tbuckley/cabot-search huggingface dataset:
Aspirin use and mortality in men with localised prostate cancer: A cohort study.
Authors: Evelyn M Flahavan, Kathleen Bennett, Linda Sharp, Thomas Ian Barron
Journal: Journal of Clinical Oncology (2013)

5084 Background: Cyclooxygenase-2 (COX-2) expression in prostate cancer has been associated with high grade tumours and poorer prognosis. Use of aspirin, a COX-2 inhibitor, has been associated with reduced prostate cancer mortality in some studies. These studies have not, however, provided information on the dose and timing of aspirin use. Methods: National Cancer Registry Ireland data was used to identify men with stage I-III prostate cancer (ICD10 C61) diagnosed 2001-2006. Aspirin use in the year preceding prostate cancer diagnosis was identified from linked prescription refill data (General Medical Services) and stratified by dose (low ≤75mg, high &gt;75mg) and dosing intensity (proportion of days in that year with aspirin supply available). Cox proportional hazards models, adjusted for age, smoking status, year of incidence, comorbidity score, Gleason score, tumour size, pre-diagnostic statin use, and receipt of radiation (time varying) were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between aspirin use and all-cause and prostate cancer-specific mortality. Interactions with tumour characteristics were examined. Results: 2,936 men with stage I-III prostate cancer were identified (aspirin users, N=1,131; 38.5%). Median patient follow-up was 5.5 years. In multivariate analyses, aspirin use was not associated with a significant reduction in prostate cancer-specific (HR 0.90, 95% CI 0.68-1.20) or all-cause mortality (HR 0.98, 95% CI 0.84-1.15). In dose response analyses aspirin use was associated with a significantly lower risk of prostate cancer-specific mortality in men receiving &gt;75mg of aspirin (HR 0.59, 95% CI 0.35-1.00, p=0.048) but not ≤75mg aspirin (HR 1.01, 95% CI 0.75-1.37, p=0.938). Stronger associations were also observed in men with higher aspirin dosing intensity or a Gleason score &gt;7. Conclusions: Pre-diagnostic aspirin use, measured using objective prescription refill data, was associated with a significant reduction in prostate cancer-specific mortality in men with stage I-III prostate cancer receiving &gt;75mg of aspirin. These results confirm previous findings, and provide important new information regarding the dose of aspirin associated with survival benefit.
Toll-like receptor 8 agonist nanoparticles mimic immunomodulating effects of the live BCG vaccine and enhance neonatal innate and adaptive immune responses
Authors: David J. Dowling, Evan A. Scott, Annette Scheid, Ilana Bergelson, Sweta Joshi, Carlo Pietrasanta, Spencer Brightman, Guzman Sanchez-Schmitz, Simon D. Van Haren, Jana Ninković, Dina Kats, Cristiana Guiducci, Alexandre de Titta, Daniel K. Bonner, Sachiko Hirosue, Melody A. Swartz, Jeffrey A. Hubbell, Ofer Levy
Journal: Journal of Allergy and Clinical Immunology (2017)

Newborns display distinct immune responses, leaving them vulnerable to infections and impairing immunization. Targeting newborn dendritic cells (DCs), which integrate vaccine signals into adaptive immune responses, might enable development of age-specific vaccine formulations to overcome suboptimal immunization.Small-molecule imidazoquinoline Toll-like receptor (TLR) 8 agonists robustly activate newborn DCs but can result in reactogenicity when delivered in soluble form. We used rational engineering and age- and species-specific modeling to construct and characterize polymer nanocarriers encapsulating a TLR8 agonist, allowing direct intracellular release after selective uptake by DCs.Chemically similar but morphologically distinct nanocarriers comprised of amphiphilic block copolymers were engineered for targeted uptake by murine DCs in vivo, and a range of TLR8 agonist-encapsulating polymersome formulations were then synthesized. Novel 96-well in vitro assays using neonatal human monocyte-derived DCs and humanized TLR8 mouse bone marrow-derived DCs enabled benchmarking of the TLR8 agonist-encapsulating polymersome formulations against conventional adjuvants and licensed vaccines, including live attenuated BCG vaccine. Immunogenicity of the TLR8 agonist adjuvanted antigen 85B (Ag85B)/peptide 25-loaded BCG-mimicking nanoparticle formulation was evaluated in vivo by using humanized TLR8 neonatal mice.Although alum-adjuvanted vaccines induced modest costimulatory molecule expression, limited TH-polarizing cytokine production, and significant cell death, BCG induced a robust adult-like maturation profile of neonatal DCs. Remarkably, TLR8 agonist polymersomes induced not only newborn DC maturation profiles similar to those induced by BCG but also stronger IL-12p70 production. On subcutaneous injection to neonatal mice, the TLR8 agonist-adjuvanted Ag85B peptide 25 formulation was comparable with BCG in inducing Ag85B-specific CD4+ T-cell numbers.TLR8 agonist-encapsulating polymersomes hold substantial potential for early-life immunization against intracellular pathogens. Overall, our study represents a novel approach for rational design of early-life vaccines.
Neratinib after adjuvant chemotherapy and trastuzumab in HER2-positive early breast cancer: Primary analysis at 2 years of a phase 3, randomized, placebo-controlled trial (ExteNET).
Authors: Arlene Chan, Suzette Delaloge, Frankie Ann Holmes, Beverly Moy, Hiroji Iwata, Vernon J. Harvey, Nicholas J. Robert, Tajana Silovski, Erhan Gokmen, Gunter Von Minckwitz, Bent Ejlertsen, Stephen K. L. Chia, Janine Mansi, Carlos H. Barrios, Michael Gnant, Alvin Wong, Richard Bryce, Bin Yao, Miguel Martin
Journal: Journal of Clinical Oncology (2015)

