractions/week). Pts were evaluated by clinical examination, CT scan of the nasopharynx, and nasofibroscopy with biopsy. The primary end point was tumor response. Secondary end points were disease-free survival (DFS), toxicity, and overall survival (OS). Results: 93 pts (65 male, 28 female) were enrolled. Median age was 42 years (range 18–69), WHO performance status was 0–1 in 87 pts and 2 in 6 pts. 75 pts (81%) had an undifferentiated carcinoma of nasopharyngeal type (UCNT) and 18 pts (19%) a differenciated carcinoma of the nasopharynx. 31 pts had stage IVA disease and 62 pts had stage IVB. Toxicity, tumor response, and survival at 5 years (median follow up 49.5 months) were assessable in 90 pts. After 270 cycles, grade 3–4 toxicities (WHO) were: neutropenia (12 %), febrile neutropenia (2%), anemia (1%), nausea and vomiting (23%), diarrhea (8%), mucositis (1%), reversible alopecia (70%). Two pts had onycholysis. Response rates for the 90 pts were: complete response 32.2% (29 pts), partial response 54.4% (49 pts), stable disease 11.1% (10 pts), and progressive disease 2.2% (2 pts). The overall response rate (ORR) was 86.6% and 89% amongst the UCNT. After radiotherapy, 88 pts had a complete response and one patient had stable disease. DFS and OS at 5 years were 52% and 55%, respectively. Conclusions: DC chemotherapy followed by radiation therapy is an effective regimen for the treatment of advanced UCNT and has an acceptable safety profile. These data need to be compared with concurrent chemoradiotherapy to assess the best strategy for the management of advanced UCNT. No significant financial relationships to disclose.
Activation of KATP channels suppresses glucose production in humans
Authors: Preeti Kishore, Laura Boucai, Kehao Zhang, Weijie Li, Sudha Koppaka, Sylvia Kehlenbrink, Anna Schiwek, Yonah B. Esterson, Deeksha Mehta, Samar Bursheh, Ya Su, Roger Gutierrez-Juarez, Radhika Muzumdar, Gary J. Schwartz, Meredith Hawkins
Journal: Journal of Clinical Investigation (2012)