tbuckley/cabot-search huggingface dataset:
Early palliative care: Recognizing the patient in need of palliative care and proactive palliative care planning with the GP as coordinator—An RCT.
Authors: Yvonne Engels, Marieke de Groot, Bregje Thoonsen, Stans Verhagen, Kris Vissers, Chris van Weel
Journal: Journal of Clinical Oncology (2014)

69 Background: In the Netherlands, many patients that might profit of palliative care don't receive it or don't receive it until the terminal phase. GPs in the Netherlands consider palliative care as an important task, but they don't feel confident to recognize the patients in need of palliative care and to provide it in a structured way. For that reason, we performed an RCT in which GPs in the intervention condition received training in recognozing the palliative patient and in early palliative care provision. Methods: Randomized controlled cluster trial (intention to treat) with GP as cluster. GPs in the intervention group received a 5-hours training in early recognition of the palliative patient, with the help of the RADPAC tool, and in proactive palliative care planning. They were invited to identify the patients in need of palliative care and provide the care as learned in the training. Primary outcome: number of out-of-hours contacts with the out-of-hours service, as measured retrospectively by analysing all patients that died during the intervention period of one year. Secondary outcomes: number of hospitalizations and place of death, also collected retrospectively. Results: Within one month, 159 GPs showed their interest to participate. Per responding GP, a mean number of 7 patients died during the intervention period. About 45% of the patients died at home, in both study groups. We did not find differences in out-of-hours contacts, hospitalizations and place of death between intervention and control group. Conclusions: We did not find differences between intervention and control group. As learning to identify the palliative patients was part of the intervention, we were not able to collect patient-related outcomes in the control group. This might explain why we did not find significant effects of early palliative care, in contrast to findings of Temel et al, and Zimmermann et al. and Bakitas et al. For that reason, we recommend to measure quality of life as primary outcome. Clinical trial information: NTR2815.
Tracing the Archaeal Origins of Eukaryotic Membrane-Trafficking System Building Blocks
Authors: Christen M. Klinger, Anja Spang, Joel B. Dacks, Thijs J.G. Ettema
Journal: Molecular Biology and Evolution (2016)

In contrast to prokaryotes, eukaryotic cells are characterized by a complex set of internal membrane-bound compartments. A subset of these, and the protein machineries that move material between them, define the membrane-trafficking system (MTS), the emergence of which represents a landmark in eukaryotic evolution. Unlike mitochondria and plastids, MTS organelles have autogenous origins. Much of the MTS machinery is composed of building blocks, including small GTPase, coiled-coil, beta-propeller + alpha-solenoid, and longin domains. Despite the identification of prokaryotic proteins containing these domains, only few represent direct orthologues, leaving the origins and early evolution of the MTS poorly understood. Here, we present an in-depth analysis of MTS building block homologues in the composite genome of Lokiarchaeum, the recently discovered archaeal sister clade of eukaryotes, yielding several key insights. We identify two previously unreported Eukaryotic Signature Proteins; orthologues of the Gtr/Rag family GTPases, involved in target of rapamycin complex signaling, and of the RLC7 dynein component. We could not identify golgin or SNARE (coiled-coil) or beta-propeller + alpha-solenoid orthologues, nor typical MTS domain fusions, suggesting that these either were lost from Lokiarchaeum or emerged later in eukaryotic evolution. Furthermore, our phylogenetic analyses of lokiarchaeal GTPases support a split into Ras-like and Arf-like superfamilies, with different prokaryotic antecedents, before the advent of eukaryotes. While no GTPase activating proteins or exchange factors were identified, we show that Lokiarchaeum encodes numerous roadblock domain proteins and putative longin domain proteins, confirming the latter's origin from Archaea. Altogether, our study provides new insights into the emergence and early evolution of the eukaryotic membrane-trafficking system.
CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer
Authors: Piero Dalerba, Debashis Sahoo, Soonmyung Paik, Xiangqian Guo, Greg Yothers, Nan Song, Nate Wilcox-Fogel, Erna Forgó, Pradeep S. Rajendran, Stephen P. Miranda, Shigeo Hisamori, Jacqueline Hutchison, Tomer Kalisky, Dalong Qian, Norman Wolmark, George A. Fisher, Matt van de Rijn, Michael F. Clarke
Journal: New England Journal of Medicine (2016)

