tbuckley/cabot-search huggingface dataset:
Differential expression of microRNAs induced by trastuzumab emtansine (T-DM1) during megakaryocytopoiesis.
Authors: Hirdesh Uppal, Kaushiki Mahapatra, Sock-Cheng Lewin-Koh, Steven Olsen, Mark X. Sliwkowski, Sandhya Girish, Dylan Hartley, Donna Dambach, Vanitha Ramakrishnan
Journal: Journal of Clinical Oncology (2013)

645 Background: Treatment with the HER2-targeted antibody–drug conjugate T-DM1 resulted in significantly longer PFS and OS vs lapatinib + capecitabine in patients previously treated with trastuzumab and a taxane in the phase 3 study EMILIA. Thrombocytopenia (TCP) was the dose-limiting toxicity for patients treated with T-DM1, although platelets do not express HER2. In EMILIA, grade 3/4 TCP was observed in 12.9% of T-DM1-treated patients. We have previously shown that T-DM1 inhibits megakaryocyte (Mk) production and differentiation. Here, we investigated the effect of T-DM1 on microRNAs (miRNAs) associated with megakaryocytopoiesis. Methods: Human stem cells (HSCs; CD133+/CD34+) from 8 donors were differentiated into Mks in the presence of T-DM1, trastuzumab, or vehicle. Total RNA was extracted using the miRNeasy MiniKit. cDNA was prepared using the Taqman miRNA RT Kit, FAM-MGB probes, and stem-loop RT primer pool set. miRNA expression was measured using the 96.96 Dynamic Array Chip on the Biomark HD Reader. Data were analyzed using Fluidigm real-time analysis software Spotfire 5, and SAS 9.2. hsa−let−7g and hsa−miR−671−3p were chosen as reference miRNAs due to their low variation between treatments and time points. Median normalization was also applied. Results: A total of 526 miRNA RT-qPCR assays were used to map miRNA expression during differentiation of HSCs from 8 separate donors to Mks in vitro over 30 days. Several miRNAs demonstrated temporal changes in their expression profiles during maturation, suggesting these miRNAs are potential drivers of Mk differentiation. T-DM1 treatment inhibited Mk production and differentiation. Concomitant modifications in the expression of specific miRNAs were observed. These modifications were not present in trastuzumab- or vehicle-treated cells, suggesting these miRNAs may be involved in the development of T-DM1–induced TCP. Conclusions: These results suggest that the miRNAs have the potential to be used as biomarkers for TCP in patients treated with T-DM1 and possibly other DM1 conjugates. Specific miRNA alterations related to T-DM1 treatment will be discussed following investigations using clinical samples to validate these preliminary data.
Evaluation of cyclophosphamide as an immune enhancer for the NY-ESO-1/ISCOMATRIX vaccine in patients with metastatic melanoma.
Authors: Oliver Klein, Ian D. Davis, Grant A. McArthur, Andrew Mark Haydon, Phillip Parente, Nektaria Dimopoulos, Heather Jackson, Eugene Maraskovsky, Wendie Hopkins, Rodica Stan, Weisan Chen, Jonathan S. Cebon
Journal: Journal of Clinical Oncology (2013)

