tbuckley/cabot-search huggingface dataset:
Updated results of a phase II study of oral multi-kinase inhibitor sorafenib in sarcomas, CTEP study #7060
Authors: R. G. Maki, M. L. Keohan, S. D. Undevia, M. Livingston, M. M. Cooney, A. Elias, M. F. Saulle, J. J. Wright, D. R. D’Adamo, S. M. Schuetze
Journal: Journal of Clinical Oncology (2008)

10531 Background: The efficacy of sorafenib in sarcomas was suggested in a phase I study in solid tumors. We conducted a multicenter, phase II study of sorafenib in sarcoma patients (pts) with six histologic strata (leiomyosarcoma [LMS], MFH, MPNST, vascular sarcomas [Angio], synovial sarcoma, other). Methods: Adults with sarcomas had received 0–1 prior lines of therapy, needed good organ function and ECOG PS 0–2. Starting sorafenib dose was 400 mg oral BID. A Simon two-stage design was used for each arm of the 6-arm study. If 1 of 12 pts on a study arm had a RECIST PR, 25 more pts were accrued. Imaging was performed q8wk for the first 24 wk. Results: Accrual was completed, with 147 pts entered from 10/05 to 11/07 (94F, 53M), and median age 55 (range 18–90). 145 eligible pts received a median of 2 cycles of sorafenib. 22 (15%) were ineligible for response, not completing 2 cycles of therapy due to adverse events (AE). There were 4 RECIST PR and 1 CR in 37 Angio pts (response rate [RR] 14 %); 0/3 pts with epithelioid hemangioendothelioma had a PR. Two of 37 LMS pts had a PR (RR 6%). No other PR was observed. Minor responses were seen (MPNST 2, synovial 1). Median time to progression (mTTP) was 5.2±0.7 mo, 5.5±0.8 mo, and 2.8±0.6 mo for the LMS, Angio, and other pts, respectively (Kaplan-Meier estimate±SE). Angio data compare favorably with mTTP of 4.0 mo (paclitaxel) and 3.7 mo (doxorubicin) from a single institution series. Median survival for all evaluable pts was 13.7 mo. 78/122 evaluable pts (64%) had dose reductions; female gender was associated with toxicity. 39 pts had 57 G3–4-5 AE, most notably DVT/PE(3), CNS bleeding or ischemia (2), cardiomyopathy (1), GI bleeding (1, G5) or perforation (2, 1 was G5), and hemoptysis (1, G5). Sorafenib steady state pharmacokinetics were similar for pts on full dose therapy vs those pts with dose reduction for toxicity. Markers of MAPK pathway activation were not consistently changed in pre- vs. post-treatment biopsies from 6 pts, some of whom were responders, all of whom had therapeutic plasma levels. Conclusions: Sorafenib induces objective responses in some patients in angiosarcoma and has minor activity in LMS. Combination therapy with other agents appears warranted in selected sarcoma subtypes. Supported in part by NCI P01-CA47179 and N01-CM62202. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer
Low <sup>18</sup>f-fluorodeoxyglucose uptake on positron emission tomography as a prognostic factor for stage I and II pancreatic cancer.
Authors: Jose Mario Pimiento, Hinda Boutrid, Jill M. Weber, Saqib Razzaque, Jeffrey M. Farma, Richard D. Kim, Pamela Joy Hodul, Ravi Shridhar, Sarah E. Hoffe, Khaldoun Almhanna, Michael D. Chuong, Dung-Tsa Chen, Gregory M. Springett, Edward Eikman, Jason Klapman, Park Jong, Richard C. Karl, Mokenge Peter Malafa
Journal: Journal of Clinical Oncology (2012)

