tbuckley/cabot-search huggingface dataset:
A randomized, double‑blind, controlled phase IIb study of the safety and efficacy of ICT‑107 in newly diagnosed patients with glioblastoma multiforme following resection and chemoradiation.
Authors: Elma S. Hawkins, Robert Aiken, James Chandler, Karen L. Fink, Michael J. Glantz, Jai Grewal, Michael L. Gruber, Santosh Kesari, Joseph C. Landolfi, Renato V. LaRocca, Glenn Jay Lesser, James Markert, Tina M. Mayer, Donald O'Rourke, David M. Peereboom, Surasak Phuphanich, David Schiff, Andrew E. Sloan, Baldassarre Stea, Jay-Jiguang Zhu
Journal: Journal of Clinical Oncology (2012)

TPS2107 Background: Tumor stem cells have been correlated with recurrence and clinical outcome in glioblastoma multiforme (GBM). ICT‑107 is an autologous vaccine consisting of the patient’s dendritic cells pulsed with 6 synthetic peptide CTL epitopes targeting the GBM tumor and tumor‑stem cell associated antigens MAGE‑1, HER‑2, AIM‑2, TRP‑2, gp100 and IL‑13Rα2. Phase I results showed a good safety profile and interesting clinical potential (ASCO, 2010, abs#2097 and ASCO, 2011, abs#2042) in 16 newly diagnosed GBM patients with a median progression-free survival (PFS) of 16.9 months (measured from surgery) and a median overall survival (OS) of 38.4 months. Methods: In this Phase II study eligible patients have newly diagnosed GBM and complete surgical resection or minimum residual tumor &lt; 1 cm 3 , are HLA-A1 and/or HLA-A2 positive, older than 18, have Karnofsky Performance Score (KPS) of ≥ 70% and have adequate hematologic and chemistry parameters. Patients with a serious immune or autoimmune disorder or other systemic disease are excluded. Patients undergo apheresis to isolate peripheral blood mononuclear cells (PBMCs) to be used for preparation of study treatment (ICT‑107 and Control). Pre-study treatment consists of 6 weeks of concurrent temozolomide (TMZ) and radiation. After stratification by site and age, patients are randomized 2:1 to receive either ICT-107 or its matching control (autologous, unpulsed dendritic cells). Patients then receive induction ICT-107 or control once a week for four weeks. All patients subsequently receive maintenance TMZ for 5 days per month for 12 months. Booster vaccinations occur at Cycles 1, 3, 6 and 10, and every six months thereafter. The primary endpoint is OS and secondary endpoints include PFS, rates of OS and PFS at 6 months after surgery and every 3 months thereafter, safety and tolerability of ICT‑107, immune response to ICT-107 and predictors of response. 120 patients have been enrolled in this ongoing trial. It is expected that approximately 200 patients will be enrolled for screening with the intention to randomize at least 102 patients. The trial significance is alpha=0.025 one-sided.
Use of high white blood cell (WBC) count to predict poor survival outcome in gastrointestinal (GI) cancer with thrombotic event.
Authors: Myung Ah Lee, Guk Jin Lee, Ji Hyung Hong, Hee Yeon Lee, Sang Young Roh
Journal: Journal of Clinical Oncology (2012)

