tbuckley/cabot-search huggingface dataset:
Elderly patients evaluated for phase I clinical trials enrollment: Analysis of “screen-failures.”
Authors: Julie Haewon Rowe, Martin Goros, Brian C Dinh, Steven Weitman, Anand B. Karnad
Journal: Journal of Clinical Oncology (2014)

e20511 Background: Elderly patients with cancer are under-represented in clinical trials. Barriers to enrollment for elderly participation include stringent eligibility criteria, clinician bias, or access to care. However, other reasons for elderly patients who are screened for clinical trial enrollment but did not get to the next steps of signing informed consent, termed as a “screen failure,” are not well-delineated. One of the research priorities in geriatric oncology is the specific study of treatment algorithms in patients who would be otherwise considered ineligible or unfit for current treatment protocols. In an effort to provide more data, we reviewed our Phase I experience. Methods: We conducted a retrospective analysis of 1264 patients who were evaluated for enrollment in Phase I clinical trials at the Cancer Therapy Research Center (CTRC) from 2009 to 2012 to assess the reasons for non-enrollment. Results: The elderly (E) represented 19% (235/1264) who were screened and 66% (155/235) who were not eligible for enrollment. In the non-elderly (NE), 59% (607/1,029) were not eligible. The most common reason for not enrolling in E included not meeting eligibility requirements (18%) and not being interested in enrolling (15%). Of the patients who were screened, 48% (114/235) of E and 51% (527/1,029) of NE consented for enrollment (P=0.45). Of the consenting patients who were ineligible, 30% (34/114) of E and 20% (105/527) of NE were unable to enroll with the most common reason being unable to meet eligibility criteria (E 52% versus NE 67%, P=0.09). The types of agents (i.e. cytotoxic, immunotherapy, targeted, or hormonal) used in the clinical trials were not significantly different between E and NE (P=0.33) who consented but ineligible. Conclusions: Elderly patients consent for enrollment for early phase clinical trials. The most commons reasons for screen failures among the elderly and non-elderly included not meeting eligibility criteria or not being interested in participating. Careful evaluation of eligibility criteria that prevents patients from enrolling and the reasons for not participating is warranted in order to improve clinical trial enrollment.
MURANO Trial Establishes Feasibility of Time-Limited Venetoclax-Rituximab (VenR) Combination Therapy in Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)
Authors: John F. Seymour, Thomas J. Kipps, Barbara Eichhorst, Peter Hillmen, James D'Rozario, Sarit Assouline, Carolyn Owen, Tadeusz Robak, Javier de la Serna, Ulrich Jaeger, Guillaume Cartron, Marco Montillo, Nicole Lamanna, Maria E. Verdugo, Elizabeth A Punnoose, Yanwen Jiang, Jue Wang, Michelle Boyer, Kathryn Humphrey, Mehrdad Mobasher, Arnon P. Kater
Journal: Blood (2018)
Image Gallery: Poikiloderma with neutropenia
Authors: X. Chen, Y. Yang, Z. Lin
Journal: British Journal of Dermatology (2019)

Dear Editor, A 20-year-old man presented with reticulated hyper- and hypopigmentation with erythema since early childhood, overlying his body (a, b). His nails showed pachyonychia (c). Additionally, he reported a history of photosensitivity, interventricular septal defect and recurrent infections. Laboratory examinations showed neutropenia (0·63 × 109 cells L−1, normal range 2·00–8·00 × 109). Mutation analysis revealed compound heterozygous mutations in USB1: a nonsense mutation (c.229G>T, p.E77*) and a frameshift mutation (c.748delinsGG, p.G250Efs*67). Taking the evidence together, the diagnosis of poikiloderma with neutropenia (PN) was confirmed. PN is characterized by poikiloderma, pachyonychia and persistent neutropenia; it is caused by recessive mutations in USB1.1 This patient was recommended to avoid sun exposure.
