tbuckley/cabot-search huggingface dataset:
Evaluation of the prognostic value and phenotypic determinants of Bcl-2 expression in breast invasive carcinoma.
Authors: Maria Isabel Luengo, Elisa Garcia-Garre, Francisco Martinez-Diaz, Pilar de la Morena, Elena Garcia-Martinez, Patricia Castaño, Gines Luengo-Gil, Angeles Vicente, Guzman Ortuño-Pacheco, Vicente Vicente, Francisco Ayala
Journal: Journal of Clinical Oncology (2012)

e11024 Background: Bcl-2 expression has been related to hormonal dependence and better prognosis of breast cancer. Although some reports suggest that its expression has an independent prognostic value, especially in N positive patients, the clinical relevance of determining Bcl-2 is unclear. The aim of this work was to analyze which other tumor markers predict Bcl-2 expression in breast cancer and explore its prognostic value. Methods: Immunohistochemical expression of ER, PR, Her2-neu, Ki-67, p53, cathepsin-D and Bcl-2 was prospectively examined in a series of 87 consecutive invasive BC patients. Bcl-2 was semiquantitavely scored according to a validated system (Treré, 2007). Correlation between variables was analyzed with Chi-square test; disease free (DFS) and overall survival (OS) were analyzed by log-rank test and Cox models. Results: Patient characteristics: median age 57 yrs (31-86), 64.5% postmenopausal; treatment: 49.5% breast-preserving surgery, 71.6% adjuvant-neoadjuvant chemotherapy, 72.1% adjuvant radiotherapy ; tumor histology: 83.9% ductal invasive carcinoma, 28.2% grade 3; stage: T1:57%, T2:31.2%, T3-4:8.6%, 48.9% nodal metastasis (pN1:36.7%; pN2:12.2%); tumor phenotype: 77.2% ER+ , 78.3% PgR+ , 9.7% Her2-neu+, 50.6% high Ki-67 (&gt;13%). Immunohistochemical evaluation for Bcl-2: 41/87 (47.1%) positive cases. No expression of Bcl-2 was observed in ER/PgR negative tumors (p&lt; 0.001). Bcl-2 expression was associated to histological grade 1-2 (p=0.009), absence of Her2-neu amplification (p=0.03), p53+ status (p=0.008) and lower cathepsin-D expression (p&lt;0.001), but no association was found for proliferation (Ki-67) or stage (pT or pN). A significant effect of Bcl-2 on overall (p=0.27) or disease free survival (p=0.28) was found neither in the whole group nor in pN+ or pN- subgroups. The only independent prognostic factors for DFS were hormone-sensitivity (OR: 0.10; p=0.009) and pN (OR=2.77; p=0.05). Conclusions: Expression of Bcl-2 in invasive breast cancer seems to be dependent on hormonal sensitivity, p53 status and Her2 expression; no independent prognostic value for recurrence or survival was found in our series.
Factors Associated with Bleeding and Thrombosis in Children Receiving Extracorporeal Membrane Oxygenation
Authors: Heidi J. Dalton, Ron Reeder, Pamela Garcia-Filion, Richard Holubkov, Robert A. Berg, Athena Zuppa, Frank W. Moler, Thomas Shanley, Murray M. Pollack, Christopher Newth, John Berger, David Wessel, Joseph Carcillo, Michael Bell, Sabrina Heidemann, Kathleen L. Meert, Richard Harrison, Allan Doctor, Robert F. Tamburro, J. Michael Dean, Tammara Jenkins, Carol Nicholson
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Extracorporeal membrane oxygenation (ECMO) is used for respiratory and cardiac failure in children but is complicated by bleeding and thrombosis.(1) To measure the incidence of bleeding (blood loss requiring transfusion or intracranial hemorrhage) and thrombosis during ECMO support; (2) to identify factors associated with these complications; and (3) to determine the impact of these complications on patient outcome.This was a prospective, observational cohort study in pediatric, cardiac, and neonatal intensive care units in eight hospitals, carried out from December 2012 to September 2014.ECMO was used on 514 consecutive patients under age 19 years. Demographics, anticoagulation practices, severity of illness, circuitry components, bleeding, thrombotic events, and outcome were recorded. Survival was 54.9%. Bleeding occurred in 70.2%, including intracranial hemorrhage in 16%, and was independently associated with higher daily risk of mortality. Circuit component changes were required in 31.1%, and patient-related clots occurred in 12.8%. Laboratory sampling contributed to transfusion requirement in 56.6%, and was the sole reason for at least one transfusion in 42.2% of patients. Pump type was not associated with bleeding, thrombosis, hemolysis, or mortality. Hemolysis was predictive of subsequent thrombotic events. Neither hemolysis nor thrombotic events increased the risk of mortality.The incidences of bleeding and thrombosis are high during ECMO support. Laboratory sampling is a major contributor to transfusion during ECMO. Strategies to reduce the daily risk of bleeding and thrombosis, and different thresholds for transfusion, may be appropriate subjects of future trials to improve outcomes of children requiring this supportive therapy.