508 Background: Neratinib (N) is an irreversible pan-HER tyrosine kinase inhibitor with clinical efficacy in trastuzumab (T) pre-treated HER2-positive (HER2+) metastatic breast cancer. In HER2+ early breast cancer (EBC), a significant proportion of patients (pts) recur with invasive disease despite T-containing adjuvant therapy. Methods: Women with stage 1–3c EBC with the last T dose ≤2y (later modified to stage 2–3c and ≤1y, respectively) and locally confirmed HER2+ were eligible. Pts were randomized to N 240mg PO once daily or placebo (P) for 12m, stratified by ER/PR, nodal status and T schedule. A global amendment reduced follow-up to 2y from study entry. A current amendment restores the original 5-y follow-up. Invasive DFS (IDFS) at 2y is the primary endpoint and other secondary endpoints include DFS + DCIS, distant DFS (DDFS), CNS incidence, and patient-reported outcomes. Overall survival (OS) is an event-driven secondary endpoint. Efficacy analyses were ITT using a stratified Cox model and log-rank test (1-sided α=0.025). Results: 2,821 pts were randomized between 07/2009 and 10/2011 (1,409 N; 1,412 P). Median time from last T was 4.4m N vs 4.7m P. Baseline characteristics were balanced between arms. Efficacy results are shown below. Pre-planned subset analyses showed a lower IDFS HR in ER/PR+ pts (n=1,616; HR=0.51 [0.33–0.77]) and in a centrally confirmed HER2+ cohort (HR=0.52 [0.34–0.79]). Diarrhea was the most common adverse event (AE) for N pts with 40% G3 (1pt G4). Other individual AEs ≥G3 occurred in < 4% N pts. Ejection fraction decrease ≥G2 was seen in 1.3% N vs 1.1% P pts. Mean relative dose intensity (RDI) was 88% in N vs 98% in P pts. Conclusions: ExteNET demonstrates that 12m of N following standard chemotherapy + T improves IDFS and DFS-DCIS at 2y in HER2+ EBC. Diarrhea, the most common AE, was manageable. Additional follow-up will allow assessment of 5-y IDFS and OS. ClinicalTrials.gov: NCT00878709. Clinical trial information: NCT00878709. Efficacy endpoint 2-y rate, % HR (95% CI) P-value (1-sided) stratified log rank N (n=1,409) P (n=1,412) IDFS 93.9 91.6 0.67 (0.50–0.91) 0.0046 DFS-DCIS 93.9 91.0 0.63 (0.46–0.84) 0.0009 DDFS 95.1 93.7 0.75 (0.53–1.05) 0.0447
Management of breast cancer during pregnancy: Results of a large registry from a single institution.
Authors: Fedro Peccatori, Maria Anna Sarno, Hatem Abdel Azim, Oreste Davide Gentilini, Viviana Galimberti, Stefano Martella, Giancarlo Pruneri, Giuseppe Renne, Giovanna Scarfone, Monica Fumagalli, Claudia Sangalli, Marzia Adelia Locatelli, Nicole Rotmensz, Matteo Lambertini, Marco Colleoni, Aron Goldhirsch
Journal: Journal of Clinical Oncology (2013)