The identification of high-risk stage II colon cancers is key to the selection of patients who require adjuvant treatment after surgery. Microarray-based multigene-expression signatures derived from stem cells and progenitor cells hold promise, but they are difficult to use in clinical practice.
Carboplatin, Paclitaxel and Gemcitabine As Induction Treatment Followed By Surgery and/or Radiotherapy: an Exploratory Analysis in Locally-Advanced Non-Small Cell Lung Cancer (Nsclc)
Authors: L. Bonanno, G. Zago, M. Schiavon, P. l De Bianco, G. Pasello, V. Polo, F. Canova, F. Rea, L. Loreggian, P.F. Conte, A. Favaretto
Journal: Annals of Oncology (2014)
A phase I study of the AKT inhibitor (MK-2206) with concurrent trastuzumab and lapatinib in patients with HER2-positive solid tumors.
Authors: H. S. Han, C. Swanton, Y. Y. Janjigian, S. C. Sutherland, S. Chandarlapaty, R. Lehman, N. Hamilton, J. Knowles, R. Lee, L. Yan, D. Sullivan, C. Hudis
Journal: Journal of Clinical Oncology (2011)

3028 Background: Trastuzumab (T) is effective in HER2 overexpressing breast and gastric cancer, but patients eventually develop clinical resistance. Lapatinib (L) with chemotherapy is active after progression on T. Preclinical data suggest that signaling downstream of HER2 via PI3K-AKT pathway may be one mechanism of resistance. MK-2206, an investigational allosteric AKT inhibitor, should inhibit this compensatory signaling. As a single agent, DLTs of MK-2206 are rash and diarrhea. Combined with either T or T/L, MK-2206 could provide more effective HER-family signaling blockade in HER2 positive disease. Methods: Patients with HER2+ treatment-refractory breast and gastroesophageal cancer with adequate organ function were enrolled. In part 1, patients were treated with standard doses of IV T (8 mg/kg load, followed by 6 mg/kg Q3W), and escalating dose levels of PO MK-2206 using either a QOD or QW schedule. In part 2, patients are treated with MK-2206 at the MTD dose derived from part 1 with standard T and escalating doses of L. Results: Between Sept. 2009 and Jan. 2011, a total of 40 HER2+ patients were screened and 32 were enrolled. The MTD for MK-2206 in combination with q3W T (part 1) is 60 mg for QOD schedule and 135 mg QW schedule. The major toxicity is consistent with prior experience and no grade 4 or 5 toxicity. The DLT is skin rash in the 200 mg QW cohort occurring in 2/4 patients. There were one complete remission (CR) after 12 weeks of therapy for a breast cancer patient who had skin only metastasis during enrollment, and another unconfirmed partial remission (PR) lasting less than 4 weeks but 4/24 patients have had prolonged stable disease (SD) for at least 4 months despite progression on multiple prior T and L-based therapies. Part 2 (T/L/MK-2206) is anticipated to start in Feb. 2011 and updated information will be available for the ASCO meeting. Conclusions: The AKT inhibitor MK-2206 can be safely combined with T and is associated with clinical activity in phase I. The addition of L is predicted to further increase efficacy and is now being tested. Updated results will be provided.
An interpersonal approach to hysteria
Authors: D Celani
Journal: American Journal of Psychiatry (1976)

The author defines hysteria in terms of specific observable classes of interpersonal behaviors and examines the impact of these behaviors on the receiver. The hysteric communicates frailty and helplessness, thus structuring the interpersonal environment to ensure attention and inhibit aggression. The development of these roles is shown in histories of female hysterics, who were selectively reinforced for frailty, seductiveness, and passivity as children. The major classes of symptoms shown by adult hysterics--conversion symptoms and dissociative reactions--reflect these interpersonal roles. The author concludes that hysteria is a relatively specific interpersonal style that results from cultural, social, and interpersonal influences.
Tumor-Associated Fetal Antigens in Human Tumors2
Authors: P. Avis, M. G. Lewis
Journal: JNCI Journal of the National Cancer Institute (1973)

Antisera prepared by giving New Zealand white rabbits injections of perchloric acid extracts of 12-week human fetuses demonstrated the presence of fetal antigenic components on the surface of human malignant melanoma cells and the cells of other human tumors. The antifetal serum reacted only with the surface of tumor cells and fetal cells, not with a number of normal adult cells. The relationship with carcinoembryonic antigen and other fetal antigens is briefly discussed. The antifetal serum did not block or was not blocked by tumor-specific surface membrane reactions in the same individuals.
The Thymus and Myasthenia Gravis
Authors: A M Taha, R Haddad, C Allam, A Baraka
Journal: New England Journal of Medicine (1960)