3093^ Background: We have previously demonstrated potent immunogenicity of the NY-ESO-1/ISCOMATRIX vaccine in patients with resected melanoma; however the same vaccine induced only a few vaccine antigen specific immune responses in patients with advanced disease. Therefore, we have enrolled a second cohort of patients with advanced melanoma in the clinical trial LUD2002-013 to investigate whether pre-treatment with the immune-modulator cyclophosphamide could improve the immunogenicity of the NY-ESO-1/ISCOMATRIX vaccine. Methods: LUD2002-013 was an open-label phase II study intended to evaluate the safety and immunogenicity of the NY-ESO-1/ISCOMATRIX vaccine in patients with advanced melanoma. The first cohort of patients received vaccine alone; a second cohort with 19 patients was added after evaluation of responses in Cohort 1 and received vaccine in combination with low-dose cyclophosphamide. Patients received 3 injections of NY-ESO-1 ISCOMATRIX preceded, in Cohort 2, by cyclophosphamide at a dose of 300 mg/m 2 every four weeks. Assessment of clinical and immunological responses was undertaken at week 11. Results: Fifteen patients of Cohort 2 completed at least one cycle of vaccination. No objective responses were observed with three patients having stable disease for more than three months. The inclusion of cyclophosphamide into the vaccination protocol did not lead to any significant toxicity. Seven of fourteen patients in Cohort 2 developed a vaccine induced NY-ESO-1 specific CD4 T cell response, a significant increase compared to cohort 1 (p=0.019). No differences were observed in the frequency of vaccine induced antibody or CD8 T cell responses. No change in the frequency of peripheral blood regulatory T cells or myeloid derived suppressor cells was detected. Conclusions: The administration of low dose cyclophosphamide has significantly increased the NY-ESO-1 specific CD4 T cell response of the NY-ESO-1/ISCOMATRIX vaccine in patients with metastatic melanoma. Given the emerging importance of CD4 T cells in tumour regression, the present findings warrant further clinical exploration of combining cyclophosphamide with vaccines and other immune-modulatory agents. Clinical trial information: NCT00518206.
ECOG performance status as a predictor of adjuvant chemotherapy (AC) toxicities in stage III colorectal cancer (CRC) patients.
Authors: Akie Watanabe, Charlie Yang, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2017)

789 Background: Toxicities acquired from AC can greatly impact quality of life. ECOG performance status is a clinical factor that is frequently considered in AC treatment decision-making, but its associations with common toxicity outcomes remain unclear. Methods: We reviewed a cohort of 371 CRC patients treated with adjuvant monotherapy (Capecitabine) or combination therapy (FOLFOX or CAPOX) within 12 weeks of curative resection at the British Columbia Cancer Agency, and determined the associations between ECOG (0, 1, ≥ 2) and toxicity outcomes. We also categorized toxicities into early, intermediate, or late based on their time of onset. Results: Among 371 patients, median age was 65 years, 52% were men, and 45%, 41%, and 14% were ECOG 0, 1, and ≥ 2, respectively. In this cohort, 41% received monotherapy and 59% received combination therapy. There was a trend of decreased toxicity for specific side effects, such as nausea, vomiting, and diarrhea, with each additional treatment cycle. For monotherapy, ECOG was found on univariate analyses to be associated with several toxicities including early onset hand foot syndrome and early onset anemia (both P &lt; 0.05). When compared to ECOG 0, multivariate analyses showed that patients with worse ECOG were more likely to develop early hematological toxicities (ECOG 1, OR 2.75, 95% CI 1.01-7.49, P= 0.04; ECOG ≥ 2, OR 4.38, 95% CI 1.24-15.49, P= 0.02). ECOG ≥ 2 patients also had higher odds of experiencing late hematological toxicities (OR 4.52, 95% CI 1.05-19.52, P= 0.04) and neuropathy (OR 5.73, 95% CI 1.25-26.14, P= 0.02). In univariate analyses of combination therapy, ECOG was associated with early gastrointestinal and late hematologic toxicities (both P &lt; 0.05). On multivariate analyses, however, ECOG was predictive of only early hematologic toxicities (ECOG 1, OR 2.13, 95% CI 1.05-4.32, P= 0.04; ECOG ≥ 2, OR 3.85, 95% CI 1.18-12.6, P= 0.03). Further analyses did not show any consistent correlations between ECOG and other toxicity outcomes. Conclusions: Although specific toxicities appear to decrease with each successive cycle of AC, poor ECOG is associated with an increased likelihood of certain side effects that can further inform AC discussions.
A novel melittin nano-liposome exerted excellent anti-hepatocellular carcinoma efficacy with better biological safety
Authors: Jie Mao, Shujun Liu, Min Ai, Zhuo Wang, Duowei Wang, Xianjing Li, Kaiyong Hu, Xinghua Gao, Yong Yang
Journal: Journal of Hematology & Oncology (2017)