589 Background: Given the rising trend of delaying pregnancy to later in life, more women are diagnosed with breast cancer during pregnancy. Management is still controversial and relies on expert guidelines. Thus the experience of single centres with high patients’ volume remains of interest. Methods: All breast cancer patients (pts) diagnosed at the European Institute of Oncology (IEO) in Milan were included in a specific registry since 1995. Results: Out of 8340 patients &lt; 47 y/o registered up to Dec 2012, 167 were diagnosed during pregnancy (2%). Median age was 36 years (24-47y). Median gestational age was 18 weeks (1-38 w). 73 % pts had a pT1-2 tumor, with positive nodes in 48%. 9,6% had luminal A, 38% luminal B, 26% basal like and 16% HER2+ tumors, according to St Gallen criteria. 29/167 pts (17%) opted for an induced abortion. Of the remaining 97 pts, 81 (84%) underwent definitive surgery during pregnancy; 58 (72%) and 23 pts (28%) had quadrantectomy and mastectomy, respectively. Immediate breast reconstruction was performed in 13 cases. Sentinel node procedure (SLN) was performed in 42 pts (52%), with positive axilla in 10 pts. 41 pts (51%) received chemotherapy during pregnancy. Regimens included weekly epirubicin (24 pts), EC/AC (12 pts), FAC/FEC (3 pts), q21 epirubicin (2 pts). No G3-G4 toxicities were reported. No pregnancy complications were observed, with the exception of 1 case of premature delivery at 28 weeks. Median gestational age at delivery was 36 weeks (29-40 w). No major malformations were observed. Gestational age at birth and birth-weight were similar in babies who received chemotherapy in-utero (36 w and 2555g) and in babies who did not receive gestational chemotherapy (37w and 2600g). At a median follow-up of 42 months (range: 1-178 m), all children had normal neurological and physical development with no late adverse effects observed. Conclusions: Managing breast cancer during pregnancy should follow standard practice as in non-pregnant pts. Surgeries like SLN and breast reconstruction were performed with no serious complications. Our results further emphasize the safety of anthracycline-based gestational chemotherapy without major effects on pregnancy course or fetal health.
Comparison of quantitative methods of assessing the hepatic burden of disease as predictors of overall survival at the initial diagnosis of stage IV colorectal cancer.
Authors: Michael Hayden Rosenthal, Stephanie Anne Holler Howard, Kyung Won Kim, Jeffrey A. Meyerhardt, Charles S. Fuchs, Nikhil H. Ramaiya
Journal: Journal of Clinical Oncology (2014)

3630 Background: The metastatic tumor burden in the liver may be related to prognosis in patients with stage 4 colorectal cancer, but it is unclear if standard measurement techniques such as those used in the Response Evaluation Criteria for Solid Tumors (RECIST) will capture that prognostic information. Counting all liver lesions >= 1cm in size could offer a feasible alternative for whole-liver disease assessment. Methods: In this IRB-approved, HIPAA-compliant retrospective study, two board-certified radiologists independently reviewed the baseline imaging studies of 60 subjects with treatment-naïve stage 4 colorectal cancer. The hepatic tumor burden was assessed in two ways: by measuring the longest dimensions of the five largest measurable liver lesions, and by counting the number of lesions measuring at least 1 cm in size. Overall survival was assessed from diagnosis to death or censoring via the electronic medical record, which also references the social security death master file. No subject was lost to follow-up over a median of 1233 days. The sum of the longest dimensions of the five largest liver lesions (SLD5, in cm; RECIST 1.0 standard), the sum of the longest dimensions of the two largest liver lesions (SLD2, in cm; RECIST 1.1 standard), and the count of lesions measuring at least 1 cm in size were assessed as continuous predictors of overall survival using both univariate and multivariate Cox proportional hazards models. Results: Univariate analyses showed hazard rate ratios of 1.02 (CI 0.99-1.05), 1.01 (0.95-1.07), and 1.02 (CI 1.01 – 1.04) per unit change for the SLD5, SLD2, and count metrics, respectively (p=0.33, p=0.77, and p=<0.001). The multivariate model showed that only the count of liver lesions remained an independent predictor of survival with a hazard rate ratio of 1.02 per unit change (CI 1.01 – 1.04, p<0.001). Conclusions: In this cohort, the whole-liver count of lesions larger than 1 cm is superior to the RECIST 1.0 and 1.1 baseline assessments of sums of longest dimensions as a predictor of overall survival at the initial diagnosis of stage 4 colorectal cancer. Further research is necessary to validate this result in a larger cohort.
ATRA, Arsenic Trioxide (ATO), and Gemtuzumab Ozogamicin (GO) Is Safe and Highly Effective in Patients with Previously Untreated High-Risk Acute Promyelocytic Leukemia (APL): Final Results of the SWOG/Alliance/ECOG S0535 Trial
Authors: Jeffrey E. Lancet, Anna Moseley, Rami S Komrokji, Steven E. Coutre, Daniel J. DeAngelo, Martin S. Tallman, Mark Litzow, Megan Othus, Frederick R Appelbaum
Journal: Blood (2016)
A phase I first-in-human study of REGN910 (SAR307746), a fully human and selective angiopoietin-2 (Ang2) monoclonal antibody (MAb), in patients with advanced solid tumor malignancies.
Authors: Kyriakos P. Papadopoulos, Solmaz Sahebjam, Robin Katie Kelley, Anthony W. Tolcher, Albiruni R.A. Razak, Amita Patnaik, Philippe L. Bedard, Rebecca Arcos, Lieve Adriaens, Carrie M. Brownstein, Israel Lowy, Bo Gao, A Thomas DiCioccio, Pamela Trail, Lillian L. Siu
Journal: Journal of Clinical Oncology (2013)