e19614 Background: There are some known risk factors for deep vein thrombosis in cancer patients, such as primary site of cancer, white blood cell count (WBC), hemoglobin (Hb), platelet count (PLT). We investigated the association between these factors and the overall survival as prognostic factor in gastrointestinal (GI) cancer patients. Methods: All the patients with gastrointestinal cancer, who developed deep vein thrombosis or pulmonary thromboembolism through the clinical course, were retrospectively reviewed between January 2009 and June 2011 at Seoul St. Mary’s Hospital. According to treatment, patients were classified into two groups; the chemotherapy group and the supportive care group. Results: Of the fifty-six patients, median age was sixty three year-old. Stomach cancer was most common 35% , pancreatic cancer 31%, colorectal cancer 19%, and biliary cancer was 15%. There were three pattern of thrombosis: 19 (34%) deep vein thrombosis (DVT) only, 12 (21%) pulmonary thromboembolism (PTE) only, 25 (45%) combined DVT with PTE. WBC count above 11,000/µ° showed the poor overall survival than other group (median survival 3.4 months vs. 1.7 months, respectively, p=0.015) However, other risk factor did not show any significant association (Hb: p=0.521, PLT: p=0.295) In chemotherapy group, twelve (55%) patients had progressive disease and ten (45%) patients had stable disease at the time of thrombotic event. There was no statistically significant association between thrombosis and tumor response. The chemotherapy group had tendency of better survival outcome than the supportive care group without statistical significance (median survival 2.4 months vs. 5.3months, p=0.07). Conclusions: In GI cancer patients, elevated white blood cell count above 11,000/µ° can be important prognostic and risk factor for thrombosis with poor survival outcome. And the response of chemotherapy seemed to have no influence on thrombotic event during chemotherapy. This is very limited study due to small sample size and retrospective analysis, and heterogenous type of cancer. Further large study should be warranted to define the thrombotic risk factor as prognostic marker.
A phase I study of BBI608, a cancer stemness inhibitor, administered with paclitaxel (PTX) as combination therapy (Rx) for pretreated unresectable or recurrent gastric cancer.
Authors: Kohei Shitara, Yasutoshi Kuboki, Yoshiaki Nakamura, Ayako Doi, Kazuaki Harada, Akihito Kawazoe, Toshihiko Doi, Takayuki Yoshino, Yasuhide Yodo, Reigetsu Yoshikawa, Atsushi Ohtsu
Journal: Journal of Clinical Oncology (2015)

e15089 Background: BBI608 is an oral cancer stemness inhibitor which inhibits STAT3, β-catenin, and Nanog stemness pathways through targeting activated STAT3 (Proc Natl Acad Sci USA, 2015). Preclinical studies show its potent, broad-spectrum anti-tumor and anti-metastatic effects, and marked synergy in combination with PTX. The previous phase 1b study of BBI608 plus PTX showed favorable safety profiles and encouraging anti-tumor activities at a recommended dose for a phase 2 study (RP2D) of 480 mg b.i.d. in various solid tumors (J Clin Oncol 32:5s, 2014, suppl; abstr 2530). Here we report the first assessment of BBI608 plus PTX for pretreated unresectable or recurrent gastric cancer. Methods: This open-label, uncontrolled study was conducted to evaluate safety, tolerability, PK, and efficacy of BBI608 at the RP2D in combination with weekly PTX for gastric cancer. BBI608; 480 mg b.i.d., was administered in combination with PTX; 80 mg/m2weekly, on day 1, 8, and 15 of each 28-day study cycle, until progression of disease or unacceptable toxicity. Results: Six patients were enrolled. Median number of previous chemotherapy was 2 (1 to 5). Three patients previously received taxane therapy. No DLT was observed. Diarrhea was the most common toxicity, but it was mild, with grade 1 in all 6 patients. Anorexia (grade 1) was also observed in 2 patients (33.3%). No other severe side effects were observed. Two patients (33.3%) achieved PR (66.7% and 36.8% regression), one of them maintained response > 7.5 months. Two additional patients achieved SD (2.8 months) or non CR/PD (7.5 months). Notably, there were no significant differences of pharmacokinetic profile between the patients with (n = 3) or without (n = 3) partial/total gastrectomy. Conclusions: This phase 1 study has shown that administration of BBI608 plus PTX can be safely administrated at full dose with promising efficacy signals. Based on these encouraging results, the phase 3 (BRIGHTER) study in 2nd-line is currently ongoing (NCT02178956). Clinical trial information: JapicCTI-142420.
Relationship between body mass index (BMI) at diagnosis of ER+ node negative breast cancer (BC) and Oncotype DX recurrence score.
Authors: Caroline A. Lohrisch, Ashley Davidson, Stephen K. L. Chia, Karen A. Gelmon, Tamara Nina Shenkier, Susan Ellard, Ryan Woods, Linda Wong, Janice Pope
Journal: Journal of Clinical Oncology (2012)

