tbuckley/cabot-search huggingface dataset:
Combined MEK and mTOR suppression is synergistic in human NSCLC and is mediated via inhibition of protein translation
Authors: H. M. McDaid, M. Legrier, C. H. Yang, H. G. Yan, L. Lopez-Barcons, S. M. Keller, S. B. Horwitz
Journal: Journal of Clinical Oncology (2007)

10615 Background: Lung cancer is a heterogeneous disease characterized by the acquisition of somatic mutations in numerous protein kinases, including components of RAS and AKT. These intersect at various points rendering the network highly redundant. Hence, dual suppression of both, using MEK and mTOR inhibitors may be a promising rational drug combination that can overcome the intrinsic plasticity of this signaling network. Methods: The concurrent combination of the MEK inhibitor CI-1040 and the mTOR inhibitor AP23573 was evaluated in non-small cell lung cancer (NSCLC) cell lines, using the combination index method of Chou and Talalay. The concurrent combination of Rapamycin and the MEK inhibitor PD0325901 was also evaluated in animal models of human lung cancer. Results: The MEK inhibitors, CI-1040 or PD0325901, in combination with the mTOR inhibitor rapamycin, or its analog AP23573, were synergistic in human lung cancer cell lines. Statistically significant enhancement of cell death by the combination of MEK and mTOR inhibitors was not observed. Rather, synergism was associated with suppression of proliferation and inhibition of protein translation. Concurrent suppression of both MEK and mTOR inhibited ribosomal biogenesis by forty percent after twenty-four hours and was associated with a block in the initiation phase of translation. Furthermore, the combination of PD0325901 and rapamycin was significantly superior to either drug alone, or PD0325901 at the maximum tolerated dose, in xenograft and human heterotransplanted lung tumor models grown in nude mice. Conclusions: These data support therapeutic strategies in lung cancer that simultaneously suppress RAS and mTOR signaling networks, and provide evidence that both pathways converge on factors that regulate protein translation initiation. No significant financial relationships to disclose.
Central Review of PET/TC: First Spanish Experience in a Phase 2 Randomized Trial in Diffuse Large B-Cell Lymphoma (DLBCL) Patients
Authors: Mónica Coronado-Poggio, Ana Cristina Hernandez-Martinez, M. Pilar Sarandeses, Montse Cortés-Romera, Marc Simó-Perdigó, Xavier Setoain, Amanda Rotger, Carlos Grande-Garcia, González-Barca Eva, Isabel Borrego, Pilar Tamayo, Lina García-Cañamaque, Javier Banzo, González Francisco Manuel, Rodriguez Begoña, Bello Pilar, Pablo Sopena, Fernando Ortega, Ana Allende, Jaime Daumal, Jose Manuel Nogueiras, Armando López-Guillermo, Dolores Caballero
Journal: Blood (2015)
Anti-Idiotypic-Designed-Ankyrin-Repeat-Molecules (DARPins) Universally Neutralize Plasma-Derived Autoantibodies in Acquired TTP Patients
Authors: Monica M Schaller, Monique Vogel, Magdalena Skowronska, Irmela Sulzer, Johanna A. Kremer Hovinga Strebel
Journal: Blood (2015)
Prostate Cancer Early Detection, Version 2.2015
Authors: Peter R. Carroll, J. Kellogg Parsons, Gerald Andriole, Robert R. Bahnson, Daniel A. Barocas, Erik P. Castle, William J. Catalona, Douglas M. Dahl, John W. Davis, Jonathan I. Epstein, Ruth B. Etzioni, Thomas Farrington, George P. Hemstreet, Mark H. Kawachi, Paul H. Lange, Kevin R. Loughlin, William Lowrance, Paul Maroni, James Mohler, Todd M. Morgan, Robert B. Nadler, Michael Poch, Chuck Scales, Terrence M. Shaneyfelt, Marc C. Smaldone, Geoffrey Sonn, Preston Sprenke, Andrew J. Vickers, Robert Wake, Dorothy A. Shead, Deborah Freedman-Cass
Journal: Journal of the National Comprehensive Cancer Network (2015)