The relationship between the thymus and the pathogenesis of myasthenia gravis is reviewed. Ten cases of myasthenia gravis who underwent thymectomy at the American University Hospital of Beirut are presented. The various pathologic features of the thymus encountered in myasthenia gravis are presented. The indications for thymectomy and the results of surgical intervention on the course of the disease are reviewed. The conclusion is made that thymectomy should be done on all patients with generalized myasthenia gravis irrespective of age, sex, duration of disease or pathological features of the thymus.
Abstract 18094: Multimorbidity and 30-Day All-Cause Readmission Among Hospitalized Medicare Beneficiaries With Heart Failure
Authors: Sridivya Parvataneni, Chakradhari Inampudi, Kanan Patel, Christine Ritchie, Gregg C Fonarow, Cynthia J Brown, Charity J Morgan, Sumanth D Prabhu, Wilbert S Aronow, Prakash Deedwania, Javed Butler, Richard M Allman, Ali Ahmed
Journal: Circulation (2013)

Background: According to the Centers for Medicare and Medicaid Services (CMS), Medicare beneficiaries with ≥6 chronic conditions have the highest (25%) 30-day all-cause readmission rate (Chronic Conditions among Medicare Beneficiaries, Chartbook, 2012). Heart failure (HF) is the only single chronic condition with similarly high 30-day all-cause readmission rates (PMID: 19339721). In the current analysis, we examined the additional impact of comorbidity burden on 30-day all-cause readmission in patients with HF. Methods: We analyzed data from 8049 Medicare beneficiaries discharged alive from 106 U.S. hospitals during 1998-2001. We identified 14 chronic medical conditions used by the CMS (HF being index condition in the current analysis) and categorized patients into 0 (n=123), 1 (n=533), 2 (1395), 3 (n=2016), 4 (n=1986) and ≥5 (n=1996) comorbidities. Because the incidence of 30-day all-cause readmission was similar for those with 0-3 morbidities (20%, 16%, 18% and 18%, respectively; overall, 18%), we combined these 4 groups and used them as reference to estimate age-sex-race-adjusted hazard ratios (HR) for those with 4 and ≥5 comorbidities using Cox regression models. Results: Patients had a mean age of 76 (±11) years, 58% were women, and 25% were African American. Age-sex-race-adjusted associations of 4 and ≥5 comorbidities with outcomes are displayed in the Table below. Conclusions: For hospitalized older patients with HF, the risk of 30-day all-cause readmission was comparable for those with 0-3 comorbidities, which progressively increased for those with 4 and ≥5 comorbidities. However, comorbidity burden seems to have a modest association with 30-day all-cause mortality. These findings suggest that the CMS’s chronic condition list may be used to identify hospitalized older HF patients at higher risk for 30-day all-cause readmission, a current target of health care reform which could reduce costs for Medicare. _
Tribunal was “unduly lenient” over psychiatrist’s deception, says High Court
Authors: Clare Dyer
Journal: BMJ (2016)

The Medical Practitioners Tribunal Service made an error of judgment in finding that the fitness to practise of a psychiatrist who falsified dozens of documents was not impaired, a High Court judge has ruled.

The Professional Standards Authority for Health and Social Care brought a rare High Court appeal after a tribunal decided that Okwuolisa Igwilo should not face a sanction for an “isolated period of dishonesty that occurred against a background of severe personal stress.”

Igwilo unsuccessfully applied in 2010 for entry to the General Medical Council’s specialist register for forensic psychiatrists, …
Report of the Jumpstarting Brain Tumor Drug Development Coalition and FDA clinical trials clinical outcome assessment endpoints workshop (October 15, 2014, Bethesda MD)
Authors: Jennifer L. Helfer, Patrick Y. Wen, Jaishri Blakeley, Mark R. Gilbert, Terri S. Armstrong
Journal: Neuro-Oncology (2016)

a workshop was held on the use of clinical outcome assessments in clinical trials for high-grade glioma of the brain.
Updated safety and efficacy results from phase I/II study of HM61713 in patients (pts) with EGFR mutation positive non-small cell lung cancer (NSCLC) who failed previous EGFR-tyrosine kinase inhibitor (TKI).
Authors: Keunchil Park, Jong-Seok Lee, Ki Hyeong Lee, Joo-Hang Kim, Young Joo Min, Jae Yong Cho, Ji-Youn Han, Bong-Seog Kim, Jin-Soo Kim, Dae Ho Lee, Jin Hyoung Kang, Eun Kyung Cho, In-Jin Jang, Jina Jung, Hyo-Yeon Kim, Hui Jung Sin, Jeewoong Son, Jong Soo Woo, Dong-Wan Kim
Journal: Journal of Clinical Oncology (2015)