582 Background: Inferior stage-adjusted survival for BC among obese (O) women has been reported. This may reflect differences in treatment planned for O women, in treatment received (due to toxicity), or in tumor biology arising in different cellular environments, such as high serum insulin levels, which are associated with a higher risk of recurrence. Methods: We examined whether overweight (BMI 25-30) or obese (BMI &gt;30) women had a higher Oncotype Dx Recurrence Score (RS) after ER+, node negative (NN) or N0i+ BC than normal weight women. Included were all participants at the BC Cancer Agency in a RS clinical utility study in consecutive ER+ NN, N0i+ BC (n=156) at the BC Cancer Agency and in the TAILORx trial (n=56). Sixteen were excluded (n=5 withdrew consent; 1 triple negative; 3 test failed; 2 her2+; 1 neoadjuvant treatment, n=4 height and weight missing). Results: A similar proportion of O patients had low, intermediate, and high RS tumors. Cancers with a high RS were more likely to be grade 3 (55% of grade 3 tumours had high RS, 33% intermediate RS, 12% low RS) and fewer were strongly ER positive (69% of high RS versus 97% of intermediate and low RS). Conclusions: While this data does not support differences in tumor risk arising in O versus non obese environments in ER+, NN BC, examination of a larger data set may be more informative. [Table: see text]
Late mortality and relapse after dexrazoxane (DRZ) treatment: An update from the Children’s Oncology Group (COG).
Authors: Eric Jessen Chow, Barbara Asselin, Cindy L. Schwartz, David Doody, Wendy M. Leisenring, Sanjeev Aggarwal, Kevin Scott Baker, Smita Bhatia, Lu Chen, Louis S. Constine, David Robert Freyer, Marcia Leonard, Steven E. Lipshultz, Saro Armenian
Journal: Journal of Clinical Oncology (2014)

10024 Background: DRZ use as a cardioprotectant in pediatric oncology has been limited by concerns regarding its efficacy and possible induction of second cancers, both of which may compromise overall long-term survival. Methods: COG protocols P9404 (T-cell acute lymphoblastic leukemia/lymphoma, n=537), P9425 (advanced stage Hodgkin lymphoma, n=216), and P9426 (low/intermediate stage Hodgkin, n=255) were conducted between 1996 and 2001. Patients were randomly assigned to treatment with or without DRZ (10:1 DRZ:doxorubicin alone given as IV bolus before each doxorubicin dose); cumulative protocol-specified doxorubicin dose: 100-360 mg/m2. Data from all 3 trials were aggregated to examine overall relapse rates, and also linked with the US National Death Index to determine overall and cause-specific mortality by DRZ status (intent-to-treat). The combined sample had 80% power to detect differences in mortality and relapse rates of 5-7% and 6-8%, respectively. Results: Among 1,008 patients (DRZ+, n=507) with a median follow-up of 8.3 years (range 0-16.7), 132 died (DRZ+ n=67). With similar duration of follow-up by DRZ status, DRZ did not affect overall mortality (DRZ+, 12.8% vs. DRZ-, 12.2% at 10 years; HR 1.02, 95% CI 0.72-1.43) or relapse (10-year cumulative incidence: DRZ+, 15.6% vs. DRZ-, 18.8%; HR 0.82, 95% CI 0.60-1.10). Findings were similar when each protocol was examined separately. DRZ also was not associated with differential causes of death, with the original cancer accounting for 75.8% of all deaths (DRZ+/-, n=48/52; HR 0.91, 95% CI 0.61-1.34), followed by second cancers (DRZ+/-, n=10/9; HR 1.08, 95% CI 0.44-2.67), toxicity (DRZ+/-, n=7/3; HR 2.30, 95% CI 0.60-8.91), and other/unknown causes (DRZ+/-, n=2/1). There was no detectable difference in deaths due to acute myeloid leukemia/myelodysplasia (DRZ+/-, n=6/5) or with a cardiovascular event as a contributing cause (DRZ+/-, n=4/2). Conclusions: DRZ was not associated with a differential risk of mortality or relapse among randomized pediatric leukemia and lymphoma patients. Whether DRZ reduced cardiotoxicity is the focus of an ongoing prospective study. Clinical trial information: NCT01230983, NCT00005578, NCT00002827.
Frequent Clinical Overlap of Histiocytic Neoplasms and WHO-Classified Myeloid Malignancies Leads to Functional Insights into the Cell-of-Origin of Histiocytoses
Authors: Benjamin Heath Durham, Akihide Yoshimi, Matthias Papo, Young Rock Chung, Neval Ozkaya, Chezi Ganzel, Ahmet Dogan, David M. Hyman, Christopher Y. Park, Raajit K. Rampal, Damien Roos Weil, Francois Michel Lemoine, Zahir Amoura, Olivier A. Bernard, Eli L. Diamond, Jean-François Emile, Julien Haroche, Omar Abdel-Wahab
Journal: Blood (2016)
Abstract 115: Nuclear CaMKII is a Histone H3 Kinase that Remodels Chromatin During Cardiac Hypertrophy
Authors: Salma Mahmoud, Muhammad Kunhi, Gillian H Little, Yan Bai, Woojin An, Larry Kedes, Coralie Poizat
Journal: Circulation Research (2013)

