tbuckley/cabot-search huggingface dataset:
Erythropoietic cellular analyses in luspatercept-treated lower-risk myelodysplastic syndromes (MDS): Phase 2 PACE-MDS study.
Authors: Uwe Platzbecker, Aristoteles Giagounidis, Philipp M. Kiewe, Ulrich Germing, Katharina S. Gotze, Karin Mayer, Markus Radsak, Thomas Wolff, Jörg Chromik, Joseph Reynolds, Carolyn Barron, Chris Rovaldi, Rajasekhar NVS Suragani, Xiaosha Zhang, Abderrahmane Laadem, Peter G. Linde, Matthew L. Sherman, Uta Oelschlägel
Journal: Journal of Clinical Oncology (2018)

7018 Background: Luspatercept (ACE-536) is a TGF-β family ligand trap promoting late-stage erythroid (E) differentiation and increases in hemoglobin. Endpoints of the ongoing, phase 2, open-label study in MDS include E response (IWG HI-E), RBC transfusion independence (RBC-TI, ≥8 weeks), and molecular/bone marrow (BM) morphological characteristics associated with response. Methods: MDS IPSS low or int-1 patients (pts) were treated every 3 weeks subcutaneously (up to 1.75 mg/kg) in the base/extension studies (NCT01749514/NCT02268383). BM and blood samples were analyzed prior to and at the end of 5 cycles of treatment (EOT) by central morphology and flow cytometry according to ELN guidelines to investigate E precursors, soluble transferrin receptor (sTfR), and reticulocytes (retics) in relation to response. Results: Data (as of 08Sept2017) were available for 49 pts (≥0.75 mg/kg) with evaluable flow and BM data. HI-E and RBC-TI responses were 61% (30/49 pts) and 55% (16/29 pts), respectively. At baseline, M/E ratio was lower and sTfR two-fold higher in R vs NR, mirrored by an increase in erythroid precursors. By EOT, retics were increased in R and remained unchanged in NR. Conclusions: These data suggest that expanded late-stage erythropoiesis at baseline is associated with a response to luspatercept. Responses were accompanied by further expansion of erythropoiesis (or activation of bone marrow) and increased release of reticulocytes, supporting luspatercept as an erythroid-maturation agent (EMA). Clinical trial information: NCT01749514, NCT02268383.HI-E responder characteristics. (n) Baseline EOT M/E ratio (BM morphology) R (30)** 1.0 (0.3, 11.5) 0.9 (0.1, 3) NR (19) 2.1 (0.6, 9)* 1.5 (0.2, 32.3)* BM erythroid precursors (%, flow cytometry) R (30) 9.5 (0.9, 43.6) 14.7 (3, 53.3) NR (19) 4.5 (1.2, 24.3)* 5.6 (0.6, 41)* BM proerythroblasts (%, flow cytometry) R (30) 8 (1, 22.2) 5.9 (0.6, 30.7) NR (19) 10.9 (1, 57.5) 11.2 (3.9, 32.3)* sTfR (nmol/L) R (29)** 68.4 (23.7, 181.1) 79.6 (10.6, 270) NR (19)** 35.6 (8.8, 249.7)* 44.7 (11.6, 279.9)* n = 17 Absolute retics (10^9/L) R (26)** 35.9 (7, 154) 53.2 (9.9, 200) n = 25 NR (15) 29.2 (21, 168) 38.6 (14, 183) n = 16 Median (min, max) *p < 0.05 R vs NR **p < 0.05 baseline vs EOT M = myeloid; NR = non responder; R = responder
Osteogenesis: The Effect of Addition of Calcium Phosphate Particles to Hydrogel‐Based Composite Materials on Stiffness and Differentiation of Mesenchymal Stromal Cells toward Osteogenesis (Adv. Healthcare Mater. 18/2018)
Authors: Kshama S. Sen, Daniela F. Duarte Campos, Marius Köpf, Andreas Blaeser, Horst Fischer
Journal: Advanced Healthcare Materials (2018)