Phase (Ph) I study of pazopanib (P) in combination with vinorelbine (V) in patients with metastatic non-small cell lung cancer (mNSCLC) and breast cancer (mBC).
Authors: Ryan D. Gentzler, Virginia G. Kaklamani, Rebekah Worden, Therese Zumdahl, Hala D Simm, Alfred Rademaker, Melissa Lynne Johnson, Jyoti D. Patel
Journal: Journal of Clinical Oncology (2013)

e13568 Background: V is an established treatment for mNSCLC and mBC, but combination 2nd line chemotherapy has not shown clear benefit for either disease. The anti-VEGF agent bevacizumab improves response rate and progression free survival (PFS) for mNSCLC and mBC. P is a tyrosine kinase inhibitor targeting the VEGF receptors. We hypothesize that because CYP3A4 is inhibited by P and responsible for metabolism of V, there may be synergy between P + V. This is a ph I study testing the combination of P + V in previously treated pts with mNSCLC and mBC. Methods: Pts with Stage IIIB/IV NSCLC or Stage IV mBC with ≤ 2 (lung) or ≤ 3 (breast) prior chemotherapies, no prior VEGF inhibitors, and PS 0-2 were treated with P + V. The objective was to determine the maximum tolerated dose (MTD) of P + V. Dose escalations followed a standard 3+3 design. After 6 pts, the protocol was amended to add an intermittent dosing cohort (2a) to improve tolerability. Response assessment (RA) occurred q 42 days (d) while on study. Pts had weekly toxicity assessments, and PK data was collected on d 1-2 of the first 2 cycles. Results: Eight pts (7 mNSCLC, 1 mBC) were enrolled in 3 of 9 planned cohorts. Pts received a median of 2 cycles. All pts experienced at least 1 grade (gr) 3/4 toxicity. Six dose-limiting toxicities occurred in 4 pts in cohort 2/2a. Five severe adverse events were reported in 4 pts and included thrombocytopenia, neutropenia, abdominal (abd) pain, pneumonia, and hepatotoxicity. Gr 3/4 toxicities were: neutropenia (6), fatigue (2), thrombocytopenia (1), hyperbilirubinemia (1), transaminitis (1), hypertension (1), abd pain (1), and pneumonia (1). 1 pt refused treatment after 1 cycle and had no RA. 5 of 8 pts expired due to progressive disease. No partial responses were noted. Median PFS was 66 d (95% CI 35 to 384 d). Conclusions: Combination of P + V in pre-treated mNSCLC and mBC results in high rates of gr 3/4 toxicities at all dose levels. The trial was suspended due to significant drug-drug interactions before the MTD could be determined. No further study of P in combination with V is warranted in either pt population. Clinical trial information: NCT01060514. [Table: see text]
Creating an integrative survivorship program within a conventional medical culture within a lean economic environment.