Background and Purpose: Calcium/calmodulin-dependent protein kinase II (CaMKII) is a ubiquitous serine/threonine kinase implicated in pathological events such as cardiac hypertrophy. In this study we investigated the role of a specific nuclear isoform of CaMKII in chromatin remodeling and in transcriptional regulation in cardiac muscle. Methods: Comprehensive experimental approaches performed in primary cardiomyocyte cultures were used including chromatin immunoprecipitation assays (ChIP), q-PCR, chromatin remodeling assays, in vitro phosphorylation/transcription assays, production of recombinant adenovirus, siRNA technology, fluorescence microscopy and mass spectrometry. Results: We found that CaMKIIδB targets specific components of chromatin during cardiac hypertrophy and binds to nucleosomes through its association domain in a cooperative model. CaMKIIδB also increased chromatin relaxation, and this action was dependent on its kinase activity. The observation that CaMKIIδB interacts with chromatin suggested to us that histones maybe novel substrates of the kinase in cardiac muscle. To test this hypothesis, we performed in vitro kinase assays and found that histone H3 is a bona fide CaMKIIδB substrate and Ser-10 appears to be a predominant phosphorylation site. Increased histone H3 Ser-10 phosphorylation was observed following hypertrophic stimulation and was not associated with cellular proliferation, whereas depletion of CaMKIIδB significantly reduced histone H3 Ser-10 phosphorylation in primary cardiomyocytes. Interestingly, we found that H3 S10 phosphorylation and recruitment of CaMKIIδB occur at promoters of fetal cardiac genes. To establish the functional link between H3 phosphorylation by CaMKIIδB, chromatin remodeling and transcription activation, we developed an in vitro transcription system and using it we found that CaMKIIδB increased chromatin accessibility and mediated transcription of the Mef2 transcription factor. Conclusion: Taken together, these findings highlight a new role of CaMKIIδB as relevant histone H3 kinase and link for the first time epigenetic changes by CaMKII to cardiac hypertrophy.
Neoadjuvant chemoradiotherapy for patients with high-risk extremity and truncal sarcomas: A 10-year follow-up study.
Authors: Nicole Jannelle Look Hong, Francis J Hornicek, David C. Harmon, Edwin Choy, Yen-Lin Chen, Sam S. Yoon, G. Petur Nielsen, Jackie Szymonifka, Beow Yong Yeap, Thomas F. DeLaney, John Thomas Mullen
Journal: Journal of Clinical Oncology (2012)

