tbuckley/cabot-search huggingface dataset:
A two-part safety and exploratory efficacy randomized double-blind, placebo-controlled study of a 1:1 ratio of the cannabinoids cannabidiol and delta-9-tetrahydrocannabinol (CBD:THC) plus dose-intense temozolomide in patients with recurrent glioblastoma multiforme (GBM).
Authors: Chris Twelves, Susan Short, Stephen Wright
Journal: Journal of Clinical Oncology (2017)

2046 Background: Several plant-derived cannabinoids have shown efficacy in animal models of GBM, particularly when co-administered with temozolomide, a commonly-used treatment in both primary and recurrent disease. Methods: We conducted a two-part study in patients with recurrent GBM following standard chemo-radiotherapy treatment as described by Stupp et al. In Part 1 of the study, 6 patients were treated to an MTD of 1:1 CBD:THC oro-mucosal spray, as an adjunct to dose-intense temozolomide (DIT), to assess the safety of the combination. Part 2 was a double blind, randomized, placebo-controlled study in a planned 20 patients receiving either their individualized dose of 1:1 CBD:THC or placebo plus DIT. The primary endpoint was tolerability of 1:1 CBD:THC plus temozolomide. Results: There were no Grade 3 or 4 toxicities in Part 1 of the study. In Part 2, 12 patients were randomized to CBD:THC and 9 to placebo. Mean age was 58 years in both treatment groups, but there were more males in the placebo group (5 of 12 and 8 of 9, respectively). Baseline median Karnofsky score was 90 in both groups and median time from diagnosis of recurrence to start of treatment (day 1) was similar (3.6 and 3.0 weeks in the CBD:THC and placebo group, respectively). The median number of days of dosing with CBD:THC or placebo was similar (155 days [range: 50-356] and 134 days [range: 13-359]). Median survival in the placebo group was 369 days, and &gt; 550 days in the CBD:THC treatment group (NS) and 1 year survival was 83% and 56% in the CBD:THC and placebo groups, respectively (p = 0.042). PFS6 was 42% in the CBD:THC group and 33% in the placebo group (NS). Overall, the commonest treatment related toxicities were dizziness (in 11/18 patients) and nausea (in 7/18 patients). Results of biomarker analyses are awaited. Conclusions: This randomized study provides preliminary evidence that 1:1 CBD:THC offers some efficacy in patients with recurrent GBM when used as an adjunct to dose-intense temozolomide and confirms the safety and feasibility of individualized dosing. Clinical trial information: NCT01812603.
Survival advantage associated with neoadjuvant chemotherapy compared to neoadjuvant hormonal therapy in postmenopausal women with hormone receptor positive breast cancer: A National Cancer Data Base study.
Authors: Alina Basnet, Dongliang Wang, Abirami Sivapiragasam
Journal: Journal of Clinical Oncology (2017)