159 Background: Metabolic activity as defined by the uptake of 18 F-fluorodeoxyglucose (FDG) on Positron Emission Tomography (PET) has proven beneficial as a prognostic marker for multiple malignancies; however, no study has examined the prognostic value of PET in stage I and II pancreatic cancer. We examined the value of PET FDG uptake in early pancreatic cancer. Methods: Using a comprehensive pancreatic adenocarcinoma database, we identified patients with early stage pancreatic cancer (I-II) who underwent pancreatectomy for cancer and had PET scan performed as part of their preoperative evaluation from 2004 to 2010. Patients were divided by the median primary tumor standard uptake value (SUVmax) into two groups: high and low FDG uptake. The primary outcomes were overall survival (OS) and disease free survival (DFS). Kaplan-Meier estimate was used for survival analysis. Pathologic data were compared using Fisher's exact and chi-square. Results: We identified 105 patients with resected stage I and II pancreatic cancer who had PET scans as part of their preoperative evaluation. 51 patients had low FDG uptake while 54 patients had high FDG uptake. The median age at diagnosis was 69 (24-89) years, 57% of the patients were male. 84 (81%) patients had PET avid tumors, while 20 (19%) patients did not. The median SUVmax was 5.1. High FDG uptake correlated with pathologic stage (p=0.012). Median follow-up was 12.3 (0-56) months. Patients with low FDG uptake had a significantly better median OS than patients with high FDG uptake (27 vs. 16 months; p=0.036). Recurrence occurred in 64 (60%) patients. Patients with low FDG uptake had significantly longer median DFS than patients with high FDG uptake (14 vs. 12 months; p=0.049). Conclusions: Low 18 F-fluorodeoxyglucose uptake in PET scans for stage I and II pancreatic cancer correlates with improved overall survival and disease free survival. This observation supports the concept that glucose metabolic pathways are important in pancreatic cancer biology, and that PET scan activity can be used as a prognostic biomarker after pancreatectomy for pancreatic cancer.
Real-world experience with sipuleucel-T in patients (pts) ≥80 years old with metastatic castration-resistant prostate cancer (mCRPC): Data from PROCEED.
Authors: Chadi Nabhan, A. Oliver Sartor, Matthew R. Cooperberg, Jeffrey L. Vacirca, Raoul S. Concepcion, William R. Berry, Manish Dhawan, Ronald Tutrone, Andrew Sandler, Candice McCoy, James Boyd Whitmore, Robert Claude Tyler, Celestia S. Higano
Journal: Journal of Clinical Oncology (2013)

131^ Background: Sipuleucel-T is an autologous cellular immunotherapy indicated for asymptomatic or minimally symptomatic mCRPC based on data from the phase III IMPACT pivotal trial that showed a significant improvement in overall survival (OS) compared to control (HR: 0.78 [95% CI: 0.61, 0.98]; P=0.03; median OS difference 4.1 mos). Analysis of IMPACT demonstrated evidence of a positive sipuleucel-T treatment effect in men above and below the median age of 71. We sought to understand the disease characteristics and product parameters in pts ≥80 years (yrs) given the high prevalence of older men in the mCRPC pt population. Methods: PROCEED is an ongoing, multicenter (&gt;190 sites), phase 4 registry enrolling pts receiving sipuleucel-T. Information on antigen presenting cell (APC) activation and total nucleated cell (TNC) count were obtained during product manufacture. Results: Of 560 subjects who completed sipuleucel-T treatment to date: 110 (20%) pts were ≥80 yrs-old. Disease characteristics in pts ≥80 yrs vs &lt;80 yrs are detailed in the table below. Product parameters were similar between groups. Conclusions: Pts ≥80 exhibit similar product parameters compared with their younger counterparts. Future follow-up will explore OS and correlations with immune parameters in both groups. Clinical trial information: NCT01306890. [Table: see text]
Randomized phase II study of vandetanib (V), docetaxel (D), and carboplatin (C) followed by maintenance V or placebo (P) in patients with stage IIIb, IV, or recurrent non-small cell lung cancer (NSCLC): PrECOG PrE0501—Update on maintenance treatment, progression-free survival (PFS), and overall survival (OS).
Authors: J. Aisner, J. Manola, S. R. Dakhil, P. J. Stella, J. H. Schiller
Journal: Journal of Clinical Oncology (2011)

