tbuckley/cabot-search huggingface dataset:
Balugrastim: A long-acting, once-per-cycle, recombinant human albumin-fusion filgrastim.
Authors: Laurie Pukac, Steven Barash, Noa Avisar, Hermann Allgaier, Jason Bock, Udo W. Mueller, Wenyan David Shen
Journal: Journal of Clinical Oncology (2013)

e13551 Background: Balugrastim is a once-per-cycle fixed-dose genetic fusion protein composed of human serum albumin (HSA) and granulocyte colony-stimulating factor (G-CSF) in development for prevention of severe neutropenia in cancer patients receiving chemotherapy. Albumin fusion is a clinically validated technology that extends product half-life, allowing for infrequent dosing, better tolerability, lower cost, and improves drug design, potentially lowering immunogenicity risk. Here, we describe the technology used to produce balugrastim and summarize preclinical findings compared with pegfilgrastim (Neulasta). Methods: Design and production of balugrastim was described previously (Halpern et al. Pharmaceut Res 2002;19:1720−1729). Biologic activity of balugrastim was assessed in an NFS-60 cell line proliferation assay vs filgrastim and pegfilgrastim. PK and PD properties were studied in healthy and neutropenic animal models. Results: Albumin fusion produces a long-acting G-CSF with comparable pharmacologic properties to pegfilgrastim. In vitro, balugrastim had binding affinity and cell proliferation activity comparable to pegfilgrastim, and both were lower than non-PEGylated filgrastim on a molar basis. Overall increases in leukocytes, neutrophilic granulocytes, and monocytes were dose dependent and consistent with the effects expected for a long-acting G-CSF with some variation based on the specific animal model used. A single balugrastim dose in BDF1 mice elicited a dose-dependent increase in peripheral granulocytes and mobilized hematopoietic progenitor cells. In cynomolgus monkeys, balugrastim caused an increase in peripheral neutrophils similar to pegfilgrastim, with higher responses after 2nd, 3rd, and 4th doses. In mice, balugrastim had shorter terminal half-life and mean residence time, and faster clearance than pegfilgrastim. In monkeys, terminal half-life of balugrastim was slightly longer than pegfilgrastim. Conclusions: An albumin fusion technology platform was used to produce balugrastim – a novel, biologically active albumin G-CSF fusion protein with greater structural homogeneity and comparable pharmacologic properties to conventionally PEGylated G-CSFs.
Avelumab in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Farhad Fakhrejahani, Ravi Amrit Madan, William L. Dahut, Fatima Karzai, Lisa M Cordes, Jeffrey Schlom, James L. Gulley
Journal: Journal of Clinical Oncology (2017)

159 Background: Despite recent progress, mCRPC remains a lethal disease. While programmed cell death 1 (PD-1) and PD-1 ligand (PD-L1) inhibitors have shown activity in variety of malignancies, to this point there is minimal evidence of activity in mCRPC. This is a report of avelumab, anti-PDL1 in mCRPC patients (pts). Methods: This is an expansion cohort of the first in human, phase I trial (JAVELIN Solid Tumor; EMR100070-001) that evaluated 10 mg/kg of avelumab in pts with mCRPC who had progressive disease (PD) on previous treatment. Pts who had PD on an androgen receptor antagonist (ARA) could enroll on trial and continue their ARA. Avelumab was administered as a 1-hour intravenous infusion every 2 weeks (w) with restaging scans every 6 w. Prostate cancer working group 2 criteria were used to determine PD. Results: 18 patients were enrolled on this cohort; the median age of pts was 67 years. Median on study PSA was 11ng/mL. 11 pts had Gleason score (GS) ≥ 8 and 7 had GS of 7. 3 pts had previous chemotherapy with docetaxel, 8 pts received previous vaccine treatment including 4 pts with sipuleucel-T and 4 pts with Prostvac. Overall avelumab treatment was safe and tolerable. 15 pts experienced grade ≤ 2 treatment related adverse events (TRAEs), fatigue being the most common one. 4 pts developed treatment related hypothyroidism, 3 with grade 2 and 1 with grade 1. In addition, 2 pts had grade 3 asymptomatic TRAEs (amylase &amp; lipase elevations). 7 pts had stable disease (SD) &gt; 24 w post treatment, 6 pts had PD after first restaging scans at 6 w which was reconfirmed in 2 nd restaging scan at 12 w. PSA doubling time (PSADT) prior to avelumab was compared with PSADT after 3 months (m) of treatment. Among 17 pts with available data, 3 pts had a prolonged PSADT which was defined at 3 m (twice as high as on-study PSADT), 7 pts had stable PSADT and 7 had decreased PSADT. 5 of 18 pts enrolled while on enzalutamide with a rising PSA. Among these pts 1 had prolonged PSADT, 2 had a stable PSADT and 2 with decreased PSADT after 3 m of follow up. 3 of 5 pts had SD &gt; 24 m, 1 had SD for 13 w and 1 had PD at first restaging scans. Conclusions: These data provide safety data of avelumab on a population of pts with mCRPC. Immune analysis is under way to determine correlation with immune responses in the pts on this trial that had prolonged SD. Clinical trial information: NCT01772004.
KEYNOTE-224: Phase II study of pembrolizumab in patients with previously treated advanced hepatocellular carcinoma.
Authors: Andrew X. Zhu, Jennifer J. Knox, Masatoshi Kudo, Stephen L. Chan, Richard S. Finn, Abby B. Siegel, Junshui Ma, Pat Watson, Ann-Lii Cheng
Journal: Journal of Clinical Oncology (2017)