e12119 Background: Neoadjuvant endocrine therapy (NET) and neoadjuvant chemotherapy (NCT) are both considered effective strategies in postmenopausal, hormone receptor positive breast cancer patients. Small prospective studies show comparable response rates and breast conservation rates. Using National Cancer Data Base (NCDB) we report overall survival (OS) differences between these two strategies with subgroup analysis by Estrogen Receptor (ER), Progesterone Receptor (PgR) status. Methods: We extracted data on hormone receptor positive breast cancer patients without metastasis in women aged ≥ 50 from the NCDB registry (2004-2014). We excluded patients who did not receive adjuvant endocrine therapy after NCT and patients who received adjuvant chemotherapy after NET as this could affect OS. We calculated OS using Kaplan Meier analysis with hazard ratio (HR) from cox regression model. Subgroup analysis was performed by ER, PgR status. Results: Out of 2,246,279 patients, 30,348 patients met our inclusion criteria. 7836 received NET and 22512 received NCT. OS rate was 70.8% vs 81.7% at 5 yrs and 42.5% vs 62.1% at 9 yrs for NET and NCT respectively with adjusted hazard ratio (HR) of 1.818; 95% CI (1.657-1.996). OS outcome for ER+/PgR+ group was 72.3% vs 83.5% at 5 yrs and 43.5% vs 64% at 9 yrs for NET and NCT respectively with adjusted HR of 1.807; 95% CI (1.624-2.010). OS for ER+/pgR- group was 62.9% vs 76.8% at 5 yrs and 33.1% vs 54.2% at 9 yrs for NET and NCT respectively with adjusted HR of 1.890; 95% CI (1.549-2.306). Our analysis also revealed that 5591 T1 patients received neoadjuvant therapy among which 2541 received NET and 3050 received NCT. Conclusions: We find a significant survival advantage in patients treated with NCT as opposed to NET. All subgroups showed imporved OS with NCT compared with NET. Limitations that should be considered in this registry based study are: not accounting for Her-2 status, differences in surgical technique, duration and choices of adjuvant chemotherapy and radiotherapy options.
Combined peripheral natural killer (NK) cell and circulating tumor cell (CTC) enumeration to enhance prognostic efficiency in patients (pts) with triple-negative breast cancer (TNBC).
Authors: Xiao-ran Liu, Bin Shao, Hui-ping Li, Yan-lian Yang, Hope S. Rugo, Wei-yao Kong, Guo-hong Song, Han-fang Jiang, Xu Liang, Ying Yan, Zhi-yuan Hu, Guo-bing Xu
Journal: Journal of Clinical Oncology (2017)

1105 Background: CTCs have emerged as an independent prognostic factor for metastatic breast cancer. However, the prognostic value of baseline CTCs regarding PFS in TNBC is still controversial, especially beyond first-line. We evaluated a novel combined NK cell/CTC detection system for enumeration to better understand the impact of cell count on prognosis in TNBC. Methods: 83 consecutive patients with metastatic TNBC were enrolled and received a new line of therapy (median=2, range: 1~5). Baseline circulating CTCs and NK cells were isolated and enumerated simultaneously prior to starting a new line of therapy using our previously published method targeting EpCAM (Bai et al. J Mater Chem B, 2014) and flow cytometry (antibodies against CD3 - , CD45 + , CD56 + ) respectively. The NK cell level was expressed as the proportion of total lymphocytes (%). Patients with normal to high NK cell proportion (≥ 9.15%) and &gt; 2 CTC/2 ml were defined as NK resistant CTC, the rest were defined as non-NK resistant CTC. Results: 33 out of 83 TNBCs had first-line of therapy. Pts with ≤ 2 CTC/2 ml had a significantly longer median PFS than those with &gt; 2 CTC/2 ml ( P = 0.028). The differences in median PFS were not significant ( P=0.110) for the entire group of pts with TNBC receiving different lines of therapy. Pts with non-NK resistant CTCs had a significantly longer median PFS than those with NK resistant CTCs ( P= 0.025), regardless of line of therapy. Conclusions: Including peripheral NK cell level into consideration can improve CTC prognostic efficiency in predicting PFS for TNBCs receiving different line of therapy. Further analysis of the unique biological features of NK-resistant CTCs and associated clinical consequence holds promise in guiding clinical practice. [Table: see text]
Regional differences observed in the phase 3 trial (ELM-PC 5) with orteronel (TAK-700) plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or following docetaxel.
Authors: Karim Fizazi, Robert Jones, Stephane Oudard, Eleni Efstathiou, Fred Saad, Ronald De Wit, Johann Sebastian De Bono, Felipe Cruz, George Fountzilas, Albertas Ulys, Flavio Carcano, Neeraj Agarwal, David B. Agus, Joaquim Bellmunt, Daniel Peter Petrylak, Connie Lee, Bindu Tejura, Niels Geert Borgstein, Robert Dreicer
Journal: Journal of Clinical Oncology (2014)