In article 1800343 by Horst Fischer and co-workers, single human mesenchymal stromal cells (hMSCs) show calcification triggered by a surrounding composite hydrogel, made of agarose and β-tricalcium phosphate nanoparticles. As well as exhibiting enhanced mechanical stability, these scaffolds in the presence of calcium phosphate particles leads to better osteogenesis of hMSCs.
High incident of EGFR mutant for lung cancer brain metastases patients and low risk of brain metastases in hippocampus.
Authors: Xingwen Fan, Kailiang Wu
Journal: Journal of Clinical Oncology (2018)

e21200 Background: Whole brain radiotherapy is one of main treatments for brain metastases, but it will induce neurotoxicity. As the development of target therapy, epidermal growth factor receptor (EGFR) mutant lung cancer patients with brain metastases live longer and longer, with the median survival time more than 25 months. Therefore, late term neurotoxicity, especially cognitive dysfunction, became the hot attention. Hippocampus avoidance could decrease the rate of cognitive impairment as shown in RTOG 0933. But risk of hippocampus metastases for EGFR mutant lung cancer patients is unknown. The purpose of this study was to analysis the distribution characteristics of EGFR mutant brain metastases. Methods: Patients in Fudan University Shanghai cancer center were collected. Inclusion criteria: (1) Histology or cytology confirmed lung cancer; (2) EGFR mutant; (3) have enhance magnetic resonance imaging (MRI) in our center before brain metastases treatment. The distribution of brain metastases on analysis based on T1 weighted enhancement images. Results: From 2006 to 2016, 920 lung cancer patients with brain metastases were diagnosed in our center. 266 patients detected whether EGFR mutant, and 49% (131/266) patients were with EGFR mutant. Finally, 114 patients and 738 brain metastases were included in the analysis, except 17 patients did not detected MRI in our center. 39% (44/114) patients had one brain metastases, 20% (23/114) patients had two brain metastases, 10% (11/114) patients had three brain metastases, 19% (22/114) patients had from four to ten brain metastases, and 12% (14/114) patients had more than ten brain metastases. The distribution rate of metastases in different brain region: frontal lobe, 23%; temporal lobe, 20%; parietal lobe, 22%; occipital lobe, 13%; insular lobe, 3%; cerebellum, 17% ; brainstem, 2%. The distribution rate of metastases in hippocampus, 5mm around hippocampus, 10mm around hippocampus, and 15mm around hippocampus was 0.8%, 1.3%, 1.4%, and 1.8%, respectively. Conclusions: Nearly half of gene detected lung cancer brain metastases patients were EGFR mutant. And the risk of metastases developed in the hippocampus was very low.
Abstract 11973: Decrease In Mortality Rate And Hospital Admissions For Acute Myocardial Infarction After The Enactment Of The Smoking Ban Law In Sao Paulo City
Authors: Tania Ogawa
Journal: Circulation (2016)