10058 Background: Patients with high-risk extremity and truncal soft tissue sarcomas (STS) are at considerable risk for recurrence. A regimen of preoperative mesna, doxorubucin hydrochloride (Adriamycin), ifosfamide, and dacarbazine (MAID), interdigitated with radiotherapy (RT), followed by resection and postoperative chemotherapy with or without RT, has demonstrated high rates of local and distant control. The goal of this series is to study outcomes of our most recent cohort of patients treated on this regimen. Methods: We retrospectively reviewed records of 55 consecutive patients with STS of the extremity or superficial trunk who completed all phases of treatment at our institution from January 2000–July 2011. Clinicopathologic characteristics and patient outcomes were analyzed. Results: Fifty-five patients were analyzed and had a median age of 53 years (range 18-73). The median tumor size was 10.1cm (range 2.5-35.5 cm). Twenty-seven (49%) and 28 (51%) patients had grade 2 and 3 tumors, respectively. Margins were negative in 49 (89%) patients, and positive in 6 (11%) patients. At a median follow-up of 43 months, there were 7 (13%) locoregional, and 17 (31%) distant recurrences. The local and distant 5-year recurrence-free survival (RFS) rates were 92% and 64%, respectively. The 5-year overall (OS) and disease-specific survival rates were 86% and 89%, respectively. There were no treatment-related deaths or secondary myelodysplasias. There were no significant predictors of OS or RFS. Conclusions: Outcomes of a contemporary cohort of patients with extremity and truncal STS treated with an intense regimen of neoadjuvant chemoradiotherapy and surgery are consistent with previous reports from our institution and better than reports of chemotherapy alone. [Table: see text]
Endogenous anti-β-glucan antibodies as a potential predictive biomarker for clinical response to imprime PGG immunotherapy in non-small cell lung cancer (NSCLC) patients.
Authors: Nandita Bose, Mary Antonysamy, Myra Louise Patchen, Jamie R. Lowe, Paulette Mattson, Michele Anne Gargano, Keith Gorden, Steven Leonardo, Richard Walsh, Xiaohong Qui, Nadine Ottoson, Katie E. Ertelt, Lindsay R. Wurst, Diane McMurray, Anissa S.H. Chan, Adria Jonas, Richard Dale Huhn, Michael Thomas, Parvis Sadjadian, Folker Schneller
Journal: Journal of Clinical Oncology (2014)

3045 Background: Imprime PGG (IPGG) is a yeast-derived β-1,3/1,6 glucan that primes innate immune cells to kill antibody-targeted cancer cells via a complement receptor 3 (CR3)-dependent mechanism. In humans, naturally occurring anti-β-glucan antibodies (ABA) are required for binding of IPGG to CR3 and subsequent changes in innate cell functions. Methods: In a 32-donor healthy volunteer study, using a qualified quantitative ELISA assay, ABA levels and the threshold for binding and modulation of innate immune functions were evaluated, including a) complement activation, b) complement receptor expression, c) activation marker modulation, and d) selective chemokine production. The potential of the ABA level as a clinical biomarker for clinical response to IPGG was evaluated in a Phase 2 clinical trial by retrospectively segregating subjects into populations at or above the ABA threshold (biomarker positive; BM+) or below the ABA threshold (biomarker negative; BM-). Advanced NSCLC patients received cetuximab, carboplatin and paclitaxel without (Control) or with IPGG 4mg/kg on Days 1, 8 and 15 of each 3-week treatment cycle for the first 4 to 6 cycles. Maintenance treatment with cetuximab alone or with IPGG was continued in subjects achieving radiographic disease control (RECIST 1.0). Results: The objective response rate (ORR; primary endpoint) was 23% in the control group (6/26), 48% in the entire IPGG group (22/46; p= 0.047 vs control), 67% in the BM+ IPGG group (10/15; p=0.009 vs control) and 39% in the BM- IPGG group (12/31; p=0.26 vs control). Median overall survival was 11.3 mo in the control group, 12.4 mo in the entire IPGG group (HR 1.04; p=0.88 vs control), 16.7 mo in the BM+ IPGG group (HR 0.70; p=0.37 vs control) and 9.4 mo in the BM- IPGG group (HR 1.28; p=0.43 vs control). Three-year survival was 0% in the control group, 7% in the entire IPGG group, 17% in the BM+ IPGG group and 0% in the BM- IPGG group. Conclusions: In summary, the addition of Imprime PGG to carboplatin, paclitaxel and cetuximab resulted in improved outcomes in BM+ patients, suggesting the potential clinical use of ABA level as a predictive biomarker for response to Imprime PGG. Clinical trial information: NCT00874848.
Targeted therapy of mesothelin expressing mesotheliomas (MM), ovarian cancer (OC) and pancreatic cancer (PC): Results of phase I study of SS1(dsFv)PE38 (SS1P)
Authors: R. Hassan, S. Bullock, R. J. Kreitman, H. L. Kindler, I. Pastan
Journal: Journal of Clinical Oncology (2004)