5042 Background: Orteronel is an investigational, nonsteroidal, selective 17,20-lyase inhibitor. ELM-PC 5 (NCT01193257) did not meet the primary endpoint of OS (P = 0.1898) despite improvement in radiographic PFS (rPFS; P = 0.00038) (Dreicer, ASCO GU 2014, Abstract #7). Here we analyze baseline characteristics and outcomes across study regions (Europe [E], North America [NA], and non-E/NA). Methods: Men with progressive mCRPC who had received prior docetaxel but not orteronel, abiraterone or ketoconazole were randomized 2:1 to orteronel 400 mg BID plus prednisone 5 mg BID (O+P) or placebo plus prednisone (P). Enrollment (N = 1099) was stratified by region (E, n = 590; non-E/NA, n = 397; NA, n = 112). The primary endpoint was OS; other key endpoints were rPFS, ≥50% prostate-specific antigen (PSA50) decrease and pain response. Results: Baseline characteristics were generally balanced, except for pain score, ≥2 prior chemotherapies, PSA and lacate dehydrogenase (LDH). Substantial regional differences were noted in OS, rPFS and PSA50 rates.Regional data are summarized below (Table). Conclusions: Substantial differences in efficacy were seen across regions, with differences in OS possibly being related to subsequent therapies. Clinical trial information: NCT01193257. E non-E/NA NA O+P N = 394 P N = 196 O+P N = 265 P N = 132 O+P N = 75 P N = 37 Baseline characteristics Median time from diagnosis, yrs 5.3 5.7 5.3 5.6 7.5 7.3 Median Brief Pain Inventory-Short Form worst pain score 3.0 3.0 4.0 3.5 2.0 2.5 Pts with ≥2 prior chemotherapies, % 18 23 32 34 7 27 Median PSA, ng/mL 138.0 127.5 131.0 169.0 53.6 51.6 LDH >225 U/L, % 42 34 54 52 28 38 Outcomes Median treatment duration, mos 5.7 4.6 5.7 4.7 5.95 3.7 Median OS, mos 18.3 17.8 15.3 10.1 20.9 16.9 P value 0.721 0.019 0.680 Median rPFS, mos 8.3 6.4 6.7 5.2 11 8.3 P value 0.0745 0.00076 0.5387 PSA50 response at 12 wks, % 27 9 20 13 35 5 P value <0.0001 0.0965 0.00083 Pain response at 12 wks, % 12 9 14 11 7 3 P value 0.204 0.540 0.385 Subsequent therapy N = 392 N = 194 Pts with ≥1 subsequent therapy, % 49 61 35 44 53 54 Abiraterone, % 26 32 9 5 27 24 Abiraterone or enzalutamide, % 30 35 9 5 36 27 Abiraterone, enzalutamide, or cabazitaxel, % 38 48 15 16 44 41
Abstract TMEM-018: IN VITRO MODELS OF HGSC BASED ON MURINE OVIDUCTAL EPITHELIAL ORGANOIDS
Authors: Yali Zhai, Eric R. Fearon, Kathleen R. Cho
Journal: Clinical Cancer Research (2017)

Abstract Mouse models of high-grade serous carcinoma (HGSC) arising from oviductal epithelium provide excellent in vivo systems with which to define the cellular and molecular events associated with HGSC development and progression. However, tumors in mice typically develop over months rather than weeks, and tumor progression in vivo cannot be easily monitored. Murine organoid models that closely mimic the biology of fallopian tube epithelium would facilitate research exploring HGSC pathogenesis. We have developed Ovgp1-iCreERT2 mice in which the Ovgp1 promoter controls expression of tamoxifen (TAM)-inducible Cre recombinase in the oviductal epithelium – the murine equivalent of human fallopian tube epithelium. We have established long-term, 3-dimensional oviductal epithelial organoid cultures from Ovgp1-iCreERT2;R26LSL-EYFP double transgenic mice, and show that the organoids contain both ciliated and secretory cells, and express oviductal epithelial markers including cytokeratin 8, ER, PAX8 and OVGP1. Organoids treated in vitro with 4-hydroxy-tamoxifen (4-OH-TAM) activate the EYFP reporter. Oviductal epithelial organoids established from Ovgp1-iCreERT2;Brca1del/fl; Trp53mut/fl;Rb1fl/fl (BPR) mice and treated in vitro with 4-OH-TAM show selection for the recombined tumor suppressor gene alleles by passage 6, accompanied by morphological and behavioral changes associated with neoplastic transformation. Stable organoid cultures can also be established from the oviductal epithelium of BPR mice treated in vivo with Tamoxifen (TAM). We show that long-lived 3-dimensional organoids can be generated from normal oviductal tissue; can undergo Cre-mediated recombination in vitro to inactivate tumor suppressor genes relevant to human HGSC pathogenesis; and can acquire properties associated with neoplastic transformation in a relatively short period of time (weeks). As we have already generated Ovgp1-iCreERT2 mice with various combinations of constitutional and Cre-inducible mutant tumor suppressor gene (Trp53, Rb1, Brca1, Pten, Nf1, Apc) and oncogene (PIK3CA, KRAS) alleles, the roles of specific genetic alterations in HGSC pathogenesis can be explored in a relatively rapid and controlled experimental system. Citation Format: Yali Zhai, Eric R. Fearon, and Kathleen R. Cho. IN VITRO MODELS OF HGSC BASED ON MURINE OVIDUCTAL EPITHELIAL ORGANOIDS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr TMEM-018.
<i>Shigella</i>depends on SepA to destabilize the intestinal epithelial integrity via cofilin activation
Authors: Ana Maldonado-Contreras, James R. Birtley, Erik Boll, Yun Zhao, Karen L. Mumy, Juan Toscano, Seyoum Ayehunie, Hans-Christian Reinecker, Lawrence J. Stern, Beth A. McCormick
Journal: Gut Microbes (2017)