Prostate cancer represents a spectrum of disease that ranges from nonaggressive, slow-growing disease that may not require treatment to aggressive, fast-growing disease that does. The NCCN Guidelines for Prostate Cancer Early Detection provide a set of sequential recommendations detailing a screening and evaluation strategy for maximizing the detection of prostate cancer that is potentially curable and that, if left undetected, represents a risk to the patient. The guidelines were developed for healthy men who have elected to participate in the early detection of prostate cancer, and they focus on minimizing unnecessary procedures and limiting the detection of indolent disease.
Long Term Treatment with Hydroxyurea Does Not Prevent Development of Renal Dysfunction and Osteodystrophy in Patients with Sickle Cell Disease.
Authors: Ersi Voskaridou, Evangelos Terpos, Alexandra Margeli, Eugenia Hantzi, Eleni Stoupa, Aphroditi Loutradi, Ioannis Papassotiriou, Dimitris Loukopoulos
Journal: Blood (2004)
What Is the Frequency of Transplant-Eligible Multiple Myeloma Patients Being Cured? the Impact of an MGUS-like Signature at Diagnosis and MRD-Negativity
Authors: Bruno Paiva, Maria Belen Vidriales, Noemi Puig, Teresa Cedena, Lourdes Cordon, Maria-Victoria Mateos, Joaquin Martinez-López, Laura Rosiñol, Alfonso Garcia de Coca, Natalia De Las Heras, Josefina Galende, Jose Mariano Hernandez, Luis Palomera, Javier De La Rubia, Joan Blade, Jesus San Miguel, Juan Jose Lahuerta
Journal: Blood (2015)
Prognostic significance of vascular endothelial growth factor (VEGF), VEGF receptors (VEGFR), and vascularity in diffuse large B-cell lymphoma treated with immunochemotherapy (R-CHOP)
Authors: D. Gratzinger, R. Advani, S. Zhao, N. Talreja, R. J. Tibshirani, S. J. Horning, R. Levy, I. S. Lossos, R. D. Gascoyne, Y. Natkunam
Journal: Journal of Clinical Oncology (2009)

8581 Background: Diffuse large B cell lymphoma (DLBCL) cells coexpress VEGF, VEGFR1 and VEGFR2. In patients (pts) treated with CHOP chemotherapy alone, VEGFR1 predicted improved overall survival (OS) while microvessel density (MVD) predicted poorer OS; VEGF and VEGFR2 were not predictive (Lab Invest. 2008;88:38). We now assess these factors in pts treated with R-CHOP. Methods: 162 pts with de novo DLBCL treated with R-CHOP and median followup of 44 months were evaluated retrospectively with immunohistochemistry on tissue microarrays. Scoring: VEGF, VEGFR1, VEGFR2, and phosphoVEGFR2 (pVEGFR2) in lymphoma cells (categorical variable) &lt;5%, none; 5–30%, weak; &gt;30%, strong. MVD (continuous variable): average CD34+ microvessels/4 hpf. Statistics: univariate Cox proportional hazards regression, and multivariate Cox regression for testing independence from the International Prognostic Index (IPI) for two endpoints, OS and progression-free survival (PFS). Pearson chi-square testing for independence of variables. Results: VEGF and MVD did not correlate with OS or PFS. Pts with higher VEGFR2 (53%) had poorer OS but not PFS independent of the IPI (z=3.15, p=0.0016; 2 yr OS 100%/84%/76%). Pts with any pVEGFR2 (13%) had worse PFS independent of IPI (z=1.98, p=0.048) and a trend toward poor OS (p=0.056). VEGFR1 did not correlate with OS or PFS in the group as a whole. Since VEGFR1 and VEGFR2 expression correlate strongly (Χ 2 =56, p =9.8E-12) opposing associations with outcome could be masked. On subset analysis the 39% of pts with weak VEGFR2 had better OS with higher VEGFR1 (z=-1.64, p=0.016; 2 yr OS 68%/85%/92%). Conclusions: In contrast to our prior observations in CHOP treated pts, in DLBCL treated with R-CHOP MVD was not prognostically significant. The association of VEGFR1 with better OS was previously seen with CHOP alone, whereas the correlation of VEGFR2 and phosphorylated VEGFR2 with poorer OS was only seen with R-CHOP. Independent confirmation will be important, especially because multiple comparisons were made with 5 predictors and 2 endpoints tested. It is possible that VEGFR1 and VEGFR2 oppose each other functionally; future studies are indicated to address the mechanism of this effect. No significant financial relationships to disclose.
Dietary grape-derived resveratrol for colon cancer prevention.
Authors: M. Martinez, C. Hope, K. Planutis, M. Planutiene, A. Pontello, B. Duarte, C. G. Albers, R. F. Holcombe
Journal: Journal of Clinical Oncology (2010)