Abstract Melittin is the main effective component of bee venom and has extensive biological functions; however, serious side effects have restricted its clinical application. Preclinical and clinical studies showed that the main adverse events were allergic reaction and pain at the administration site. To decrease the toxicity, we prepared melittin nano-liposomes by encapsulating melittin with poloxamer 188 and explored the inhibitory activities on liver cancer together with biological safety. Here, we showed that melittin nano-liposomes significantly inhibited the survival of hepatocellular carcinoma (HCC) cells in vitro and prominently suppressed the growth of subcutaneous and orthotopic HCC transplantation tumors in vivo. It was important that it induced less inflammation and allergy in mice compared with melittin. Overall, melittin nano-liposomes would have a better application in HCC therapy due to its significant anti-tumor activity and better biological safety.
Presidential Immigration Policies
Authors: Lawrence O. Gostin, Katharina Eva Ó Cathaoir
Journal: JAMA (2017)

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Short and long-term effects of two different surgery approaches for remnant gastric cancer.
Authors: Lin Chen, Yingkun Ren, Yajie Zheng
Journal: Journal of Clinical Oncology (2017)

180 Background: To evaluate the short- and long-term effects of two different surgery approaches for remnant gastric cancer after distal gastrectomy. Methods: Clinical data of 48 remnant gastric cancer patients were collected retrospectively from the period of January 1 st 2010 to December 31 st 2012 in this matched-pair study. Twenty four patients in the experimental group underwent radical surgery in antegrade approach (starting from the esophagus to the gastrointestinal anastomosis), another 24 matched patients in the control group underwent radical surgery in retrograde approach (starting from the gastrointestinal anastomosis to the esophagus). Constants in the study were patient age, the operating surgeon, Borrmann type, TNM stage and operation range. Pearsonχ 2 testor t-test were used to compare the clinicopathological characteristics between the two groups. Survival rates of 1- and 3-years were analyzed with Kaplan-Meier survival curve and compared with Log-rank test. Results: The 48 patients were treated successfully without any mortality during their hospital stay. The mean operative time and bleeding volume in the experimental and control groups were (126.6±5.7) min and (154.1±23.9)ml , and (168.3±11.7) min and (180.8±15.0)ml respectively. The difference in the mean operative times (t = -3.089, P = 0.005) and the mean bleeding volumes (t = -3.269, P = 0.004) were statistically significant. The average hospital stay after surgery and the average number of lymph nodes resected were (9.5±0.9) days and 18.7±1.6 in the experimental group,(9.2±0.8) day and 17.4±1.4 in the control group. There was no statistical differences between the two groups in terms of the average hospital stay (t = 0.692, P = 0.496) and the average number of resected lymph nodes (t = 2.101, P = 0.247). The overall 1- year and 3-years survival rates were 75%, 49% in the experimental group and 67%, 35% in the control group. There was also no statistical difference in the 1-year (P = 0.745) and 3-years (P = 0.878) survival rates. Conclusions: Compared with retrograde approach, performing radical surgery in antegrade way for remnant gastric cancer patients can shorten the operation time, reduce blood loss and simplify the operation procedure.
Association of Pre-chemotherapy neutrophil-to-lymphocyte ratio with overall survival in underserved pancreatic cancer.
Authors: Hussein Hamad, Muhammad Umair Mushtaq, Ankit Mangla, Michael Russell Mullane
Journal: Journal of Clinical Oncology (2015)