Shigella is unique among enteric pathogens, as it invades colonic epithelia through the basolateral pole. Therefore, it has evolved the ability to breach the intestinal epithelial barrier to deploy an arsenal of effector proteins, which permits bacterial invasion and leads to a severe inflammatory response. However, the mechanisms used by Shigella to regulate epithelial barrier permeability remain unknown. To address this question, we used both an intestinal polarized model and a human ex-vivo model to further characterize the early events of host-bacteria interactions. Our results showed that secreted Serine Protease A (SepA), which belongs to the serine protease autotransporter of Enterobacteriaceae family, is responsible for critically disrupting the intestinal epithelial barrier. Such disruption facilitates bacterial transit to the basolateral pole of the epithelium, ultimately fostering the hallmarks of the disease pathology. SepA was found to cause a decrease in active LIM Kinase 1 (LIMK1) levels, a negative inhibitor of actin-remodeling proteins, namely cofilin. Correspondingly, we observed increased activation of cofilin, a major actin-polymerization factor known to control opening of tight junctions at the epithelial barrier. Furthermore, we resolved the crystal structure of SepA to elucidate its role on actin-dynamics and barrier disruption. The serine protease activity of SepA was found to be required for the regulatory effects on LIMK1 and cofilin, resulting in the disruption of the epithelial barrier during infection. Altogether, we demonstrate that SepA is indispensable for barrier disruption, ultimately facilitating Shigella transit to the basolateral pole where it effectively invades the epithelium.
Efficacy of a 4-Food Elimination Diet for Children With Eosinophilic Esophagitis
Authors: Amir F. Kagalwalla, Joshua B. Wechsler, Katie Amsden, Sally Schwartz, Melanie Makhija, Anthony Olive, Carla M. Davis, Maria Manuel-Rubio, Seth Marcus, Ronda Shaykin, Maureen Sulkowski, Kristen Johnson, Jessica N. Ross, Mary Ellen Riffle, Marion Groetch, Hector Melin-Aldana, Deborah Schady, Hannah Palac, Kwan-Youn A. Kim, Barry K. Wershil, Margaret H. Collins, Mirna Chehade
Journal: Clinical Gastroenterology and Hepatology (2017)
Continuous lenalidomide (LEN) therapy versus observation following nonimmunomodulatory compound-based induction therapy in newly diagnosed multiple myeloma (NDMM): MM-027 trial.
Authors: Saad Zafar Usmani, Yasir M. Nagarwala, Catherine Balint, Anjan Thakurta, Shankar Srinivasan, Noopur S. Raje
Journal: Journal of Clinical Oncology (2014)