7560 Background: We tested if V, a dual inhibitor of VEGFR and EGFR, could improve PFS in patients (PTS) with NSCLC when given as induction therapy (INRx) with D and C, followed by maintenance V or P. We report updated PFS, OS, and toxicity. Methods: PTS with advanced stage NSCLC were randomized to INRx D (75 mg/m2) + C (AUC 6) on day 1 of a 21-day cycle and daily V (100 mg/day po) for 4 cycles, followed by daily V (300 mg/day po) or P until progression. We designed the study to show an improvement in PFS with the addition of V maintenance to a median of 6.2 months (mos), compared to 4.5 mos for D+C alone. Eligible PTS had measurable disease, ECOG PS 0/1, no prior cytotoxic or targeted agents for advanced disease. PTS with uncontrolled hypertension or history of QT prolongation were ineligible. Results: 162 PTS were randomized from May 2008 to Nov. 2009; 158 began INRx. 91% had Stage IV/recurrent disease; 52% were male. Median age was 63 (36-82). 58 PTS began maintenance V/P (median 3.5 cycles). 4 PTS remain on maintenance. Neither arm showed significant improvement over historical median PFS of 4.5 mos. With median follow-up of 13.5 mos, median PFS for PTS randomized to maintenance V is 4.5 mos (95% CI, 3.3–5.8); median PFS for PTS randomized to maintenance P is 4.2 mos (95% CI, 2.8–4.9, stratified log rank p=0.07). Prolonged PFS for V maintenance was shown in a multivariate model adjusting for stage (p=0.02). Toxicities during induction were previously reported. Gr 3-4 toxicities during maintenance (39 V/30 P) included gr3 rash (5/2), diarrhea (3/0), and hypertension (2/0). Death on study was reported for 22 PTS, due to progressive disease (12), treatment-related events during INRx (7), and unrelated events during INRx (3). Median OS among PTS randomized to maintenance V is 9.8 mos (95% CI, 7.3–15.7), and 9.4 mos (95% CI, 7.5–12.2, stratified log rank p=0.68) for PTS randomized to maintenance P. Conclusions: Neither arm was superior to historical control, but PTS randomized to V had longer PFS but not OS, compared to those randomized to P maintenance.
Prognostic factors after neoadjuvant radiochemotherapy for rectal cancer: Update of the CAO/ARO/AIO-94 Phase III study
Authors: R. Sauer, C. Roedel, P. Martus, R. Fietkau, C. Wittekind
Journal: Journal of Clinical Oncology (2005)

3503 Background: Rectal wall invasion and spread to the regional lymph nodes are the main criteria to estimate prognosis in rectal cancer. Preoperative radiochemotherapy (RCT) may alter the original pathologic stage by causing tumor regression, manifested by size reduction, downstaging, and - in a varying percentage - even complete disappearance of the tumor in the rectal wall or the lymph nodes. Does this alter the impact of established prognostic factors? Methods: 406 patients received preoperative RCT within our randomized trial CAO/ARO/AIO-94: 50.4 Gy of radiation were delivered in 28 fractions. Concurrent 5-FU was given as a 120 hours continuous infusion at a dose of 1000 mg/m2/d in the 1. and 5. week of RT. Surgery was scheduled six weeks after completion of RCT. Four cycles of bolus 5-FU (500 mg/m2 per day, five times weekly, repeated every four weeks) were started four weeks after surgery. Results: Five year disease free survival (DFS) was 74% for patients after complete resection (R0). It was 86%, 95%, 81%, 65%,42% for ypT0, T1, T2, T3, T4-tumors (p<.0001), and 85%, 46% for ypN0, N+ disease (p<.0001), respectively. Grading (p=.003), lymph vessel invasion (p<.0001), and the tumor regression grading (ranging from no regression, TRG 1, to complete pathologic response, TRG 5, p=0.02) were also significantly related to DFS in univariate analysis. In multivariate analysis, the lymph node status was the most important prognostic factor (p<.001). For the subgroup of ypN0-tumors, only TRG reached borderline statistical significance (p=.06). Conclusion: Positive pelvic lymph nodes after neoadjuvant radiochemotherapy are associated with a very unfavourable prognosis justifying more intense adjuvant chemotherapy. For the group of patients with negative nodes, TRG may help to guide further treatment. No significant financial relationships to disclose.
A review of carboplatin and gemcitabine with sequential radiation therapy in the treatment of stage III and IV non-small cell lung cancer in the community setting
Authors: C. W. Seidler, D. Kodali, D. Gupta
Journal: Journal of Clinical Oncology (2005)