TPS504 Background: The tyrosine kinase inhibitor sorafenib is the standard of care for first-line hepatocellular carcinoma (HCC). For patients with HCC after disease progression on sorafenib or for those with intolerance to sorafenib, no approved therapies are available. Because HCC is often driven by inflammation and is also associated with a suppressed immunoenvironment, there is a strong rationale to evaluate immunotherapy in patients with this type of cancer. The single-arm, multisite, phase 2 KEYNOTE-224 study (ClinicalTrials.gov, NCT02702414) was designed to evaluate the efficacy and safety of the anti–PD-1 antibody pembrolizumab in patients with previously treated advanced HCC. Methods: Approximately 100 patients will be enrolled. Inclusion criteria include age ≥18 years, histologically or cytologically confirmed diagnosis of HCC Barcelona Clinic Liver Cancer (BCLC) stage C disease or BCLC stage B disease not amenable to or refractory to locoregional therapy, and disease not amenable to a curative treatment approach (eg, transplantation, surgery, or ablation). Patients must also have measurable disease based on RECIST v1.1 as confirmed by central imaging vendor review, documented objective radiographic progression after stopping treatment with sorafenib or intolerance to sorafenib, Child-Pugh liver score A, ECOG performance status 0-1, and predicted life expectancy &gt; 3 months. Patients will be allocated to receive pembrolizumab 200 mg IV every 3 weeks for up to 35 cycles (~2 years) or until disease progression, unacceptable toxicity, patient withdrawal of consent, or investigator decision. Response will be assessed every 9 weeks per RECIST v1.1 by central imaging vendor review. Adverse events (AEs) will be assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and graded per NCI CTCAE v4.0. The primary end point is objective response rate per RECIST v1.1 by central imaging vendor review. Secondary end points are overall survival; safety and tolerability; and duration of response, disease control rate, time to progression, and progression-free survival per RECIST v1.1 by central imaging vendor review. Enrollment in KEYNOTE-224 is ongoing. Clinical trial information: NCT02702414.
Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism
Authors: Oliver Hahn, Sebastian Grönke, Thomas M. Stubbs, Gabriella Ficz, Oliver Hendrich, Felix Krueger, Simon Andrews, Qifeng Zhang, Michael J. Wakelam, Andreas Beyer, Wolf Reik, Linda Partridge
Journal: Genome biology (2017)

Dietary restriction (DR), a reduction in food intake without malnutrition, increases most aspects of health during aging and extends lifespan in diverse species, including rodents. However, the mechanisms by which DR interacts with the aging process to improve health in old age are poorly understood. DNA methylation could play an important role in mediating the effects of DR because it is sensitive to the effects of nutrition and can affect gene expression memory over time. Here, we profile genome-wide changes in DNA methylation, gene expression and lipidomics in response to DR and aging in female mouse liver. DR is generally strongly protective against age-related changes in DNA methylation. During aging with DR, DNA methylation becomes targeted to gene bodies and is associated with reduced gene expression, particularly of genes involved in lipid metabolism. The lipid profile of the livers of DR mice is correspondingly shifted towards lowered triglyceride content and shorter chain length of triglyceride-associated fatty acids, and these effects become more pronounced with age. Our results indicate that DR remodels genome-wide patterns of DNA methylation so that age-related changes are profoundly delayed, while changes at loci involved in lipid metabolism affect gene expression and the resulting lipid profile.
Arg72Pro <i>P53</i> gene polymorphism: Clinical relevance and relation with <i>P53</i> mutations in non-small cell lung cancer (NSCLC) patients
Authors: J. Jassem, A. Szymanowska, E. Jassem, A. Borg, K. Holm, R. Dziadziuszko, W. Rzyman, G. Kobierska-Gulida, J. Limon
Journal: Journal of Clinical Oncology (2004)