e15241 Background: Inflammatory response in tumor microenvironment plays a critical role in cancer progression. The study explored association of pre-chemotherapy neutrophil-lymphocyte ratio (NLR) and other correlates with overall survival (OS) in underserved pancreatic cancer patients. Methods: A retrospective review of 168 patients diagnosed with pancreatic cancer (2005-2014) was conducted at Cook County Hospital, Chicago. 92 patients who received chemotherapy were included in the final analysis. Socio-demographic, clinical and pathologic factors were recorded at the time of diagnosis. Univariate and multivariate cox regression analyses were conducted to correlate factors with OS. Crude (HR) and adjusted (aHR) hazard ratios with 95% confidence intervals (CI) were obtained. Results: The study included 49% Afro-Americans, 22% Caucasians and 20% Hispanics. Median age was 58.5 years and 54% were males. Past history was significant for hypertension (48%), diabetes (37.5%), smoking (49%) and alcohol abuse (47%). Stage 4 cancer was seen in 60% patients and 63% had tumor located in the head of pancreas. Median OS was 9 months (95% CI 7.5-10.5). Median NLR was 3. The patients in the study group received radiation therapy (RT) (59%), surgical resection (29%) and palliative reduction (20%). Significant correlates of improved OS included stage 1-2 cancer as compared to stage 4 cancer (HR 0.33, 95% CI 0.16-0.65, P = 0.001), RT (HR 0.50, 95% CI 0.29-0.86) and surgical resection (0.29, 95% CI 0.15-0.55, P < 0.001). Correlates with poor OS included high leukocyte count (HR 1.11, 95% CI 1.01-1.21, P = 0.024), high neutrophil count (HR 1.15, 95% CI 1.03-1.27, P = 0.010), high monocyte count (HR 2.19, 95% CI 1.02-4.69, P = 0.044), and NLR above the median 3.0 (HR 1.98, 95% CI 1.21-3.27, P = 0.007), In multivariate model, high NLR (aHR 2.19, 95% CI 1.01-4.76, P = 0.047) predicted poor OS and surgical resection predicted better OS (aHR0.38, 95% CI 0.17-0.87, P = 0.022). Median OS in patients with high NLR was 8 (95% CI 4.9-11.1) months versus 15 (95% CI 5.6-24.4) months in those with low NLR (P = 0.005). Conclusions: High pre-chemotherapy NLR independently predicted poor prognosis in underserved pancreatic cancer patients.
Evaluating the effect of therapy duration on survival in patients with metastatic castration-resistant prostate cancer receiving radium-223.
Authors: Noelle L. Williams, Kamila Nowak-Choi, Jenna Skowronski, Tu Dan, Harriet Belding Eldredge, Jean H. Hoffman-Censits, Jianqing Lin, William Kevin Kelly, Leonard G. Gomella, Costas D. Lallas, Edouard John Trabulsi, Mark Hurwitz, Adam Dicker, Benjamin E. Leiby, Nooreen Dabbish, Robert B. Den
Journal: Journal of Clinical Oncology (2017)

e593 Background: The use of radium-223 in patients with metastatic castration-resistant prostate cancer (mCRPC) improves overall survival (OS) and quality of life. Combination of radium-223 with second-generation anti-androgens has further improved OS; however, the optimal length of radium-223 treatment for maximal effect remains unknown. Methods: We reviewed 35 consecutive patients with mCRPC who received radium-223 from December 2012 to August 2015 at Thomas Jefferson University. Patients were divided into two groups: those who received full treatment of 6 injections (n = 18) versus those who received less than 6 injections (n = 17). Kaplan-Meier analysis of OS were tested for difference by treatment group using Log Rank test. Univariable association with survival outcomes was calculated with univariable Cox regression and Log Rank tests. Results: Mean age was 73 ± 10 years and Karnofsky performance status (KPS) ranged from 50-90 (median, 80). Median follow-up was 13.9 months. Eighteen patients were receiving concurrent second generation anti-androgens at the start of treatment. Median OS was 12 months for patients who received 6 injections and 6.48 months for patients who received less than 6 injections (p = 0.0045). The results of univariate Cox regression analysis revealed full treatment was associated with increased OS (p = 0.0013). On multivariate analysis accounting for KPS, full treatment was significantly associated with improved OS (p = 0.0028). Conclusions: In this retrospective, single-institution analysis, we demonstrated that full course completion of radium-223 was associated with improved OS in patients with mCRPC. These patients should be optimally supported during treatment to allow for therapy completion.
Phase 1 study of the angiopoietin 1/2 neutralizing peptibody, trebananib, in acute myeloid leukemia.
Authors: Eunice S. Wang, Gerald J. Fetterly, Laura Pitzonka, William E. Brady, Wei Tan, Jessica Greene, Deborah Munster, Carlos Vigil, Jason Harold Mendler, Michael W Becker, Kristen Marie Carr-O'Dwyer, Meir Wetzler, Jane Liesveld
Journal: Journal of Clinical Oncology (2014)