Introduction: Smoking restriction laws have been spread over the world in the last decade. Previous studies and meta-analyses showed a decline in the community rates of myocardial infarction and/or heart attack after enactment of these laws. However, there are few data about the Latin American population. In the first phase of this study, we reported a well succeed implementation of the law in Sao Paulo city, with decrease in carbon monoxide rates in places like restaurants, bars and night clubs. Hypothesis: To evaluate whether the 2009 implementation of a smoking ban law in Sao Paulo city was associated with reduction in rates of mortality and hospital admissions for myocardial infarction. Methods: We performed a time series study of monthly rates of mortality and hospital admissions for acute myocardial infarction from January 2005 to December 2010. The data derived from DATASUS, the main public health information system existent in Brazil and from SIM (Mortality Information System). Adjustments and analysis were done using Autoregressive Integrated Moving Average with exogenous variables (ARIMAX) method modeled by environmental variables and atmospheric pollutants to evaluate the tendency of mortality and hospital admissions before the law and forecast events after the law. We also used Interrupted Time Series Analysis (ITSA) associated to ARIMAX to compare the period before the law, the moment of implementation of the law and the period after the law. Results: We observed a reduction in the hospital admissions (-5,4% in the first 2 months after the law) and mortality rate (-11,9% in the first 17 months after the law) for myocardial infarction. Conclusions: Hospital admissions and mortality rate for myocardial infarction were reduced in the first months after smoking ban law. Graphic 1: Hospital admission rate for myocardial infarction, São Paulo city, 2005 to 2010. Graphic 2: Mortality rate for myocardial infarction, São Paulo city, 2005 to 2010.
Malignant pericardial effusions: Single centre retrospective review.
Authors: Elizabeth Anne Connolly, Paul Andrew Bamford, Girish Mallesara Hiriyanna Gowda
Journal: Journal of Clinical Oncology (2018)

e13580 Background: There is limited recent data in the current era of new therapies regarding malignant pericardial effusions. We aimed to retrospectively analyse the frequency of admission, current management and outcomes, of symptomatic malignant pericardial effusions. Methods: Based on hospital admission coding, from 2008 to 2017, 72 admissions were identified. 12 were excluded as pericardial effusion was not a significant component of the presentation. No notes were available for one patient. After review 56 patients, with 59 admissions, with symptomatic malignant pericardial effusions were identified. Data was collected from electronic records. Results: 58% were female with a median age of 59 years (range 28-76). Non small cell lung cancer (NSCLC) was the most frequent attributable malignancy (59%, n = 35). In 4 patients a diagnosis of malignancy was made after presentation with pericardial effusion. Effusions were small (36%; n = 21), moderate (31%; n = 18) and large (34%; n = 20) respectively. Dyspnoea was the most frequent presenting symptom (71%). Other presenting symptoms included chest pain, cough, palpitations, peripheral oedema, fever, and altered mental status. 68% also had a pleural effusion (n = 40). Tamponade was identified in 22% of presentations (n = 13). 36% required management with pericardiocentesis (n = 21). Median survival, from admission when a diagnosis of malignant pericardial effusion was made, was 89 days (n = 56). Survival ranged from 6-1712 days. 50% (n = 28) survived less than 90 days and 16% (n = 9) survived greater than 12 months. Median survival was less in those whom pericardial effusion had been identified prior to commencing treatment (n = 13), compared with those who later developed effusions (n = 43); median 72 days and 91 days respectively. Median survival, in those with NSCLC, was 87 days (n = 35). Conclusions: Pericardial effusions were an infrequent precipitant for medical oncology admission. Small to moderate effusions were often managed conservatively without intervention. Malignant pericardial effusions continue to be associated with a poor prognosis, particularly when present at diagnosis. They often herald the terminal phase of disease with 50% of patients in this series surviving less than 90 days.
TCT-22 The residual SYNTAX score predicts prognosis in ST elevation Myocardial infarction in both single vessel and multivessel disease.
Authors: Sonya Burgess, John French, Tuan Nguyen, Melissa Leung, David Richards, Liza Thomas, Christian Mussap, Sidney Lo, Craig Juergens
Journal: Journal of the American College of Cardiology (2018)
Next generation sequencing in non metastatic high grade pediatric osteosarcoma: A useful tool to identify new therapeutic targets.
Authors: Elise Lavit, Arnaud Lagarde, Corinne Bouvier, Aurelie Fabre, Anne Brouchet, Jean-Claude Gentet, Alexandre Atkinson, Florence Duffaud, Sylviane Olschwang, Sebastien Salas
Journal: Journal of Clinical Oncology (2018)