Authors: Francinne Lawrence, Brandon Reeves
Journal: Journal of Clinical Oncology (2017)

177 Background: The Institute of Medicine report, From Cancer Patient to Cancer Survivor: Lost in Transition (2005) identified gaps in services for cancer patients upon completion of their initial phase of treatment. In response to these needs, the Commission on Cancer (CoC) (2015) defined survivorship as an official phase of treatment along the cancer care continuum. This case study examined the process of developing an integrative survivorship program that introduces complementary health approaches within a conventional oncology setting using limited financial resources. Methods: A case study design was applied to examine using complementary health approaches as the foundation of a newly implemented cancer survivorship program. A regional CoC accredited community was the research site. Data was collected from: empirical literature, a self-report inventory completed by participants, and archival data and was interpreted using the logic model framework. Results: Findings revealed that using a survivorship model with complementary health approaches as its foundation within a conventional cancer treatment facility resulted in positive outcomes for cancer survivors. Seven core concepts were identified as significant to the process of developing an integrative program. Findings also showed that using a volunteer-staffed program was an effective implementation plan within a lean economic environment. Additionally, this case demonstrated that complementary components resulted in self-reported improvements among cancer survivors in mood, pain, social connectedness, stress, fatigue, and coping capacity. Conclusions: Within this case study, there were seven elements significant to the process of successfully developing and implementing an integrative survivorship program within a conventional medical cancer setting. A cancer survivorship program that integrates complementary health approaches within a conventional cancer treatment facility appears efficacious in assisting cancer survivors in addressing long-term and late-onset side effects of cancer treatment. Using a volunteer-staffed program model was effective for implementing the program within a lean economic environment.
Significance of baseline quality of life scores in predicting clinical outcomes in an international phase III trial of advanced pancreatic cancer: NCIC CTG PA.3.
Authors: Michael M. Vickers, Dongsheng Tu, Chee Lee, Paul Wheatley-Price, Wendy Parulekar, Michael Donald Brundage, Malcolm J. Moore, Heather-Jane Au, Christopher J. O'Callaghan, Derek J. Jonker, Jolie Ringash, David Goldstein
Journal: Journal of Clinical Oncology (2013)

4053 Background: There is insufficient information regarding the prognostic significance of baseline Quality of life (QoL) scores on overall survival (OS) and adverse events (AEs) in advanced pancreatic cancer. Methods: QoL was assessed prospectively using the EORTC QLQ-C30 and AEs were graded using the NCI Common Toxicity Criteria version 2.0 as part of the PA.3 trial of gemcitabine + erlotinib (G+E) vs. gemcitabine + placebo (G+P). Relevant clinical variables, ECOG performance status (PS), and QoL scores at baseline were analyzed by Cox stepwise regression to determine predictors of OS and AEs. QoL scores were transformed by square root. Results: 222 of 285 patients (pts) (78%) treated with G+E and 220 of 284 pts (77%) treated with G+P completed baseline QoL assessments. In a multivariate Cox analysis (MVA) combining all pts, better QoL physical function (PF) score independently and incrementally predicted longer OS (HR 0.91; CI: 0.83-1.00), as did non-white race (HR 0.62; CI: 0.42-0.91), PS 0-1 (vs. PS 2 - HR 0.64; CI: 0.49-0.84), locally advanced pancreatic cancer (LAPC) (vs. metastatic - HR 0.54; CI: 0.42-0.69) and G+E (vs. G+P - HR 0.79; CI: 0.64-0.98). More financial difficulty (HR 0.92; CI: 0.87-0.98) and PS 0-1 (HR: 0.36; CI: 0.17-0.77) predicted a lower risk of grade 3 or higher AEs. In a MVA of pts treated with G+E, pain intensity &lt;20 (vs. ≥ 20 - HR 0.68; CI:0.52-0.88) and LAPC (HR 0.67; CI: 0.48-0.91) were associated with longer OS, while better QoL cognitive (HR 0.71; CI: 0.50-1.00), worse constipation (HR 0.89; CI: 0.81-0.98) and worse financial scores (HR 0.86; CI: 0.78-0.94), better dyspnea score (HR 0.82; CI: 0.71-0.93) and PS 0-1 (HR 0.21; CI: 0.05-0.78) predicted for lower risk of AEs. In a MVA of pts treated with G+P, better global QoL score (HR 0.91; CI:0.85-0.98) and LAPC (HR 0.57; CI: 0.40-0.82) were predictors of longer OS while no variables predicted grade 3 or higher AEs. Conclusions: In addition to clinical variables (including physician assessed PS), patient reported QoL scores added incremental predictive information regarding survival and adverse events for advanced pancreatic cancer patients treated with systemic chemotherapy.