7349 Background: The combination of Carboplatin plus Gemcitabine with or without sequential radiation therapy is widely used in advanced NSCLC. To review the efficacy and toxicity of the combination of carboplatin and gemcitabine in patients with stage III/IV NSCLC, and XRT a retrospective study was performed to determine the survival impact and QOL/toxicity in the community practice setting. Methods: The outcome of 34 consecutive patients with stage III/IV NSCLC treated with carboplatin plus gemcitabine as their initial therapy were reviewed for response rate, toxicity and survival. All patients received at least 2 cycles of carboplatin AUC=5.0 d1 and gemcitabine 100mg/M d1and d8. This was followed by involved field radiation XRT (47%)or 2–4 additional cycles as initial therapy. Results: The patients had the following characteristics: Stage III 73.5%, IV 26.4%, male 64.7%, female 35.2%, median age 62.14 (range 42–81), ECOG 0–2. Overall tumor response rates: Partial response (41.2%); stable disease (8.8%); and progressive disease (50.0%). Median progression free survival(PFS) was 8.1 months (range16–902d) and median overall survival(OS) 11.9 months (r=28–1255d+). Myelosuppression was mild with carboplatin/gemcitabine (Grade 3/4 neutropenia and thrombocytopenia was 8.8% and 5.8% respectively). Non-hematological toxicity was minimal: alopecia (2.9%), fatigue (17.6%) nausea (14.7%). Two patients (5.8%) had neutropenic fever but no septic death. Conclusions: The combination of carboplatin and gemcitabine followed by sequential radiation therapy attained a response rate and PFS and OS compairable to more toxic protocols. This combination with sequential radiation in selected cases is appropriate for community setting. No significant financial relationships to disclose.
Nab-paclitaxel plus gemcitabine followed by radiotherapy with concurrent 5-FU in locally advanced unresectable pancreatic cancer: A Western Australian experience.
Authors: Andrew Peter Dean, Nigel Spry, Alycea McGrath
Journal: Journal of Clinical Oncology (2016)

430 Background: The optimal management of patients with locally advanced unresectable pancreatic cancer is unclear. In the metastatic setting, superior response rates have been seen with nab-paclitaxel plus gemcitabine compared to gemcitabine alone. We investigate the efficacy and safety of nab-paclitaxel plus gemcitabine followed by radical radiotherapy with concurrent 5-FU in patients with locally advanced unresectable pancreatic adenocarcinoma. Methods: A retrospective review was conducted of all patients with locally advanced unresectable pancreatic cancer treated with nab-paclitaxel plus gemcitabine, the majority proceeding to radical radiotherapy with concurrent 5-FU, at two large Western Australian metropolitan hospitals from January 2009 to December 2014. Charts were reviewed to obtain patient characteristics, efficacy and tolerability. Kaplan-Meier analysis was utilised to obtain survival curves. Results: Forty-two patients were identified as having locally advanced unresectable pancreatic adenocarcinoma, receiving nab-paclitaxel plus gemcitabine to a mean number of 5 cycles, the majority requiring dose reductions. Of these, thirty proceeded to radical radiotherapy; the majority receiving 3DCRT, 54 Gy, with concurrent 5-FU. Seven had sufficient response to therapy to be offered radical resection. Six went on to radical resection, all with R0 or close resection margins (2 with complete response). Median length of stay following surgery was 18 days, and there were no perioperative deaths. The median survival for patients proceeding with surgery was 30 months. Median survival was 23 months for those treated with chemoradiotherapy, and 10 months with chemotherapy alone. Conclusions: This retrospective investigation demonstrates that nab-paclitaxel plus gemcitabine followed by radical radiotherapy with concurrent 5-FU is a tolerable treatment option with encouraging results for patients with locally advanced unresectable pancreatic cancer. The R0 resection rate in patients that had adequate response to allow for radical resection is promising. Further studies are warranted.
Cognitive rehabilitation for brain tumor survivors: A pilot study.
Authors: Nadine M. Richard, Lori J. Bernstein, Warren P. Mason, Normand Laperriere, Caroline Chung, Barbara Ann Millar, Catherine Maurice, Kim Edelstein
Journal: Journal of Clinical Oncology (2016)