2517 Background: REGN910 is a selective, fully human Ang2 MAb that potently blocks signaling through the Tie2 receptor regulating tumor angiogenesis and growth. In multiple mouse xenograft models of human solid tumors, REGN910 inhibits tumor growth. Methods: This first-in-human phase I study (3+3 design) explored the safety, recommended phase II dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of REGN910 as a single agent. REGN910 was given IV at escalating doses. At RP2D, expansion cohorts were initiated to confirm safety and assess anti-tumor activity in about 20 patients (pts). Results: 37 pts [17M/20F; median age 57 (range 22-82); ECOG PS 0(9)/1(28)] were enrolled. Twenty-three (23) pts were enrolled in the dose escalation cohorts. No DLTs were reported, and a MTD was not reached. Most common G1/2 treatment-related adverse events (TRAEs) were fatigue 7(19%), peripheral edema 6(17%), diarrhea 5(14%), abdominal distension 4(11%), and decreased appetite 4(11%). There were no ≥ Grade 3 TRAEs. A confirmed sustained PR (16 wks) was observed in 1 pt with adrenocortical cancer treated at 1 mg/kg. SD (range 6.9-46.8 wks) was reported for 17 of 32 (53%) pts evaluable for efficacy. Fourteen pts received treatment &gt;16 wks. One pt with thyroid cancer had SD for 46 wks, and 1 pt with hepatocellular cancer had SD for 16 wks with ≥50% decline in alpha-fetoprotein. Across all dose levels, REGN910 pharmacokinetics appeared linear and dose-proportional. The PK profile was characterized by an initial distribution and a single mono-exponential elimination phase. Total circulating serum Ang2 levels appeared saturated following treatment in all cohorts, indicating systemic target engagement at all doses tested. Conclusions: Administration of REGN910 in patients with advanced cancer is well tolerated, with generally mild and moderate TRAEs. Dose escalation is completed, and enrollment to the expansion cohorts continues. The safety profile supports combination with chemotherapy and/or other anti-angiogenic agents. Clinical trial information: NCT01271972.
The usefulness of Roux-en-Y reconstruction with aboral pouch following total gastrectomy for gastric cancer.
Authors: Shirou Iwagami, Sugihara Hidetaka, Takao Mizumoto, Tatsuo Kubota, Nobutomo Miyanari, Hideo Baba
Journal: Journal of Clinical Oncology (2017)

209 Background: Patients with gastric cancer that involves the upper part of the stomach should undergo total gastrectomy for their curative resection. Roux-en-Y reconstruction is the most common procedure followingtotal gastrectomy. However, this reconstruction causes them various postgastrectomy symptoms and problems of their nutritional status and QOL. Although the development of the new reconstruction to prevent these symptoms have being carried out, we have not generally established procedures. Methods: To compare the feasibility and the nutritional parameters of the patients with Roux-en-Y reconstruction with aboral pouch following total gastrectomy to the simple Roux-en-Y. From February 2011 to June 2014, sixty three patients with gastric cancer underwent total gastrectomy. We analyzed the short-term outcome of surgery and the nutritional parameters in two groups. Results: The aboral pouch was created as a side to side anastomosis approximately 50 cms distal to the esophagojejunostomy, 12 cm in length. Most nutritional parameters after surgery were similar in two groups. However, lymphocyte, serum albumin and prognostic nutritional index in aboral pouch group one year later were good tendency compared with simple Roux-en-Y group. Conclusions: Roux-en-Y reconstruction with aboral pouch might become one of the standard methods after total gastrectomy for gastric cancer.
Thymidylate synthase polymorphisms and immunohistochemistry in non-small cell lung cancer
Authors: J. Stoehlmacher, E. Goekkurt, G. Hoeffken, R. Zinsky, F. Lynch, H. Buettner, S. Scheil-Bertram, J. Schirren, G. Ehninger, A. Fisseler-Eckhoff
Journal: Journal of Clinical Oncology (2009)