7158 Background: The aim of this study was to evaluate the clinical relevance of P53 gene codon 72 polymorphism (Arg72Pro) and its relation with P53 gene mutations in NSCLC patients (pts). Methods: Study group included 157 pts from the North Poland region (35 females and 122 males), aged from 34 to 78 years (mean 60) who underwent curative pulmonary resection between 1996 and 1998. Tumor types included squamous cell (95 pts), adenocarcinoma (41 pts), large cell carcinoma (9 pts), and mixed cell carcinoma (12 pts). Pathological TNM tumor stage distribution was as follows: I (70 pts), II (19 pts), IIIA (59 pts) and IIIB (9 pts). The control group matched for age and cigarette smoking consisted of 519 healthy subjects. P53 gene codon 72 polymorphism (Arg/Arg, Arg/Pro and Pro/Pro) was evaluated by PCR-RFLP and DHPLC methods. Results:The number of Pro allele vs Arg/Arg carriers was insignificantly higher in the NSCLC group than in controls (53.5% vs 46.2%, p=0.11). NSCLC odds ratio for the Pro allele carriers was 1.34 (95% CI: 0.94–1.91). In NSCLC patients polymorphic variants did not correlate with major clinical characteristics and survival. P53 mutations (evaluated by PCR/SSCP technique and sequencing) were found in 47 out of 157 tumor samples (29.9%). There was no correlation between P53 mutations and survival (p=0.87). The presence of Pro allele was associated with increased probability of P53 mutations (p=0.026). Conclusions:Arg72Pro P53 gene polymorphism may carry slightly increased risk of lung cancer and in NSCLC patients is strongly associated with ocurrence of P53 mutations. No significant financial relationships to disclose.
Patients with extramedullary manifestation of multiple myeloma: Prognostic factors and survival.
Authors: Agnieszka Anna Wieczorek, Derya Balci, Martin Schmidt-Hieber, Philipp Lohneis, Ulrike Heider, Antonio Pezzutto, Igor Wolfgang Blau
Journal: Journal of Clinical Oncology (2012)

e18552 Background: Multiple myeloma is a plasma cell dyscrasia that primarily involves bone marrow but also occurs in the soft tissues. While observing striking differences in clinical courses of patients with extramedullary plasmacytoma (EMP), solitary bone plasmacytoma (SBP), multifocal form of multiple myeloma (MFM) and multiple myeloma (MM), we wanted to assess prognostic factors and outcomes in those groups. This retrospective analysis was performed to evaluate response rate and overall survival (OS) of patients with extramedullary manifestations. Methods: We evaluated the data from 54 patients with MM (n=17), MFM (n=19), EMP (n=12) and SBP (n=6) treated at our institution from 1994-2012 and initially selected based on provided tissue samples. The MM control cohort was matched with regard to age, gender and prior treatment regimens. In 3 of 19 cases of MFM extramedullary locations were found at initial diagnosis. Two patients with EMP converted into MFM during the treatment. All EMP lesions arised in the upper aerodigestive tract. However extramedullary involvement in MFM was found in the head and neck (37%), chest (53%), abdomen (21%) and extremities (31%). Results: The 5-year OS rate was 92% in the patients with EMP. Whereas, 5-year OS rates of MM patients achieved 70.6%. MFM patients reached only 58% 5-year OS. The 5-year probability of progression was significantly higher in the group with MFM than EMP (89.5% vs 33%, p=0.0076, log rank test). Median progression free survival was 34 months for MM and 20 months for MFM (p=0.18). Conclusions: The 5-year progression free survival could be reached in 10 out of 12 patients with EMP. Two of the patients with primary EMP developed MFM. Moreover, the secondary development of extramedullary manifestation was associated with worse prognosis. Since the differences in the disease development cannot be easily predicted, there is an need of additional predictors that take into account different genetically determined risk status. Our retrospective analysis of genetic variations in this cohort of patients indicates the need of additional predictors in future randomized studies in these rare subtypes of MM.
Impact of Thrombolytic Therapy on the Long-Term Outcome of Intermediate-Risk Pulmonary Embolism
Authors: Stavros V. Konstantinides, Eric Vicaut, Thierry Danays, Cecilia Becattini, Laurent Bertoletti, Jan Beyer-Westendorf, Helene Bouvaist, Francis Couturaud, Claudia Dellas, Daniel Duerschmied, Klaus Empen, Emile Ferrari, Nazzareno Galiè, David Jiménez, Maciej Kostrubiec, Matija Kozak, Christian Kupatt, Irene M. Lang, Mareike Lankeit, Nicolas Meneveau, Massimiliano Palazzini, Piotr Pruszczyk, Matteo Rugolotto, Aldo Salvi, Olivier Sanchez, Sebastian Schellong, Bozena Sobkowicz, Guy Meyer
Journal: Journal of the American College of Cardiology (2017)
HIP1 expression and response to chemotherapy in breast cancer.
Authors: Mireia Margeli, Vanesa Quiroga, Eva Castella, Gustavo Tapia, Montserrat Sola, Maria Sanchez-Ronco, Joaquim Radua, Cristina Buges, Laia Espasa, Laia Capdevila, Miguel Angel Luna, Rosa Ballester, Javier Arce, Antonio Mariscal, Sara Vizcaya, Laia Vila, Alberto Indacochea, Agusti Barnadas, Rafael Rosell, Beatriz Cirauqui
Journal: Journal of Clinical Oncology (2014)