e24235 Background: : Conventional osteosarcoma is the most frequent malignant tumor in adolescents. Treatment is based on neoadjuvant chemotherapy, surgery and adjuvant chemotherapy. Histological response to neoadjuvant chemotherapy is the main prognostic factor. Most recent clinical trials have failed to improve survival rates in poor responders. A better understanding of the biology of these tumors is mandatory to improve the prognosis specially for poor responders. Methods: 24 frozen pre-therapeutic biopsies of non-metastatic pediatric patients with an osteosarcoma were used for the study. They encompassed 10 poor responders and 14 good responders. The diagnosis was high grade osteosarcoma in all cases done by a pathologist of the French Bone Sarcoma network RESOS. DNA extraction was performed thanks to All prep DNA/RNA kit QIAGEN according to manufacturer’s instructions. Normal tissue was obtained from paraffin blocks from surgical specimens for 21 samples but DNA extraction was successful for only 7. 523 genes established according to Kovac’s publication were selected and sequenced on the Illumina NextSeq500. Results: Samples were sequenced with a median depth of 1212X. Coverage at 20X was on average 98.7% and 97.6% at 50X. 152 mutations were found in 109 different genes. 7 mutations were found in TP53, 2 in RB1.Fifty eight percent of our cohort had a mutation for which a drug is available or being tested in clinical trials. PI3K pathway was frequently involved with 6 samples harboring a mutation in this pathway (PIK3CA, TSC2 (3 mutations), AKT1, RICTOR). Two mutations were observed in NOTCH pathway (NOTCH2, NOTCH3) and 6 receptor tyrosine kinases were potentially actionable: ERBB2, ERBB4, KIT, PDGFRA, ALK, JAK3. However no mutation enabled discriminating good or poor responders at the time of diagnosis. Conclusions: Targeted sequencing is useful to highlight new therapeutic targets in osteosarcoma and umbrella trials have to be developed
Evofosfamide combined with gemcitabine/nab-paclitaxel in patients with previously untreated locally advanced or metastatic pancreatic adenocarcinoma (PAC): Results of a phase I trial.
Authors: Mitesh J. Borad, Eunice Lee Kwak, Andrea Wang-Gillam, Ayman Ibrahim, Julie Aldridge, Anthony J. Olszanski
Journal: Journal of Clinical Oncology (2016)

4114 Background: Gemcitabine + nab-paclitaxel (G/nab-P) is a standard first-line option for advanced PAC. Evofosfamide (Evo, previously known as TH-302) is a hypoxia-activated prodrug of bromo-isophosphoramide mustard that is preferentially activated under hypoxic conditions. The recent phase III MAESTRO study suggested that Evo + G has clinical activity (overall survival: HR = 0.84, P = 0.0589). Encouraging preclinical activity for Evo + G/nab-P and the clinical importance of G/nab-P provided a rationale for study of this triplet. Methods: This phase I, dose-escalation trial (NCT02047500) recruited pts with previously untreated locally advanced or metastatic PAC. A classical 3 + 3 design used 3 planned Evo dose levels: 170 mg/m2, 240 mg/m2, and 340 mg/m2 on days 1, 8, and 15 of a 28-day cycle, combined with nab-P 100 mg/m2 followed by G 800 mg/m2. Primary objectives: safety and tolerability, maximum tolerated dose (MTD), and the recommended phase II dose (RP2D) of Evo + G/nab-P. Secondary objectives: RECIST response rate and safety. Results: At the cut-off date of 7 Dec 2015, 17 pts were enrolled (median age 62.4 [50.0–78.2]; male 7). 7 received Evo at 170 mg/m2, 3 at 240 mg/m2, and 7 at 340 mg/m2. A pt treated with Evo 170 mg/m2 had 2 dose-limiting toxicities (DLTs; both grade 3/4 hematologic events); no other DLTs were observed and Evo 340 mg/m2 was established as the MTD. The most common treatment-related adverse events (TRAEs) were neutropenia (n = 13), thrombocytopenia (12), anemia (10), alopecia (10), and fatigue (10). Serious TRAEs reported in 4 pts were pancytopenia, febrile neutropenia, pneumonia, sepsis, lung infiltration, acute kidney injury, erythematous rash, and hypotension. One TRAE (sepsis) led to death in the Evo 170 mg/m2 cohort. Best overall response: partial response (9/17, 52.9%), stable disease (5/17, 29.4%), not evaluable (3/17, 17.6%). Conclusions: Evo plus attenuated G/nab-P showed a manageable safety profile with evidence of activity. Clinical trial information: NCT02047500.
Entering the spotlight: hepatitis B surface antigen–specific B cells
Authors: Christoph Neumann-Haefelin, Robert Thimme
Journal: Journal of Clinical Investigation (2018)