3035 Background: Mesothelin, a cell surface glycoprotein is an attractive candidate for antibody-based therapies given its limited expression on normal mesothelial cells and overexpression in MM, OC and PC. To target mesothelin we developed the immunotoxin-SS1P, consisting of an anti-mesothelin Fv linked to a mutated Pseudomonas exotoxin that mediates cell killing. Based on the antitumor activity of SS1P in preclinical studies we initiated a multicenter phase I clinical trial of SS1P. Methods: Eligible patients (pts) had previously treated MM, OC and PC, ECOG PS 0–2, and tumor mesothelin expression as determined by immunohistochemistry. SS1P was administered intravenously over 30 minutes every other day (QOD) for 6 or 3 doses. Results: A total of 20 pts (7 peritoneal MM; 4 pleural MM; 8 OC; 1 PC) have been treated to date. On the QOD x 6 schedule 17 pts were treated at 4 dose levels (8, 12, 18 and 25 μg/kg/dose) and the maximum tolerated dose (MTD) of SS1P was 18 μg/kg/dose. Dose limiting toxicities (DLT's) included Grade 3 urticaria (1 pt) and vascular leak syndrome (VLS) (2 pts). Grade 2 toxicities included hypoalbuminemia, abdominal pain, pleuritic pain, asymptomatic pleural and pericardial effusion and VLS. Since the DLT's on the SS1P QOD x 6 schedule were seen in pts who had received more than 4 doses of SS1P, the protocol was amended to treat pts QOD x 3 doses to allow further dose escalation. Three pts have been treated on the QOD x 3 schedule at 25 μg/kg/dose with no DLT's and dose escalation is ongoing. Of the 17 evaluable pts treated, 10 had stable disease; 2 had minor response and 5 had progressive disease. One pt with OC had complete resolution of abdominal and pelvic ascites lasting 6 months; 1 pt with peritoneal MM has had complete resolution of abdominal ascites lasting >30 months and has required no further treatment. Conclusions: SS1P is well tolerated and shows promising clinical activity including resolution of ascites and stable disease in some pts. SS1P could be potentially useful in pts with small volume disease and ascites who have failed standard chemotherapy. Dose escalation on the QOD x 3 schedule is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration NeoPharm Inc.
Who ‘owns’ the injury or illness? Who ‘owns’ performance? Applying systems thinking to integrate health and performance in elite sport
Authors: Mitchell Mooney, Paula C Charlton, Sadjad Soltanzadeh, Michael K Drew
Journal: British Journal of Sports Medicine (2017)

Systems thinking frameworks have gained attention in both modelling athlete performance and injury prevention in sports medicine.1–3 We believe that these fields may contribute valuably and interdependently within a larger high performance system.1 The purpose of this editorial is to explain how ‘injury’ and ‘performance’ interact within a system-based framework3 and to provide three practical implications of an integrated performance system.

The basic premise underpinning any systems model is that parts of a system are inter-related, and the objective of the whole system defines the function of each part. Therefore, the interaction between parts cannot be reduced to a number of linear cause and effect relations.1 The influence of a part on the outcome of the whole system depends on the state of the other parts. Any change to a part of the system can affect the objectives of the whole system as …