A prospective phase II study to determine the efficacy of GDC 0449 (vismodegib) in adults with recurrent medulloblastoma (MB): A Pediatric Brain Tumor Consortium study (PBTC 25B).
Authors: Amar J. Gajjar, Sridharan Gururangan, Ibrahim A Qaddoumi, Roger Packer, Stewart Goldman, Michael Prados, Annick Desjardins, Maryam Fouladi, Naoko Takebe, Shaoyi Li, David W. Ellison, Tom Curran, Richard J. Gilbertson, James M. Boyett
Journal: Journal of Clinical Oncology (2013)

2035 Background: Almost 80% of adult medulloblastoma are of the SHH subtype. Second line therapy for adult MB is limited; therefore we tested the efficacy of vismodegib, a small molecule inhibitor of Smoothened (SMO) among patients with this disease. Methods: Adult patients with refractory or recurrent MB and who had measureable disease were enrolled on the study. Immunohistochemistry (IHC) was used to stratify patients to Stratum A (non-SHH group); Stratum B (SHH tumors) and Stratum C (indeterminate). All patients were treated with vismodegib at 150 mg/day PO daily. Tumor response, which had to be maintained for 8 weeks to meet protocol definition of sustained response, was assessed using RECIST criteria and central imaging review. Separate but identical Simon 2-stage MinMax designs (α = 0.10) were used in strata A and B to test for evidence that sustained response rates exceeded 5% with 90% power to detect 25% sustained response rates. Thus, 3/20 sustained responses were needed to declare potential activity of vismodegib. Results: 32 patients with a median age of 30 years (range 22.4-51.9) were enrolled on the study [Stratum A (n = 8); Stratum B (n = 20); Stratum C (n = 4)], including 18 males and 14 females. No responses were observed in Strata A or C and the median duration of treatment was 1.5 months (range 0.66-2.33). Three of 20 patients enrolled on Stratum B had sustained responses. The median duration of therapy for Stratum B patients was 2.76 months (range 0.33- 13.61). Six patients were on treatment for ≥6.44 months and 3 remain on treatment after 5.42, 9.34 and 13.61 months. During course 1, 2 patients experienced grade 3 decrease in lymphocytes; 1 experienced a grade 4 thromboembolic event; and 2 experienced grade 3 toxicities (back pain &amp; syncope). During course 2, 3 patients experienced grade 3 toxicities (decrease in lymphocytes; myalgia &amp; seizure). One other patient experienced grade 3 hypophosphatemia in courses 1 and 2. Conclusions: Vismodegib has activity against recurrent or refractory adult ‘SHH-subtype’ medulloblastoma and should be considered as a therapeutic option for newly diagnosed patients with this disease. Clinical trial information: NCT00939484.