Hepatitis B virus–specific (HBV-specific) T cells have been identified as main effector cells in HBV clearance. In contrast, B cells producing neutralizing antibodies against the HBV surface antigen (HBsAg) have been studied in little detail, mainly due to methodical limitations. In this issue of the JCI, two reports use a new technique to specifically detect and characterize HBsAg-specific B cells ex vivo. Indeed, these cells are present, but show phenotypic alterations and impaired function during acute and chronic HBV infection. Thus, HBsAg-specific B cells are a novel attractive target for antiviral strategies toward functional cure of chronic HBV infection.
Can AI technology augment tumor board treatment decisions for stage II colon cancer care?
Authors: Peng-ju Chen, Ting-ting Sun, Tian-le Li, Irene Dankwa-Mullan, Alexandra Urman, Ching-Kun Wang, Yue Zhang, Yun-feng Yao, Guo-li He, Kyu Rhee, Aiwen WU
Journal: Journal of Clinical Oncology (2018)

e18582 Background: Studies have demonstrated the benefits of adjuvant chemotherapy in patients with stage III colon cancer. However, benefits of adjuvant chemotherapy for patients with Stage II disease are less certain. Various factors, including clinicopathologic, and MSI phenotypes, are typically used to guide care, but treatment in high-risk patients remain variable. Clinical decision support (CDS) technologies armed with machine learning continue to demonstrate potential to transform standard of care, decrease treatment disparities and improve patient quality of cancer care. Methods: A cross-sectional retrospective concordance study was conducted to assess recommendations provided by IBM Watson for Oncology (WFO), a CDS system, and a multidisciplinary tumor board (MDT) decision for treatment of Stage II colon cancer. 229 patients seen at Beijing Cancer Hospital were used in the analysis. Clinical and pathological features associated with worse prognosis and defined as high risk by the MDT, included T4 primary, high-grade, poorly differentiated histology (grade 3/4 excluding MSI-H), lymphovascular invasion, bowel obstruction or perforation, perineural invasion, and inadequately sampled lymph nodes. Subgroup concordance analyses of clinicopathologic features were conducted to examine the groups that might derive some benefit from the use of WFO where evidence was limited. Results: Overall concordance was 89.1% (204/229) with high-risk subgroup results ranging from 87.5% (p = 0.68) in T4 primary to 92.7% (p = 0.02) in poorly differentiated histology. Concordance in MSI subgroup was highly significant, MSI-H 71.4% vs MSI-L 94.5% (p = 0.0). Concordance with actual treatment decisions for tumor grade was statistically significant (p = 0.02). Reasons for non-concordance included different age threshold for oxaliplatin in elderly patients and preference for capecitabine for MSI-H. Conclusions: WFO generated treatment recommendation for Stage II colon cancer can potentially augment the clinical decision-making process within MDT. Future studies are needed to assess benefits for integrating local treatment and evidence for use outside of MDT settings.
Availability of clinical trials in rural settings for the success of precision oncology (PO).
Authors: Jasmine Kamboj, Elie Chalhoub, Susan Hudson, Christie Ellison, Peter Friedell, Steven Francis Powell
Journal: Journal of Clinical Oncology (2018)