Role of Neuronal VEGF Signaling in the Prefrontal Cortex in the Rapid Antidepressant Effects of Ketamine
Authors: Satoshi Deyama, Eunyoung Bang, Eric S. Wohleb, Xiao-Yuan Li, Taro Kato, Danielle M. Gerhard, Sophie Dutheil, Jason M. Dwyer, Seth R. Taylor, Marina R. Picciotto, Ronald S. Duman
Journal: American Journal of Psychiatry (2019)

Objective: The N-methyl-d-aspartate receptor antagonist ketamine produces rapid and sustained antidepressant actions even in patients with treatment-resistant depression. Vascular endothelial growth factor (VEGF) has been implicated in the effects of conventional monoamine-based antidepressants, but the role of VEGF in the rapid antidepressant actions of ketamine remains unclear. The authors examined whether neuronal VEGF signaling in the medial prefrontal cortex (mPFC) mediates the rapid antidepressant actions of ketamine. Methods: The authors used a combination of approaches, including conditional, neuron-specific knockout of VEGF or its receptor, Flk-1; antibody neutralization; viral-mediated knockdown of Flk-1; and pharmacological inhibitors. Further in vitro and in vivo experiments were performed to examine whether neuronal VEGF signaling was required for the neurotrophic and synaptogenic actions of ketamine that underlie its behavioral actions. Results: The behavioral actions of systemic ketamine are blocked by forebrain excitatory neuron-specific deletion of either VEGF or Flk-1 or by intra-mPFC infusion of a VEGF neutralizing antibody. Moreover, intra-mPFC infusions of VEGF are sufficient to produce rapid ketamine-like behavioral actions, and these effects are blocked by neuron-specific Flk-1 deletion. The results also show that local knockdown of Flk-1 in mPFC excitatory neurons in adulthood blocks the behavioral effects of systemic ketamine. Moreover, inhibition of neuronal VEGF signaling blocks the neurotrophic and synaptogenic effects of ketamine. Conclusions: Together, these findings indicate that neuronal VEGF–Flk-1 signaling in the mPFC plays an essential role in the antidepressant actions of ketamine.
Risk of serious infection with mTOR inhibitors everolimus and temsirolimus in the treatment of cancer: A meta-analysis of randomized controlled trials.
Authors: Christine Ann Garcia, Shenhong Wu
Journal: Journal of Clinical Oncology (2014)

2604 Background: Everolimus and temsirolimus are inhibitors of mammalian target of rapamycin (mTOR), and utilized in the treatment of a variety of cancers. The use of mTOR inhibitors is associated with serious infections. This meta-analysis of randomized controlled trials (RCTs) was conducted to determine the overall risk of infection with mTOR inhibitors in cancer patients. Methods: Databases from PubMed and abstracts presented at the American Society of Clinical Oncology annual meetings up to October 2013 were searched for relevant studies. Eligible studies included randomized controlled clinical trials in which everolimus or temsirolimus was compared to controls in cancer patients. Data on all-grade and high-grade (grade 3 and 4) infections were extracted from the safety profiles of each clinical trial. Incidence and relative risk (RR) were calculated using random- or fixed-effects models. Results: A total of 10 RCTs with 3,535 patients (mTOR 1,911, controls 1,624) of various tumors were included in the analysis. The incidence of all-grade and high-grade infections were 21.0% (95% CI 15.0-28.9%) and 4.0% (95% CI: 2.2-7.0%), respectively. In comparison with controls, mTOR inhibitors significantly increased the risk for developing all-grade (RR: 1.82, 95% CI: 1.08-3.08, P=0.03), and high-grade infections (RR: 2.86, 95% CI: P<0.001). The increased risk of high-grade infection was observed for both everolimus (RR: 3.91, 95% CI: 1.67- 9.13, P=0.002) and temsirolimus (RR: 2.42, 95% CI: 1.30-4.50, P=0.005). However, the increased risk did not vary significantly with different mTOR inhibitors (everolimus vs temsirolimus: P=0.37) and among different tumor types (P=0.47). There was also no significant difference between mTOR inhibitors alone and their combination with other agents (P=0.68). Conclusions: The mTOR inhibitors everolimus and temsirolimus are associated with a significantly increased risk of high-grade infections in cancer patients. Further studies are needed to identify the risk factors for high-grade infection.