BATF2 inhibits immunopathological Th17 responses by suppressing <i>Il23a</i> expression during <i>Trypanosoma cruzi</i> infection
Authors: Shoko Kitada, Hisako Kayama, Daisuke Okuzaki, Ritsuko Koga, Masao Kobayashi, Yasunobu Arima, Atsushi Kumanogoh, Masaaki Murakami, Masahito Ikawa, Kiyoshi Takeda
Journal: The Journal of Experimental Medicine (2017)

Inappropriate IL-17 responses are implicated in chronic tissue inflammation. IL-23 contributes to Trypanosoma cruzi–specific IL-17 production, but the molecular mechanisms underlying regulation of the IL-23–IL-17 axis during T. cruzi infection are poorly understood. Here, we demonstrate a novel function of BATF2 as a negative regulator of Il23a in innate immune cells. IL-17, but not IFN-γ, was more highly produced by CD4+ T cells from spleens and livers of T. cruzi–infected Batf2−/− mice than by those of wild-type mice. In this context, Batf2−/− mice showed severe multiorgan pathology despite reduced parasite burden. T. cruzi–induced IL-23 production was increased in Batf2−/− innate immune cells. The T. cruzi–induced enhanced Th17 response was abrogated in Batf2−/−Il23a−/− mice. The interaction of BATF2 with c-JUN prevented c-JUN–ATF-2 complex formation, inhibiting Il23a expression. These results demonstrate that IFN-γ–inducible BATF2 in innate immune cells controls Th17-mediated immunopathology by suppressing IL-23 production during T. cruzi infection.
Control of Cell Alignment and Morphology by Redesigning ECM‐Mimetic Nanotopography on Multilayer Membranes
Authors: Maria P. Sousa, Sofia G. Caridade, João F. Mano
Journal: Advanced Healthcare Materials (2017)

Inspired by native extracellular matrix (ECM) together with the multilevel architecture observed in nature, a material which topography recapitulates topographic features of the ECM and the internal architecture mimics the biological materials organization is engineered. The nanopatterned design along the XY plane is combined with a nanostructured organization along the Z axis on freestanding membranes prepared by layer‐by‐layer deposition of chitosan and chondroitin sulfate. Cellular behavior is monitored using two different mammalian cell lines, fibroblasts (L929) and myoblasts (C2C12), in order to perceive the response to topography. Viability, proliferation, and morphology of L929 are sensitively controlled by topography; also differentiation of C2C12 into myotubes is influenced by the presence of nanogrooves. This kind of nanopatterned structure has also been associated with strong cellular alignment. To the best of the knowledge, it is the first time that such a straightforward and inexpensive strategy is proposed to produce nanopatterned freestanding multilayer membranes. Controlling cellular alignment plays a critical role in many human tissues, such as muscles, nerves, or blood vessels, so these membranes can be potentially useful in specific tissue regeneration strategies.
MLN9708, an investigational proteasome inhibitor, in patients (pts) with solid tumors: Updated phase I results.
Authors: David C. Smith, Daniel Sullivan, Jeffrey R. Infante, John S. Kauh, Lillian L. Siu, Gordana Vlahovic, John A. Thompson, Neeraj Gupta, Alessandra Di Bacco, Guohui Liu, Thea Kalebic
Journal: Journal of Clinical Oncology (2012)

e13603 Background: MLN9708 is a potent, reversible, orally bioavailable, and specific 20S proteasome inhibitor. This study (NCT00830869) assessed the safety, MTD, PK, PD, and antitumor activity of intravenous (IV) MLN9708 in pts with solid tumors. Methods: Pts aged ≥18 yrs (ECOG PS 0–2) received increasing doses of IV MLN9708 (starting at 0.125 mg/m 2 ) on days 1, 4, 8, and 11 of 21-day cycles, for up to 12 cycles. MTD expansion cohorts included head and neck (H&amp;N) cancer, non-small cell lung cancer, soft tissue sarcoma, prostate cancer, and a tumor PD expansion cohort. Plasma PK and blood PD data were analyzed by a non-compartmental method using WinNonlin software v5.3. The candidate PD biomarker ATF-3 was assessed using IHC. Results: 113 pts were enrolled; 23 in dose escalation and 96 in MTD expansion (includes 6 from dose escalation) cohorts. Median age of these heavily pretreated pts was 58 yrs (range 29–80). MTD was established as 1.76 mg/m 2 . Pts have received a median of 2 cycles (range 1–12) to date (data cut-off Dec 1, 2011); 22 received ≥4 cycles. 88% had ≥1 drug-related AE; most common drug-related AEs included fatigue (40%), thrombocytopenia (39%), rash (high level term) (33%), and nausea (32%). 52% of pts experienced grade ≥3 drug-related AEs, including thrombocytopenia (20%) and rash (9%). Drug-related peripheral neuropathy (PN) was seen in 13% of pts; 2 pts had grade 3 PN. 25% had drug-related SAEs, 15% discontinued due to AEs; 7 pts died, all unrelated to treatment. Of 75 response-evaluable pts, 26 achieved SD. A partial response (PR) was observed in a pt in the H&amp;N cohort; response was achieved after 4 cycles and maintained through 8 cycles. Change in ATF-3 levels in tumor tissue post treatment was seen in 6 patients with tumor biopsy samples, indicating proteasome inhibition. PK data showed three-exponential plasma disposition, half-life of ~4–8 days, and dose linearity from 0.5–2.34 mg/m 2 . At MTD, maximal 20S proteasome inhibition in blood was approximately 60% at 0.08 hours. Whole blood PD effect was immediate and dose dependent. Conclusions: These data suggest that twice-weekly IV MLN9708 has a generally manageable safety profile and potential clinical utility; updated results will be presented.