140 Background: Brain tumor survivors often face unique challenges from chronic cognitive deficits such as memory problems or executive dysfunction. Cognitive rehabilitation is a relatively new field. With few well-controlled studies in cancer patients, oncology and supportive care teams lack accessible, reliable tools to address cognitive dysfunction. This pilot study evaluated the feasibility and potential efficacy of two behavioral interventions for brain tumor survivors. Methods: We compared two programs, each with 8 individual treatment sessions and daily homework. Goal Management Training (GMT) is a neuroscience-based integration of mindfulness and strategy training. The Brain Health Workshop (BHW) offers supportive psychoeducation about living with a brain tumor. Using a prospective randomized design, 6 brain tumor patients (with chronic cognitive dysfunction, ≥ 3 months post-radiation or surgery) were enrolled in GMT or BHW and completed a battery of measures at baseline and post-training. Composite scores were calculated by domain, with objective tests of attention, processing speed, memory, and executive functioning, and subjective measures of coping, mood, behavioral regulation and cognitive symptoms. Patient feedback was obtained in post-training qualitative interviews. Results: All patients (Table 1) completed all study activities. Analyses of group differences in composite change scores showed greater improvement in executive functions and greater attainment of pre-training functional goals in the GMT group (p's &lt; .05). The BHW group showed a trend toward greater improvement in mood and behavioral regulation that did not reach statistical significance. Patients in both groups reported satisfaction with their program and continued, frequent (daily to every other day) use of their new knowledge following training. Conclusions: This pilot study demonstrated the feasibility of cognitive rehabilitation for brain tumor survivors between 1 and 8 years post-diagnosis. Results suggest unique benefits of each intervention that will be further explored in a larger clinical trial. [Table: see text]
Theranostic Nucleic Acid Binding Nanoprobe Exerts Anti-inflammatory and Cytoprotective Effects in Ischemic Injury
Authors: Howard H. Chen, Hushan Yuan, Hoonsung Cho, Yan Feng, Soeun Ngoy, Anand T. N. Kumar, Ronglih Liao, Wei Chao, Lee Josephson, David E. Sosnovik
Journal: Theranostics (2017)

Extracellular nucleic acids are proinflammatory molecules that have been implicated in a diverse range of diseases.We report here the development of a multivalent nucleic acid scavenging nanoprobe, where the fluorochrome thiazole orange (TO) is conjugated to a polymeric 40 kDa dextran carrier.Dextran-TO (Dex-TO) has nanomolar affinity for mammalian and bacterial nucleic acids and attenuates the production of inflammatory cytokines from activated macrophages exposed to DNA and RNA.Mice with myocardial ischemia reperfusion that were treated with Dex-TO showed a decrease in myocardial macrophage infiltration at 24 hours (p<0.05) and a decrease in infarct size (18% ± 9%, p<0.01) on day 7. Dex-TO allows sites of injury to be identified with fluorescence imaging, while simultaneously exerting an anti-inflammatory and cytoprotective effect.Dex-TO could be of significant diagnostic and therapeutic (theranostic) utility in a broad range of conditions including ischemia, trauma, burns, sepsis and autoimmune disease.
Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome
Authors: Ryan L. Collins, Harrison Brand, Claire E. Redin, Carrie Hanscom, Caroline Antolik, Matthew R. Stone, Joseph T. Glessner, Tamara Mason, Giulia Pregno, Naghmeh Dorrani, Giorgia Mandrile, Daniela Giachino, Danielle Perrin, Cole Walsh, Michelle Cipicchio, Maura Costello, Alexei Stortchevoi, Joon-Yong An, Benjamin B. Currall, Catarina M. Seabra, Ashok Ragavendran, Lauren Margolin, Julian A. Martinez-Agosto, Diane Lucente, Brynn Levy, Stephan J. Sanders, Ronald J. Wapner, Fabiola Quintero-Rivera, Wigard Kloosterman, Michael E. Talkowski
Journal: Genome biology (2017)

Structural variation (SV) influences genome organization and contributes to human disease. However, the complete mutational spectrum of SV has not been routinely captured in disease association studies. We sequenced 689 participants with autism spectrum disorder (ASD) and other developmental abnormalities to construct a genome-wide map of large SV. Using long-insert jumping libraries at 105X mean physical coverage and linked-read whole-genome sequencing from 10X Genomics, we document seven major SV classes at ~5 kb SV resolution. Our results encompass 11,735 distinct large SV sites, 38.1% of which are novel and 16.8% of which are balanced or complex. We characterize 16 recurrent subclasses of complex SV (cxSV), revealing that: (1) cxSV are larger and rarer than canonical SV; (2) each genome harbors 14 large cxSV on average; (3) 84.4% of large cxSVs involve inversion; and (4) most large cxSV (93.8%) have not been delineated in previous studies. Rare SVs are more likely to disrupt coding and regulatory non-coding loci, particularly when truncating constrained and disease-associated genes. We also identify multiple cases of catastrophic chromosomal rearrangements known as chromoanagenesis, including somatic chromoanasynthesis, and extreme balanced germline chromothripsis events involving up to 65 breakpoints and 60.6 Mb across four chromosomes, further defining rare categories of extreme cxSV. These data provide a foundational map of large SV in the morbid human genome and demonstrate a previously underappreciated abundance and diversity of cxSV that should be considered in genomic studies of human disease.