Myelodysplastic Syndromes (MDS) Are an Independent Risk Factor for an Earlier Onset of Myocardial Infarction and Increased Mortality from Cardiovascular Disease (CVD)
Authors: Diego Adrianzen Herrera, Kith Pradhan, Rosebella Snyder, Siddharth Karanth, Murali Janakiram, Ioannis Mantzaris, Santosh Murthy, Amit Verma, Aditi Shastri
Journal: Blood (2018)
Age-targeted tuberculosis vaccination in China and implications for vaccine development: a modelling study
Authors: Rebecca C Harris, Tom Sumner, Gwenan M Knight, Tom Evans, Vicky Cardenas, Chen Chen, Richard G White
Journal: The Lancet Global Health (2019)

BackgroundTuberculosis is the leading single-pathogen cause of death worldwide, and China has the third largest number of cases worldwide. New tools, such as new vaccines, are needed to meet WHO tuberculosis goals. Tuberculosis vaccine development strategies mostly target infants or adolescents, but given China's ageing epidemic, vaccinating older people might be important. We modelled the potential impact of new tuberculosis vaccines in China targeting adolescents (15–19 years) or older adults (60–64 years) with varying vaccine characteristics to inform strategic vaccine development.MethodsA Mycobacterium tuberculosis transmission model was calibrated to age-stratified demographic and epidemiological data from China. Varying scenarios of vaccine implementation (age targeting [adolescents or older adults] and coverage [30% or 70%]) and characteristics (efficacy [40%, 60%, or 80%], duration of protection [10 years or 20 years], and host infection status required for efficacy [pre-infection, post-infection in latency, post-infection in latency or recovered, or pre-infection and post-infection]) were assessed. Primary outcomes were tuberculosis incidence and mortality rate reduction in 2050 in each vaccine scenario compared with the baseline (no new vaccine) scenario and cumulative number needed to vaccinate (NNV) per case or death averted, 2025–50.FindingsBy 2050, results suggest that 74·5% (uncertainty interval [UI] 70·2–78·6) of incident tuberculosis cases in China would occur in people aged 65 years or older, and 75·1% (66·8–80·7) of all cases would be due to reactivation, rather than new infection. All vaccine profiles delivered to older adults had higher population-level impact (reduction of incidence and mortality rates) and lower NNV per case and per death averted than if delivered to adolescents. For an intermediate vaccine scenario of 60% efficacy, 10-year protection, and 70% coverage, the reduction of tuberculosis incidence rates with older adult vaccination was 1·9 times (UI 1·5–2·6) to 157·5 times (119·3–225·6) greater than with adolescent vaccination, and the NNV was 0·011 times (0·008–0·014) to 0·796 times (0·632–0·970) lower. Furthermore, with older adult vaccination, post-infection vaccines provided substantially greater mortality and incidence rate reductions than pre-infection vaccines.InterpretationAdolescent-targeted tuberculosis vaccines, the focus of many development plans, would have only a small impact in ageing, reactivation-driven epidemics such as those in China. Instead, an efficacious post-infection vaccine delivered to older adults will be crucial to maximise population-level impact in this setting and would provide an important contribution towards achieving WHO goals. Older adults should be included in tuberculosis vaccine clinical development and implementation planning.FundingAeras and UK MRC.