3622 Background: Resveratrol (Res), a stilbene found in the skin of grapes and wine, inhibits Wnt signaling in vitro and is purported to have colon cancer prevention activity. Methods: We conducted a clinical trial (NCT00578396) to determine if dietary derived Res inhibits Wnt signaling in colonic mucosa. 30 normal volunteers were placed on a controlled low Res diet for 2 weeks after which sigmoidoscopy was performed to biopsy colonic mucosa. Participants were then assigned to one of three cohorts ingesting 1/3, 2/3 or 1 lbs of red grapes per day for 2 weeks, followed by an additional biopsy. Biopsies were evaluated for Ki67 expression by fluorescent IHC. Parallel samples were processed for RNA to evaluate Wnt pathway target gene expression by qRT-PCR. Pre- and post-grape results were compared by the Wilcoxon signed rank test. Results: A diet supplemented with grapes led to a reduction in weight (174.5 lbs to 172.1 lbs; p = 0.0018) and fat intake (35.1 ± 7.8% to 30.8 ± 6.1%; p = 0.01). Grape ingestion decreased colonic mucosal proliferation: cyclinD1 expression decreased significantly (p < 0.01) as did positive staining for Ki67 (18.3 ± 6.75 to 11.9 ± 4.67; p = 0.016) in colonocytes in the bottom 1/3 of the colonic crypt. Expression of several Wnt target genes was downregulated though the suppression was statistically significant only for cyclinD1 and CD133. Interestingly, participants over the age of 50 expressed significantly higher basal levels of cyclinD1, axin II, c-jun, c-myc, and CD133 (all p < 0.05) compared to younger subjects. Grape ingestion in the older participants reduced expression to levels equivalent to basal levels in younger individuals. Conclusions: After just two weeks, a grape supplemented diet reduced colonic mucosal proliferation and expression of Wnt target genes and a colonic stem cell marker (CD133). These data suggest a mechanism for and potential utility of dietary approaches with Res rich foods for colon cancer prevention. No significant financial relationships to disclose.
Rapamycin-Based GvHD Prophylaxis Is Effective in T-Cell Replete Unmanipulated Haploidentical Peripheral Stem Cell Transplantation for Advanced Haematological Malignancies: Results in 46 Patients.
Authors: Jacopo Peccatori, Daniela Clerici, Carlo Messina, Alessandra Forcina, Attilio Bondanza, Roberto Crocchiolo, Maria Teresa Lupo Stanghellini, Andrea Assanelli, Magda Marcatti, Fabio Giglio, Simone Claudiani, Sara Mastaglio, Simona Malato, Alessandro Crotta, Manuela Battaglia, Paola Ronchi, Salvatore Gattillo, Silvano Rossini, Consuelo Corti, Massimo Bernardi, Sarah Marktel, Maria Ester Bernardo, Chiara Bonini, Maria Grazia Roncarolo, Franco Locatelli, Fabio Ciceri
Journal: Blood (2009)
Efficacy of Second-line Targeted Therapy for Renal Cell Carcinoma According to Change from Baseline in International Metastatic Renal Cell Carcinoma Database Consortium Prognostic Category
Authors: Ian D. Davis, Wanling Xie, Carmel Pezaro, Frede Donskov, J. Connor Wells, Neeraj Agarwal, Sandy Srinivas, Takeshi Yuasa, Benoit Beuselinck, Lori A. Wood, D. Scott Ernst, Ravindran Kanesvaran, Jennifer J. Knox, Allan Pantuck, Sadia Saleem, Ajjai Alva, Brian I. Rini, Jae-Lyun Lee, Toni K. Choueiri, Daniel Y.C. Heng
Journal: European Urology (2016)
Clinical Relevance of a Pharmacogenetic Approach Using Multiple Candidate Gene Polymorphisms To Predict Response and Resistance to Imatinib Mesylate Therapy in Chronic Myeloid Leukemia.
Authors: Dong Hwan (Dennis) Kim, Lakshmi Sriharsha, Wei Xu, Suzanne Kamel-Reid, Xiangdong Liu, Katherine Siminovitch, Hans Messner, Jeffrey Lipton
Journal: Blood (2007)
Synergy between CD52 and CD20 Antibody-Induced Apoptosis Correlates with the Extent of Co-Expression of CD20 and CD52 Antigens on Mononuclear Cells Derived from Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin’s Lymphoma (NHL) Patients: Implications to Antibody-Based Therapy.
Authors: Yair Gazitt, Cagla Akay, Deborah Doxey, Charles Thomas
Journal: Blood (2004)
Impact of High-Resolution HLA Matching on Outcomes of Unrelated Donor Hematopoietic Stem Cell Transplantation.
Authors: Seok Yun Kang, Hyeoung Il Kim, Hyun Woo Lee, Jun Ho Jang, Joon Seong Park, Jin Hyuk Choi, Ho Yeong Lim, Hugh C. Kim
Journal: Blood (2005)
Tumor size as prognostic factor in osteosarcomas
Authors: M. G. Pallotta, S. Specterman, H. Gioseffi, M. E. Lopez Lincuez, G. Z. Beguelin, J. M. Lastiri, M. S. Varela, M. Makiya, E. Dibar, D. L. Muscolo
Journal: Journal of Clinical Oncology (2004)