7082 Background: Angiopoietins (Ang-1/2), pro-angiogenic factors binding to the Tie2 receptor on endothelial cells, have been implicated in the pathogenesis of acute myeloid leukemia (AML). Trebananib is a first-in-class neutralizing peptibody that potently inhibits Ang-1/2 by sequestering these factors and preventing their interaction with Tie2. Methods: We performed a phase 1b trial evaluating the safety, tolerability, pharmacokinetics (PK) and biologic effects of trebananib in AML patients (pts). Drug was administered at 2 doses (15 and 30 mg/kg) via weekly IV infusion over 1 hour alone (arm A) or in combination with low dose cytarabine (arm B). PK samples were collected at end of infusion (EOI), and 1-3, 4-6, 72, and 168 hrs after EOI on days 1 and 22. Plasma angiogenic factors were assessed by multiplex flow cytometry prior to first dose, on cycle 1 day 29, and at the end of study. Results: Twenty-four pts were enrolled. Median age was 74 years (range 29-84). Sixteen (67%) were male. Six had de novo, 13 had refractory, and 5 had relapsed AML. Three pts had undergone prior transplantation. Drug was generally well tolerated. Dose-limiting toxicities included mucositis (1, arm A, 15 mg/kg) and ataxia (1, arm B, 30 mg/kg). The most common AEs were fatigue, dyspnea, nausea, asthenia, anorexia, and edema. Serious AEs included thrombocytopenia (2), nephrolithiasis (1), and ataxia (1). Using a population PK approach, a 3-compartment model adequately characterized trebananib PK, with a mean clearance (CL) and plasma volume (V) estimated to be 0.09 L/hr and 2.74 L/kg, respectively. A trend existed between body surface area (BSA) and CL and V, suggesting that BSA in part explains the inter-patient variability in pts. No neutralizing antibodies were found. Seven pts had elevated plasma Ang-2 levels of unknown significance. Other factors (VEGF-A/C/D, IL-8, G-CSF, HGF, FGF-1/2, PlGF) were not altered. One pt (15 mg/kg) had a partial response, and 4 pts had stable disease over >1 cycle (2 on each arm, 3 receiving 30 mg/kg). Conclusions: Trebananib was well tolerated in AML pts alone and in combination with low dose cytarabine. Drug PK was similar to solid tumor pts. Limited clinical efficacy was seen, supporting novel combination strategies. Clinical trial information: NCT01555268, NCI-2011-02979.
Primary glioblastoma cell lines as source for analysis of the relationship between molecular phenotype and in-vitro drug sensitivity.
Authors: Carl Friedrich Classen, Christina S Mullins, Julia Schubert, Piek Jürgen, Michael Linnebacher, Björn Schneider
Journal: Journal of Clinical Oncology (2013)

e13053 Background: Glioblastoma multiforma (GBM) still has a very poor prognosis even with today’s multimodal combination therapy of resection followed by radio-chemotherapy with temozolomide. Both new molecular inhibitors and immunotherapy may represent future therapeutical tools but due to the variability of the molecular composition in individual GBM, they probably depend on better response prediction. Methods: Based on a close cooperation and logistics between surgery, pathology, laboratory researchers and animal care facilities, we established and analysed cell lines of about 30 primary brain tumors, most of them GBM. Tumors and cell lines were characterised by morphology, growth behaviour, numerous extra- and intracellular antigens, and particularly regarding molecular features. Further, tumors were established in a subcutaneous xenograft mouse model, and growth characteristics were described. These in vitro and in vivo models represent an ideal tool for response analysis of single agent or combined treatment in early cell passages in order to predict response. Besides, relevant antigens and possible shifts of antigen-presentation in tumors can be assessed. Numerous analyses using established and new antitumor compounds – e.g. the integrin inhibitor cilengitide – were performed. Results: We found that although the specific integrin expression is individually different in the tumors analysed, cilengitide sensitivity was similar in most. Addition of temozolomide led to additional, yet not over-additive cytotoxicity. In our panel of GBM specimens we found a very heterogenous pattern of molecular alterations, going along with variations of drug sensitivity. Conclusions: This indicates that, in the future field of individualized approaches, such models are required, in order to enable future strategies to predict the efficacy of immunological, small molecular, biological-based, cytotoxic or other therapeutic strategies. The project was supported by the Förderkreis für krebskranke Kinder Rostock e.V., by a Mecklenburg-Vorpommern graduate scholarship, and by a cooperation with Merck-Serono Research and Development (gift of drug).