TPS8630 Background: Several recent trials have shown improvements in progression-free survival (PFS) with continuous LEN treatment (Tx) in NDMM patients (pts). PFS was 45%-59% higher using LEN therapy vs. control arm and rates of overall survival (OS) were consistently improved (Attal, NEJM 2012; Facon, ASH 2013, McCarthy, NEJM 2012; Palumbo, NEJM 2012, Palumbo ASCO 2013). Therefore an effective strategy of continuous Tx is of great importance to outcomes. Methods: This phase 3b, multicenter, randomized, open-label study will compare PFS of LEN single-agent vs. observation after non-immunomodulatory compound based induction therapy in NDMM pts (≥ 65 yrs) or < 65 yrs non eligible for/decline SCT. Main inclusion criteria are: induction Tx with 6–12 cycles of non-immunomodulatory compound, achievement of ≥ stable disease (SD) according to the International Myeloma Working Group (IMWG) criteria. Exclusion criteria include: previous antimyeloma Tx and pts who did not achieve ≥ SD after > 6 cycles of non-immunomodulatory Tx. Eligible pts will be screened and randomized 1:1 in either the LEN arm (10 mg/day on day 1–21/28-day cycle) or observation arm until progressive disease (PD). Dose adjustments will be made in case of adverse events (AEs). All pts who progress will enter long-term follow-up and will be monitored for OS and second primary malignancy every 3 months (mos) for at least 5 yrs. Primary endpoint is PFS from time of randomization to PD or death from any cause; secondary endpoints will include overall response rate and safety. AEs will be evaluated and graded according to the NCI CTCAE Version 4.0. Group sizes were calculated for a median PFS of 20 mos in the LEN arm and 10 mos in the observation arm, 90% power and a two-sided 0.05 level test. Counting for a non-evaluable rate of 15%, a total of 172 pts will be needed (86 per arm). Exploratory objectives will include assessment of minimal residue disease (MRD), clonal heterogeneity measurements and their correlation to clinical outcomes, molecular, immunological and mechanistic biomarkers will be assessed.
Coccidioidomycosis in Workers at an Archeologic Site—Dinosaur National Monument, Utah, June-July 2001
Journal: JAMA (2001)

COCCIDIOIDOMYCOSIS IS A FUNGAL INfection caused by inhalation of airborne Coccidioides immitis spores that are present in the arid soil of the southwestern United States, California, and parts of Central and South America.Infection with C. immitis previously has not been diagnosed in patients outside these areas, except in travelers returning from areas where the disease is endemic. 1 This report describes an outbreak of coccidioidomycosis in workers at an archeologic site in northeastern Utah during June-July, 2001, and represents the first identification of coccidioidomycosis in northern Utah.Health-care providers should consider coccidioidomycosis in the differential diagnosis for patients with compatible illness who reside in or recently have traveled to this area.Interventions to minimize soil disturbance and dust inhalation can reduce the risk for coccidioidomycosis.Dinosaur National Monument (DNM) encompasses 320 square miles in northeastern Utah and northwestern Colorado; 397,800 persons visited DNM in 2000.On June 18, 2001, under the direction of National Park Service (NPS) archeologists, six student volunteers and two leaders began work at an archeologic site in DNM.Work included laying stone steps, building a retaining wall, and sifting dirt for artifacts.Peak dust exposure occurred on June 19, the day most sifting oc-
Long-term outcome of older patients with newly diagnosed de novo acute promyelocytic leukemia treated with ATRA plus anthracycline-based therapy
Authors: D Martínez-Cuadrón, P Montesinos, E Vellenga, T Bernal, O Salamero, A Holowiecka, S Brunet, C Gil, C Benavente, J M Ribera, M Pérez-Encinas, J De la Serna, J Esteve, V Rubio, J González-Campos, L Escoda, M E Amutio, M Arnan, J Arias, S Negri, B Lowënberg, M A Sanz
Journal: Leukemia (2017)
Abstract NTOC-096: INTRAPERITONEAL CHEMOTHERAPY AFTER PRIMARY OR INTERVAL DEBULKING SURGERY FOR ADVANCED EPITHELIAL OVARIAN CANCER
Authors: Jessica Lee, John P Curtin, Franco M Muggia, Bhavana Pothuri, Leslie R. Boyd, Jing-Yi Chern, Melissa K Frey, Stephanie V Blank
Journal: Clinical Cancer Research (2017)