e18613 Background: Availability of clinical trials in community setting is of utmost importance for meaningful outcomes. For the success of PO, it is critical that treatment trials are accessible in the community. Methods: We performed a retrospective analysis of patients who underwent Next Generation Sequencing (NGS) from 1/2016 to 1/2018 at our rural cancer program in Bemidji, MN and compared trial enrollment/treatment patterns with more populated centers [Bismarck, Fargo, and Sioux Falls] within Sanford Health. Sanford Health is a health system with multiple community oncology sites in Minnesota and Dakotas. Patients were enrolled through NCI MATCH and an institutional IRB approved protocol. Eligible patients had advanced solid tumors with progression on current standard of care treatment lines, had viable tumor tissue available for genomic testing, and had ECOG PS 0-2. NGS testing results were reviewed at a genomic tumor board and treatment options were identified based on actionable alterations (AAs). AAs were defined as any alteration that was inclusion criteria for a NGS-based treatment trial or treatment with an FDA approved targeted agent. Results: 167 patients underwent NGS testing and 165 concluded NGS testing Sanford wide. AAs were found in 20/23 (87%) patients at Bemidji site. NGS treatment trials were recommended for all 20 patients, which included ASCO-TAPUR [16/20], MyPathway [3/20], NCI-MATCH [9/20]. Only 1/20 (5%) enrolled on a NGS treatment study, but this patient had to travel to another center for access. The majority (17/20, 85%) patients declined accrual on trials due to unavailability of the trial in Bemidji. At the other centers, 142 patients completed NGS testing. AAs were found 120/142 (84.5%) patients. At these sites, 20/120 (16.7%) patients were enrolled on NGS interventional clinical trials. Conclusions: Our analysis highlights the importance of availability of clinical trials in rural settings. AA rates were similar at our rural program compared to the other centers, but trial enrollment was lower due to lack of access. Patient access is crucial for PO clinical trials, as we lose many patient enrollments from smaller, rural centers.
An investigator initiated multicenter phase I/II study of paclitaxel, ramucirumab with nivolumab as the second-line treatment in patients with metastatic gastric cancer.
Authors: Tomohiro Nishina, Shuichi Hironaka, Shigenori Kadowaki, Takeharu Yamanaka, Takako Eguchi Nakajima
Journal: Journal of Clinical Oncology (2018)

TPS4131 Background: Paclitaxel (PTX) and ramucirumab (RAM) is a standard regimen as the second-line treatment for metastatic gastric cancer (mGC). In the phase III ATTRACTION-2 trial, nivolumab (NIVO) significantly improved overall survival (OS) over placebo for metastatic gastric cancer (mGC) patients (pts) refractory to standard therapies. In preclinical models, anti-angiogenesis agents with immune-checkpoint inhibitors demonstrated enhanced activity against cancer cells compared with either drug alone. Methods: We are conducting a phase I/II study to determine the recommended phase II dose (RP2D) and evaluate the efficacy, safety and biomarkers of the combination regimen of PTX, RAM with NIVO in pts with mGC as the second-line treatment. Key eligibility criteria are: mGC pts who were refractory or intolerant to fluoropyrimidine and platinum in the first-line treatment, and had no prior immunotherapy; an age of 20 years or older; ECOG performance status of 0-1; and controllable hypertension. Phase I is designed to determine RP2D in the dose de-escalation design of NIVO (q4w, 3 mg/kg on days 1 and 15 for level 1 and 1 mg/kg for level −1) with fixed doses of PTX and RAM (q4w, 80 mg/m2 on days 1,8 and 15 and 8 mg/kg on days 1 and 15, respectively). Primary endpoint is progression-free survival (PFS) rate at 6 months in pts treated with RP2D. Using a single stage binomial design, this study requires 43 pts, with a PFS rate at 6 months of 50% deemed promising and 35% unacceptable (one-sided alpha = 0.1; beta = 0.25). 35 patients have been enrolled since Feb 2017. Clinical trial information: UMIN000025947.