9061 Background: Multidisciplinary treatment of osteosarcoma has achieved overall survival greater than 70%. Several prognostic factors have been described. In our country it is frequent to diagnose voluminous tumors. Greater tumors usually have worst outcome because of greater chance of tumor resistance. In order to assess the relation between tumor size and prognosis in high-grade osteosarcoma, we performed the following analysis. Methods: Retrospectively, tumor volume was determined pre and post chemotherapy in 40 patients with histological diagnosis of high-grade osteosarcoma stage IIb. All of them received neo-adjuvant chemotherapy (ifosfamide + doxorrubicin + high dose methotrexate). Tumor size was determined in plain radiography (RX) (2 dimensions) and magnetic resonance imaging (MRI) (3 dimensions), according to RECIST criteria. Tumor calcifications, pathological fracture and skip metastasis were evaluated. Results: 22 men/18 women. Median age 17 years (range 11–47). Localizations: femur (25), tibia (9), fibula (3), humerus (2) and pelvis (1). Six patients presented pathological fracture and only one skip metastasis. 14 patients had systemic progression. Median survival was 96 months (IC 95%: 80–109) and median disease free survival was 84 months (IC 95%: 69–100). Tumor volume pre chemotherapy greater than >1500 cm3 (MRI) was the variable most predictor of mortality (p=0.02). Median survival was 48 months (IC 95%: 27–70) in tumors greater than 1500 cm3 versus 104 months (IC 95%: 91–118) in those tumors smaller than 1500cm3 (p=0.001). Intensification of radiological calcification, pathological fracture and changes in size pre and post chemotherapy did not have prognostic value. Conclusions: tumor measurement at diagnosis can distinguish high-risk populations. MRI is superior to RX to estimate prognostic size value. MRI does not sub estimate soft parts of the tumor and allows delimiting better tumor margins. No significant financial relationships to disclose.
Comment on Rubino et al. Metabolic Surgery in the Treatment Algorithm for Type 2 Diabetes: A Joint Statement by International Diabetes Organizations. Diabetes Care 2016;39:861–877
Authors: Ana M. Ramos-Leví, Miguel A. Rubio
Journal: Diabetes Care (2017)

Diabetes remission after bariatric surgery: is that the only question? Remission of type 2 diabetes (T2D) after bariatric surgery (BS) has become a “trending topic.” A recent consensus conference developed global guidelines regarding the benefits and limitations of metabolic surgery for T2D (1).