11101 Background: Recently, pemetrexed has been introduced into the treatment of non-small cell lung cancer (NSCLC). There's evidence that pemetrexed appears to be more efficient in non squamous NSCLC including adenocarcinoma (AC) and large cell carcinoma (LCC). TS represents a major target enzyme of pemetrexed. We evaluated the expression of TS among different histological types of NSCLC and its association with functional genetic polymorphisms of the TS gene. Methods: Archived tumor samples from 312 individuals with NSCLC were analyzed. Immunohistochemistry (IHC) was performed using a mouse monoclonal antibody to TS. TS stained sections were scored for cytoplasmic and nuclear localization. For each compartment, the tumor was evaluated for the estimated percentage of positive cells with the greatest intensity within the tumor. Intensity was scored on a scale of 0–4. A score of 3–4 was classified as high expression. Genotyping of TS-VNTR including the G/C SNP and TS1394del6 was performed by PCR based RFLP techniques. Genotypes supposed to be associated with low expression were grouped (group A: 2R/2R or 2R/3RC or 3RC/3RC + -6/-6) and compared to genotype groups associated with high expression (group B: 2R/3RG or 3RC/3RG or 3RG/3RG + -6/+6 or +6/+6). Results: IHC and polymorphisms could be performed successfully in 312 (100%) and 287 (92%), respectively. Distribution of histology was as follows: 50% AC, 42% squamous cell carcinoma (SCC), 3% LCC and 5% mixed or other histological subtypes. Group B genotypes were significantly more present in SCC than in AC (49% vs 23%, p=.002). Tumors with group B genotypes were more likely to display high nuclear staining intensity than group A tumors (30% vs. 17%, p=.077). A similar but not significant trend was seen for cytoplasmic staining intensity. There was no significant difference between histological subtypes of NSCLC with respect to TS protein expression. AC were more common than SCC to show a G1 differentiated tumors (8% vs 1%, p&lt;.001). No difference between genotype groups were observed with respect to grading. Conclusions: TS polymorphisms are significantly associated with histology subtypes in NSCLC. These results represent a potential explanation for efficacy differences of pemetrexed in NSCLC and warrants further investigations. [Table: see text]
Targeting Cellular Metabolism and Survival in Chronic Lymphocytic Leukemia and Richter Syndrome Cells By a Novel NF-Kb Inhibitor
Authors: Tiziana Vaisitti, Federica Gaudino, Samedy Ouk, Sara Serra, Johannes L. Zakrzewski, Erica B. Bhavsar, John N. Allan, Hsiou-Chi Liou, Richard R. Furman, Silvia Deaglio
Journal: Blood (2016)
Pediatric patients undergoing hematopoietic stem cell transplantation can greatly benefit from a novel once‐daily intravenous busulfan dosing nomogram
Authors: Su‐jin Rhee, Ji Won Lee, Kyung‐Sang Yu, Kyung Taek Hong, Jung Yoon Choi, Che Ry Hong, Kyung Duk Park, Hee Young Shin, Sang Hoon Song, Hyoung Jin Kang, Howard Lee
Journal: American Journal of Hematology (2017)

Abstract Busulfan, a bifunctional alkylating agent, has been used as a conditioning regimen prior to allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this study was to derive a novel once‐daily intravenous (IV) busulfan dosing nomogram for pediatric patients undergoing HSCT using a population pharmacokinetic (PK) model. A population PK analysis was performed using 2183 busulfan concentrations in 137 pediatric patients (age: 0.6‐22.2 years), who received IV busulfan once‐daily for 4 days before undergoing HSCT. Based on the final population PK model, an optimal once‐daily IV busulfan dosing nomogram was derived. The percentage of simulated patients achieving the daily target area under the concentration‐time curve (AUC) by the new nomogram was compared with that by other busulfan dosing regimens including the FDA regimen, the EMA regimen, and the empirical once‐daily regimen without therapeutic drug monitoring (TDM). A one‐compartment open linear PK model incorporating patient's body surface area, age, dosing day, and aspartate aminotransferase as a significant covariate adequately described the concentration–time profiles of busulfan. An optimal dosing nomogram based on the PK model performed significantly better than the other dosing regimens, resulting in &gt;60% of patients achieving the target AUC while the percentage of patients exceeding the toxic AUC level was kept &lt;25% during the entire treatment period. A novel once‐daily busulfan dosing nomogram for pediatric patients undergoing HSCT is useful for clinicians, particularly in a setting where TDM service is not readily available or to optimize the dose on day 1.