1046 Background: Huntingtin Interacting Protein 1 (HIP1) is a binding protein to inositol and clathrina that is related to neurodegeneration. Signaling of growth factors receptors trought clathrina is one of the mechanisms by which cells regulate the intracellular signaling. There have been observed high levels of HIP1 protein in breast, colon, kidney, lung, melanoma, ovarian and prostate cancer. Furthermore, HIP expression was negatively correlated with survival in prostate cancer. HIP1 overexpression has been shown to inhibit the degradation of EGFR and estrogen receptor. EGFR expression has been correlated with response to chemotherapy in triple negative breast cancer. Methods: Tumor biopsies were obtained from 83 breast cancer patients (p) treated with neoadjuvant chemotherapy, based on four cycles of fluorouracil, epirubicin and cyclophosphamide. Estrogen receptor, progesterone receptor, HER2, cytokeratin 5/6, vimentin and HIP1 were examined by tissue microarray. HER2 were also assessed by chromogenic in situ hybridization. We evaluated the prognostic and predictive value of HIP1 expression. Results: HIP1 was evaluated by immunohistochemistry in 83 p, being considered negative if the result was 0 or 1, and positive if it was 2 or 3. The result was 0 in 11 p (13.3%), 1 in 40 p (48.2%), 2 in 25 p (30.1%), and 3 in 7 p (8.4%). The value of huntingtin did not correlate with any of the clinical characteristics of the series, nor with ER, PR, vimentin, or HER2, nor subgroups. Negative HIP1 was correlated in the limit of significance to positive CK5 /6. Overexpression of HIP1 was correlated to higher pathologic response, as shown in table 1. HIP1 was not statistically correlated to DFS or OS, but p with overexpression of HIP1 had a median survival of 50 months whereas it was 67 months for p without overexpression of HIP1. Conclusions: HIP1 could be a prognostic and predictive factor in breast cancer. Showing that HIP1 is necessary for breast cancer progression and modulates key growth factor receptors involved in breast cancer, fuels the idea that HIP1 inhibition has therapeutic potential. HIP1 Pathological response Positive Negative P Responder (CR+PR) 23 (71.9%) 24 (47.1%) .04 No responder (ED+PD) 9 (28.1%) 27 (52.9%)
Serum iron levels as new predictive factor in FOLFOX/FOLFIRI with or without molecularly targeted drug therapy.
Authors: Takumi Ochiai, Kazuhiko Nishimura, Tomoo Watanabe, Masayuki Kitajima, Akinori Nakatani, Takashi Inou, Naoki Sakuyama, Marie Washio, Kennji Kishine, Tsuyoshi Sato, Takanori Ochi, Satoshi Okubo, Shunji Futagawa, Isao Nagaoka
Journal: Journal of Clinical Oncology (2012)