Initial bariatric surgical series reported rates of T2D reversal of 37–95%, depending on the criteria used, the cohort of patients, the type of BS, and the time of follow-up. Then, using the criteria of Buse et al. (2), remission rates stabilized around a more realistic 50% 1 year after BS. However, studies have still used “a la carte” criteria, which, although medically less stringent—for instance, using HbA1c levels (3)—could be considered …
Smad4 is predictive for response in neoadjuvant treated esophageal squamous cell carcinoma
Authors: B. L. Brücher, F. Pühringer-Oppermann, M. Sarbia
Journal: Journal of Clinical Oncology (2007)

4591 Background: The evaluation of the prevalence of TGF-β1-pathway gene expressions (TGF-β1, Smad7 and Smad4) and its predictive value for histopathological response in patients with esophageal squamous cell carcinoma and neoadjuvant radiochemotherapy. Methods: RNA was prepared from pretherapeutic taken formalin-fixed and paraffin-embedded biopsies of 98 patients with histological proven locally advanced ESCC (cT3, cN0/+, cM0), who underwent preoperative combined simultaneous RTx/CTx with consecutive esophagectomy. All tumor biopsies underwent tumor-cell-microdissection, RNA-extraction and real-time TaqMan reverse transcriptase- polymerase chain reaction. RT-PCR-measurements were made by doublet measuring. Quantitative mRNA expression of TGFβ1 and its downstream effectors Smad4 and Smad7 was correlated with histopathological response by the percentage of residual tumor cells. Analysis was performed by dichotomized calculation and for determination of a cut-off by ROC-analysis. Results: Dichotomized analysis revealed the following median values: Smad4=0.098± 0.7 (CI: 0.024–0.396), Smad7=1.9250±1.7 (CI: 0.4–16.1) and TGFβ1=6.427±4.86 (CI: 0- 25.7). Cross-tabs-analysis for histopathological response disclosed the following correlations: TGFβ1 (p=0.671), Smad7 (p=0.672) and Smad4 (p=0.038). ROC-analysis revealed a Smad4-cut-off of 0.0635 by an area-under-curve of 6280 (p=0.038). Consecutive re-cross-tabs-analysis of histopathological response revealed a sensitivity of 80% (p=0.013). The pretherapeutic predictive value of Smad4 was 73%. Medians in survival was not reached during follow-up, whether TGFβ1 (p=0.519), Smad7 (p=0.5728) nor Smad4 (p=0.552). Histopathological responders showed a significant better survival compared to nonresponders (p&lt;0.0001). Conclusions: High levels of Smad4 gene expression are significantly correlated with histopathological response. ROC-Analysis identified a cut-off of Smad4 with a sensitivity of 80% and a predictive value of 73%. No significant financial relationships to disclose.
A mechanistic model predicting hematopoiesis and tumor growth to optimize docetaxel + epirubicin (ET) administration in metastatic breast cancer (MBC): Phase I trial
Authors: B. You, C. Meille, D. Barbolosi, B. Tranchand, J. Guitton, C. Rioufol, A. Iliadis, G. Freyer
Journal: Journal of Clinical Oncology (2007)

13013 Background: Mathematical modeling is a powerful approach to provide functional description of a real process. In medicine and biology, models are established on the basis of available clinical observations and biological covariates. Modeling applied in cancer treatment is a valuable tool to perform drug dosage adjustments. We used this methodology to regulate ET administration by predicting haematopoiesis and tumor growth in patients with MBC in a phase I trial. Methods: We developed a mechanistic model to describe leukopoiesis / thrombopoiesis / tumor growth in MBC patients under bimonthly ET + G-CSF. The model was first validated using data from clinical trials [Viens, Am J Clin Oncol. 2001;24:328, Chugai lenograstim database] and prospectively applied to individualize ET administration (dose rate and duration). The model optimizes the drug doses that could minimize the tumour burden while respecting a priori fixed constraints on deepness / duration of neutropenia and thrombocytopenia. First course administration was fixed ahead. At following courses, schedules were individually adjusted. At first dose level, patients received ET: 85/85 mg over a 48 h period with various, electronically- controlled infusion rates every 2 weeks. At dose level 2, doses were 100/100 mg. Results: Between 06/2005 and 06/2006, 3.5 median courses (range: 2–6) were administered to 6 patients (level 1: 3; level 2: 3). Rates of grade 3–4 neutropenia and thrombocytopenia were 47 and 0 % respectively. Observed toxicities were close to those predicted by the model. Predicted vs. observed neutrophil counts linear regression was significant (p&lt;0.001). Moreover, 83 and 95 % weighted residuals were comprised between [-2; +2] at all courses and first course respectively. No grade 3–4 non-hematological toxicity was observed. Partial responses were noted in 2 patients (33%) and disease stabilization in 3 patients (50%). Conclusions: We report the preliminary results of the first trial using mechanistic modeling to improve cancer chemotherapy. Using this approach, we have successfully predicted the behavior of a complex biological system and individualized drugs administration in a phase I trial. No significant financial relationships to disclose.
DrGoniometer: a reliable smartphone app for joint angle measurement
Authors: Stefano Vercelli, Francesco Sartorio, Elisabetta Bravini, Giorgio Ferriero
Journal: British Journal of Sports Medicine (2016)