A phase II study of the androgen signaling inhibitor ARN-509 in patients with castration-resistant prostate cancer (CRPC).
Authors: Dana E. Rathkopf, Neal Shore, Emmanuel S. Antonarakis, William R. Berry, Joshi J. Alumkal, Ronald Tutrone, Mansoor N. Saleh, Charles H. Redfern, Ralph J. Hauke, Glenn Liu, Jill Elise Steinbrecher, Daniel Costin Danila, Tracy Curley, Gabrielle Arauz, Peter J. Rix, Edna Chow Maneval, Isan Chen, Howard I. Scher
Journal: Journal of Clinical Oncology (2012)

TPS4697 Background: ARN-509 is a novel small molecule androgen signaling inhibitor that impairs AR nuclear translocation and binding to DNA, inhibiting tumor growth and promoting apoptosis, with no partial agonist activity. Preclinical data suggests that the maximal therapeutic index of ARN-509 can be achieved at low steady state plasma levels with minimal toxicity (Clegg et al, 2012). Enrollment in the Phase 1 dose escalation study of ARN-509 in patients with progressive CRPC with and without prior chemotherapy was completed in January 2012. The recommended Phase 2 dose of 240 mg was determined based on safety, PSA kinetics, and pharmacokinetic and pharmacodynamic analysis (Rathkopf et al, GU ASCO, 2012). Methods: The primary objective of this Phase 2 study is to determine the PSA response at 12 weeks according to Prostate Cancer Working Group 2 (PCWG2) Criteria (Scher et al, 2008). Three expansion cohorts will enroll a total of 80-90 patients for treatment with 240 mg continuous oral ARN-509 daily. These cohorts include: 1) non-metastatic treatment-naïve CRPC (50 patients); 2) chemotherapy-naïve metastatic (m) CRPC (20 patients); and 3) chemotherapy-naïve, post abiraterone mCRPC (10-20 patients). The effect of food on the PK of ARN-509 and the effect of ARN-509 on ventricular repolarization will also be evaluated. Phase 2 enrollment is ongoing. DOD/PCF PCCTC trial sponsored by Aragon Pharmaceuticals. NCT01171898.
Using a Home Ventilator with a Child
Authors: Christopher D Baker, Ann C Halbower, Laura M Sterni, Marianna Sockrider
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Why does my child need a ventilator?Breathing is the process of air going into and out of the lungs.When breathing, oxygen enters into the body and carbon dioxide is removed or exhaled.Respiratory failure occurs when a person is unable to maintain normal oxygen or carbon dioxide levels.There are a number of medical problems that can lead to respiratory failure and the need for a child to use a ventilator chronically.Some examples are: ■ ■ Conditions that affect the lungs (extremely premature birth, severe infections, other lung diseases), ■ ■ Disease of the muscles and bones that may lead to weak breathing, ■ ■ Disease of the nervous system that lead to poor breathing effort or weakness.Sometimes there are several problems that contribute to the need for a ventilator.You can talk to your child's healthcare provider about why your child needs ventilator support.