e14004 Background: An increase in serum iron levels after administration of various anticancer drugs was reported (Follezou et al, NEOPLASMA 1985). We have also reported an increase in serum iron levels during FOLFOX and FOLFIRI therapies (ASCO 2009: #e15110) and a correlation between prognosis and transition of serum iron levels in advanced colorectal cancer (CRC) patients (ASCO 2011: #e14141). The aim of this cohort study was to evaluate the correlation between prognosis and serum iron levels in advanced CRC patients treated with FOLFOX/FOLFIRI ± molecularly targeted drugs. Methods: Serum iron levels were measured before and at 48 hr after treatment (FOLFOX/FOLFIRI ± molecularly targeted drugs) in 69 advanced CRC patients, all of whom died between December 2005 and December 2011. No patients were treated with radiotherapy. Taking the median rate of increase in serum iron levels as the cut-off value in each therapy, the patients were categorized into cohort I (increase rate over cut-off value in at least one therapy) and cohort II (increase rate under the cut-off value in all therapies). Prognosis was evaluated between the two cohorts using the Kaplan-Meier method and the log rank test. Results: No significant bias in patient characteristics was observed between the two cohorts. Serum iron levels transiently increased after treatment (p&lt;0.001), then returning to baseline within 2 weeks. Median survival time (MST) in cohort I (n: 41) and cohort II (n: 28) was 430 and 377 days, respectively. The MST was significantly better in cohort I (p=0.0496). No significant differences were observed in the frequency of chemotherapies or number of patients treated with molecularly targeted drugs between the two cohorts. Conclusions: Cohort I showed a statistically significant better prognosis. The results suggest that serum iron levels could be used as a new predictive factor in FOLFOX/FOLFIRI ± molecularly targeted drug therapy. In Cohort II patients, molecularly targeted drugs should be used positively for further improvement in prognosis.
Automated quantitative analyses (AQUA) of cyclic-AMP-response-element-binding protein (CREB), phosphorylated CREB (pCREB), and ataxia-telangiectasia-mutated protein kinase (ATM) protein expression in patients (pts) undergoing thoracic radiation for locally advanced non-small cell lung cancer (NSCLC).
Authors: Bo H. Chao, Anne M. Traynor, David T Yang, Chong Zhang, Thomas Pier, KyungMann Kim, William M. Rehrauer, Donald Maurice Cannon, George M. Cannon, Tyler Bye, Randal S. Tibbetts
Journal: Journal of Clinical Oncology (2012)

e13537 Background: Increased protein expression of CREB, a DNA damage-regulated transcription factor, has been associated with poor survival in advanced NSCLC. We have demonstrated that exposure of cancer cell lines to low dose ionizing radiation (IR) increased pCREB on a Ser133 residue. However, exposure to high dose IR correlated with pCREB on Ser121 by ATM, a master regulator of the cellular DNA damage response. This unusual bimodal response of CREB to IR, reflected by activation at low doses and attenuation at high doses, suggested that CREB may control cell fate decisions in response to DNA damage. We hypothesized that patterns of protein expression of CREB, pCREB Ser133, and ATM would predict treatment response in pts who have undergone radiotherapy for locally advanced NSCLC. Methods: Diagnostic tumor specimens were obtained from pts who underwent thoracic radiation in a clinical trial for locally advanced NSCLC. Protein expression of CREB, pCREB Ser133, and ATM was assessed by AQUA. Wilcoxon rank sum test was used to assess differences in protein expression. Univariate regression was conducted to evaluate protein expression and clinical outcomes. Kruskal Wallis test was used to assess protein expression and pneumonitis. Results: Sufficient tumor tissue was available for 35 of 79 pts enrolled. Best responses in 6 months included 12% CR, 73% PR, 9% SD, and 6% PD. Pre-treatment protein expression per AQUA analyses of CREB, pCREB Ser133, and ATM were not statistically associated with time to in-field progression, time to out-of-field progression, time to distant metastasis, best response, pneumonitis, or overall survival. Unexpectedly, increased expression of pCREB Ser133 was associated with durable anti-tumor response to radiation at a median duration of 14.6 months (p=0.03). Conclusions: Protein expression per AQUA of CREB, pCREB Ser133, and ATM did not confirm our hypotheses, possibly related to our limited sample size. Further analysis of the role of CREB in response to IR in cancer pts is ongoing.