DrGoniometer.

Medicine.

Apple (iOS 7.0 or later). Available for iPhone, iPad and iPod touch.

iOS €11.99, US$11.99.

DrGoniometer is the first app validated for image-based goniometry.1 Its aim is to provide quick, simple measurement of joint mobility with all the advantages of photographic or video goniometry. Measurement is obtained by positioning a virtual goniometer—represented by two or three markers visible on the smartphone screen—on a photograph or video obtained via the smartphone camera (figure 1⇓–3). Picture taking is supported with perpendicular reference to ground level, iPhone alignment identification and patient central position referencing. The clinician chooses the desired joint or goniometric procedure from a list and the respective motion to measure (eg, flexion and extension), then simply takes a photo of the limb, saves it, measures the joint angle and observes the value.1 DrGoniometer also offers the possibility to analyse …
Effect of Medicaid Coverage on ED Use — Further Evidence from Oregon’s Experiment
Authors: Amy N. Finkelstein, Sarah L. Taubman, Heidi L. Allen, Bill J. Wright, Katherine Baicker
Journal: New England Journal of Medicine (2016)

Newly insured people will most likely use more health care across settings, including the emergency department, for at least 2 years, rather than substituting office visits for ED use, according to an analysis of additional data from Oregon's Medicaid lottery.
Bone metastases in soft tissue sarcoma patients: A survey of natural, prognostic value, and treatment.
Authors: Bruno Vincenzi, Daniele Santini, Gaia Schiavon, Anna Maria Frezza, Palma Dileo, Marianna Silletta, Francesco Bertoldo, Giuseppe Badalamenti, Giacomo G. Baldi, Stefania Zovato, Rossana Berardi, Marco Tucci, Jeremy Whelan, Roberto Tirabosco, Angelo Paolo Dei Tos, Giuseppe Tonini
Journal: Journal of Clinical Oncology (2012)

10063 Background: Given the limited data currently available, we surveyed the natural history of bone metastases in patients affected by soft tissue sarcoma (STS). Methods: This retrospective, multicenter, observational study evaluated data from 135 patients with STS metastatic to the bone who presented between 2001 and 2011. For all patients, we recorded the primary tumor histological subtype, bone metastases characteristics (onset, site), type of treatment received (surgery, radiotherapy, zoledronic acid), type and frequency of skeletal related events (SRE) and disease outcome. Results: The most represented histological subtypes among the enrolled patients were leiomyosarcoma (27%), angiosarcoma (13%) and spindle cell sarcoma (8%). The spine was the most common site for bone involvement (51%), followed by hip/pelvis (20%), long bones (15%) and other sites (14%). In 27% of cases, bone metastases were present at the time of diagnosis. Fiftyfour patients (40%) developed SREs and the median time to first SRE (if developed) was 4 months. The most common SRE was the need for radiotherapy occurring in 28% of patients followed by pathologic fracture (22%). Patients survived for a median of 6 months after bone metastases diagnosis. The occurrence of a SRE was associated with a decreased overall survival (P=0.04). A subgroup analysis revealed that zoledronic acid significantly prolonged median time to first SRE (5 versus 2 months; P = 0.002). Conversely, It did not determine an improvement in terms of overall survival, even if favorable trend was identified (median, 7 versus 5 months, respectively; P = 0.105). Conclusions: This study illustrates the burden of bone disease from STS and supports the use of zoledronic acid in this setting.