8084 Background: HM61713 is an orally available EGFR mutation-specific inhibitor with sparing EGFR WT tumors that previously showed promising efficacy in T790M positive tumors at the dose of 300 mg (overall response rate; 29.2%). We report here on updated data from the ongoing phase I/II study of HM61713 in pts with advanced NSCLC who had failed previous EGFR-TKIs (NCT01588145). Methods: Advanced NSCLC pts with EGFR mutation positive tumor were enrolled in dose escalation cohort and received doses ranging from 75-1200 mg/day. After safety evaluation, separate expansion cohorts opened for pts who failed prior EGFR TKI pts at 800 mg QD dose, respectively to investigate efficacy and tolerability of HM61713 in pts with centrally confirmed T790M positive NSCLC. Results: As of 15 Dec 2014, 173 patients were enrolled, 55 and 118 in dose escalation and expansion parts, respectively. Maximum tolerated dose (MTD) was established as 800 mg once daily (QD). Dose limiting toxicities (DLTs) included abdominal pain, diarrhoea, idiosyncratic drug reaction, and elevation of aspartate aminotransferase, alanine aminotransferase, amylase and lipase. Treatment-related adverse events occurred in 87.3% of 165 pts; mainly diarrhea, rash, skin exfoliation, nausea, pruritus, decreased appetite and dry skin. In the 34 pts with centrally confirmed T790M who received HM61713 with a dose more than 650 mg, the overall response rate was 58.8%, (10 confirmed/10 unconfirmed partial responses) and 13 pts achieved disease stabilization (disease control rate; 97.1%). Updated data will be presented at the meeting. Conclusions: HM61713 showed an encouraging clinical anti-tumor activity with good tolerability in pts with T790M positive NSCLC. Clinical trial information: NCT01588145.
Abstract 382: Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer
Authors: Anastasia Wyce, Yan Degenhardt, Yuchen Bai, BaoChau Le, Susan Korenchuk, Ming-Chih Crouthamel, Charles F. McHugh, Robert Vessella, Caretha L. Creasy, Peter J. Tummino, Olena Barbash
Journal: Cancer Research (2014)

Abstract BET (bromodomain and extra-terminal) family proteins are epigenetic regulators known to control expression of genes involved in cell growth and oncogenesis. Selective small molecule BET inhibitors prevent binding of BET proteins to acetylated histones and inhibit transcriptional activation of BET target genes. BET inhibitors attenuate cell growth and survival in a number of hematologic cancer models, partially through down-regulation of the critical oncogene, MYC. We hypothesized that BET inhibitors will similarly regulate expression of MYC family genes (MYC, MYCN, MYCL1) in solid tumor models characterized by MYC family amplification or over-expression. We and others have recently shown activity for BET inhibitors in MYCN-amplified neuroblastoma models, with concomitant down-regulation of MYCN expression. Here we describe the effects of the highly specific BET inhibitor, I-BET762, on MYC expression and cell growth in prostate cancer models. I-BET762 treatment inhibited MYC expression accompanied by growth inhibition and decreased survival in prostate cancer cell lines that over-express MYC. In addition to MYC signatures, gene expression profiling in cell lines identified numerous cell cycle-associated genes as being significantly down-regulated by I-BET762. Importantly, our data suggests that I-BET762 effects are partially driven by MYC down-regulation and underlines the critical importance of additional mechanisms of I-BET762 induced phenotypes. Consistent with our in vitro observations, BET inhibition reduces MYC expression and tumor burden in a primary model of castration resistant prostate cancer that expresses high levels of MYC. Taken together, our data highlight the potential of BET inhibitors as a novel therapeutic approach to treat prostate tumors driven by MYC over-expression. Citation Format: Anastasia Wyce, Yan Degenhardt, Yuchen Bai, BaoChau Le, Susan Korenchuk, Ming-Chih Crouthamel, Charles F. McHugh, Robert Vessella, Caretha L. Creasy, Peter J. Tummino, Olena Barbash. Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 382. doi:10.1158/1538-7445.AM2014-382
Cerebrospinal fluid concentration of HER2, IL-6, and YKL40 in breast cancer patients with meningeal carcinomatosis or brain metastasis
Authors: M. Ryberg, D. L. Nielsen, J. S. Johansen, F. Bach
Journal: Journal of Clinical Oncology (2008)