Abstract PURPOSE: To evaluate the outcomes of intraperitoneal (IP) chemotherapy compared with those of intravenous (IV) chemotherapy in patients with advanced ovarian cancer treated either with neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) or with primary debulking surgery (PDS). METHODS: Patients diagnosed with FIGO stage III or IV epithelial ovarian, fallopian tube or primary peritoneal carcinoma treated at our institutions with PDS or NACT and IDS from 2006-2014 were identified. Covariates were compared using chi-square analyses, t-tests and Mann-Whitney tests. Survival rates were calculated using the Kaplan-Meier method and compared with log rank tests and Cox multivariate regression models. RESULTS: Sixty one patients received NACT and underwent IDS with residual disease of ≤ 1 cm; 40 patients (65.6%) received IP chemotherapy and 21 patients (34.4%) were given IV chemotherapy after IDS. The median number of chemotherapy cycles was three (range 3-8), and 34 patients (85.0%) completed the prescribed dose of IP chemotherapy. The median progression free survival was 16.5 months in the IP group and 15.0 months in the IV group (p = 0.88). The estimated median overall survival was 64.0 months in the IP group and 42.0 months in the IV group (p = 0.12). During the same study period, 148 patients underwent optimal PDS after which 93 patients (83.6%) received IP chemotherapy and 55 patients (37.2%) were given IV chemotherapy. Patients after IP chemotherapy had improved survival outcomes when compared to patients after IV chemotherapy. The median progression free survival was 29.0 months after IP chemotherapy and 16.0 months after IV chemotherapy (p &amp;lt; 0.0001) and the median overall survival was 93.0 months after IP chemotherapy and 43.0 months after IV chemotherapy (p &amp;lt; 0.0001). CONCLUSIONS: Although IP chemotherapy after PDS showed improved survival, IP chemotherapy after NACT and IDS, while tolerable with high rates of completion, did not demonstrate a survival advantage over IV chemotherapy in our patients. Citation Format: Jessica Lee MD, John P Curtin MD, Franco M Muggia MD, Bhavana Pothuri MD, Leslie R. Boyd MD, Jing-Yi Chern MD, Melissa K Frey MD, Stephanie V Blank MD. INTRAPERITONEAL CHEMOTHERAPY AFTER PRIMARY OR INTERVAL DEBULKING SURGERY FOR ADVANCED EPITHELIAL OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-096.
The Integrative Human Microbiome Project: Dynamic Analysis of Microbiome-Host Omics Profiles during Periods of Human Health and Disease
Journal: Cell Host & Microbe (2014)

Much has been learned about the diversity and distribution of human-associated microbial communities, but we still know little about the biology of the microbiome, how it interacts with the host, and how the host responds to its resident microbiota. The Integrative Human Microbiome Project (iHMP, http://hmp2.org), the second phase of the NIH Human Microbiome Project, will study these interactions by analyzing microbiome and host activities in longitudinal studies of disease-specific cohorts and by creating integrated data sets of microbiome and host functional properties. These data sets will serve as experimental test beds to evaluate new models, methods, and analyses on the interactions of host and microbiome. Here we describe the three models of microbiome-associated human conditions, on the dynamics of preterm birth, inflammatory bowel disease, and type 2 diabetes, and their underlying hypotheses, as well as the multi-omic data types to be collected, integrated, and distributed through public repositories as a community resource.
Повышение эффективности лечения больных с перекрестным синдромом функциональной диспепсией и неэрозивной рефлюксной болезнью без наличия Нelicobacter рylori
Authors: D.T. Djanelidze
Journal: GASTROENTEROLOGY (2013)

При перекрестном синдроме функциональной диспепсии и неэрозивной рефлюксной болезни (ФД/НЭРБ) важно оценить и корригировать моторную функцию желудка, депрессивно-тревожные и диспептические проявления, которые влияют на качество жизни больного. Комбинация ингибитора протонной помпы с прокинетиком и препаратом мебикар для лечения больных с ФД/НЭРБ без наличия Нelicobacter рylori показала лучший результат по сравнению с другими методами лечения в разных группах.