1083 Background: Several studies indicate that patients with breast cancer and an overekspression of HER2 have a higher incidence of CNS metastasis. High serum HER2, IL-6, and YKL-40 in cancer patients indicate poor survival. Materials: Cerebrospinal fluid (CSF) from 54 breast cancer patients (median age 57 years, range 38–73) suspected for meningeal carcinomatosis (MC) was collected from 1985–1991 and stored at -80 degrees C. MC was diagnosed by tumour cells in the CSF (in case of symptoms a positive autopsy) and brain metastasis (BM) by a CT-scan. HER-2, IL-6 and YKL-40 were measured by commercial ELISAs. Results: Twelve patients had MC (11 had tumour cells in CSF and one was diagnosed by autopsy). Eleven patients had solely BM, and 31 had no CNS metastases. The CSF concentration of HER-2 was significantly higher in the patients with MC (median concentration of HER2: 2.65 ng/ml, range 0.26–213) and in the patients with BM (median concentration of HER-2: 2.22 ng/ml, range 0.0–25) compared to patients without CNS metastasis (median concentration of HER2: 0.28 ng/ml, range 0.0–14.8) (p=0.004 and p=0.038, respectively). No differences in the CSF HER2 levels were found between the MC or BM patients. The CSF concentration of IL-6 was significantly higher in the MC patients (median concentration of IL-6; 7.58 pg/ml, range 1.06–63) compared to patients with BM (median concentration of IL-6; 2.3 pg/ml, range 1.11–15) (p=0.039), and non-CNS patients (median concentration of IL-6; 2.53 pg/ml, range 1–206) (p=0.053). In addition, the CSF protein was increased in patients with MC (p=0.008). No differences in CSF YKL-40 concentration were found between the groups. Conclusions: The CSF concentration of HER2 was significantly increased in breast patients with MC or BM, compared with patients without CNS metastasis. Furthermore, the patients with MC had a significantly increased level of CSF concentration of IL-6. No significant financial relationships to disclose.
Body fat rather than weight should be considered when assessing a patient’s health, study finds
Authors: Jacqui Wise
Journal: BMJ (2016)

Keeping body fat low may be more important than maintaining a low body mass index (BMI), a study published in the Annals of Internal Medicine has found.1

The researchers said that their findings may help to explain the “obesity paradox” whereby some studies have found lower mortality rates in people with chronic diseases who are overweight or mildly obese than in those …
Tiotropium Respimat® Add-on to at Least Ics Therapy Demonstrates Reduced Risk of Severe Asthma Exacerbation and Asthma Worsening in Symptomatic Asthma, Independent of IgE or Blood Eosinophil Levels
Authors: Thomas B. Casale, Donald P. Tashkin, Reinhold Lühmann, Michael Engel, Petra Moroni-Zentgraf, Huib A.M. Kerstjens
Journal: Journal of Allergy and Clinical Immunology (2016)
Design of phase 1 trial of a human ribonuclease variant
Authors: L. Strong, J. A. Kink, M. N. Shahan, B. Mei, R. T. Raines
Journal: Journal of Clinical Oncology (2008)

14646 Background: A novel class of therapeutic agents for cancer has been developed based on variants of the human pancreatic ribonuclease 1. One of these variants, QBI-139, was selected for clinical development. IND enabling studies have been completed and a Phase 1 trial is scheduled to begin in mid-2008. Methods: QBI-139 is a protein that is expressed in inclusion bodies in E. coli and purified by traditional column chromatography. Treatment with QBI-139 causes significant inhibition of the growth of human tumors implanted in the flanks of nude mice (xenograft model). Clinical observation, body weight, and clinical chemistry were used to identify possible organ-specific toxicities in rat and dog toxicology studies. The reversible nature of these effects was also determined. Results: QBI-139 showed tumor growth inhibition comparable to FDA approved cancer drugs in the following xenograft models: prostate (DU145 cell line), pancreas (Bx-PC-3), lung (A549), and ovarian (SKOV-3) cancer. The effective doses of QBI-139 in the xenograft model include a once weekly dose of 38 mg/kg (∼115 mg/m2). The rat and dog toxicology studies utilized doses of 20–80 mg/kg (∼150–600 mg/m2) and 10–40 mg/kg (∼180–700 mg/m2), respectively. Toxicity was seen at the high dose levels and representative results will be provided. The rats were the more sensitive species and were used to select a starting dose for the Phase 1 trial. Conclusions: Due to the broad activity of QBI-139, the Phase 1 trial will include all solid tumors. Based on the toxicology results in rats and dogs, QBI-139 is anticipated to be well tolerated in the dose ranges anticipated to be efficacious. The goals of the Phase 1 trial are to evaluate the safety and tolerability of QBI-139 in patients with advanced refractory solid tumors and to determine the recommended dose for Phase II. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Quintessence Biosciences, Inc. Quintessence Biosciences, Inc. Quintessence Biosciences, Inc. Quintessence Biosciences, Inc.