Proceedings of the American College of Rheumatology/Association of Physicians of Great Britain and Ireland Connective Tissue Disease–Associated Interstitial Lung Disease Summit: A Multidisciplinary Approach to Address Challenges and Opportunities
Authors: Aryeh Fischer, Mary E. Strek, Vincent Cottin, Paul F. Dellaripa, Elana J. Bernstein, Kevin K. Brown, Sonye K. Danoff, Oliver Distler, Nik Hirani, Kirk D. Jones, Dinesh Khanna, Joyce S. Lee, David A. Lynch, Toby M. Maher, Ann B. Millar, Ganesh Raghu, Richard M. Silver, Virginia D. Steen, Elizabeth R. Volkmann, Ronan H. Mullan, David N. O'Dwyer, Seamas C. Donnelly
Journal: Arthritis & Rheumatology (2019)
Abstract 12086: Differences in Risk Factors and Primary Cause of Sudden Unexpected Death by Timing Criteria
Authors: Anthony C Nwosu, Neil D Mehta, Feng-Chang Lin, Taofik Oyekunle, Parin P Nanavati, Mary E Lewis, Omoye O Osehobo, Irion W Pursell, Ross J Simpson, Chani Hodonsky, John P Mounsey, Eugene H Chung
Journal: Circulation (2015)

Background: The World Health Organization (WHO) criteria for sudden unexpected death (SUD) describes either witnessed death or unwitnessed death occurring no more than 24 hours after the subject was last seen alive. Sudden Unexpected Death in North Carolina (SUDDEN) is a population-based study of out-of-hospital unexpected deaths using a clinical definition of sudden death without restrictions on the timing of death. Use of time-limiting definitions was found to underestimate the incidence of SUD by 4 to 19 fold. We sought to explore the characteristics and risk factors of this underestimated population. Methods: From March 2013 to March 2014, all cases of possible sudden unexpected death were identified from electronic query of the Wake County EMS database. Expected deaths were excluded and independent cardiologists made determination for cohort inclusion by review of medical history. We stratified the cohort by timing of death (less than 24 hours versus above 24 hours and unknown) and analyzed the observed difference in incidence between the two groups. Results: Out of 1138 total EMS referrals, 190 were adjudicated as SUD cases into the final cohort. SUDDEN captured 70% more people than studies that used WHO-based criteria. In comparison with cases excluded by WHO criteria, cases meeting WHO criteria were younger (50.1 ± 9.8 years 54.5 ± 8.2 years, p&lt;0.001) and had a higher likelihood of a medical examiner issued death certificate (86.3% vs. 34.9%). WHO-based criteria also include significantly more cases with the primary cause of death listed as unknown (p&lt;0.01). Differences between the groups for BMI, smoking status and dyslipidemia were suggestive. There were no time-based differences in other comorbidities (coronary artery disease, diabetes mellitus, and hypertension) or demographic risk factors (race, gender, marital status, and educational status). Conclusion: Time-limiting definitions underestimate SUD incidence. Preliminary study shows trends in some demographic and clinical characteristics between SUDDEN and WHO-recommended criteria. An expanded study sample of a population-based cohort similar to SUDDEN is needed to understand the differences in this often misclassified population.
Inhibitor of DNA Binding 2 (ID2) Plays a Key Tumor Suppressor Role in Promoting Oncogenic Transformation in Multiple Myeloma
Authors: Tommaso Perini, Raphael Szalat, Mehmet Kemal Samur, Mariateresa Fulciniti, Michael A Lopez, Matthew Lawlor, Christopher J. Ott, Na Li, Yan Xu, Kenneth Wen, Nicola Amodio, Eugenio Morelli, Kenneth Anderson, Fabio Ciceri, Nikhil Munshi
Journal: Blood (2018)
Safety of Axicabtagene Ciloleucel CD19 CAR T-Cell Therapy in Elderly Patients with Relapsed or Refractory Large B-Cell Lymphoma
Authors: Dahlia Sano, Loretta J. Nastoupil, Nathan H. Fowler, Luis Fayad, F. B. Hagemeister, Hun Ju Lee, Felipe Samaniego, Michael Wang, Maria Alma Rodriguez, Swaminathan P Iyer, Simrit Parmar, Raphael Steiner, Ranjit Nair, Sherry Adkins, Sara Arafat, Ahalya Rao, Liliana Vallejo, Misha Hawkins, Yiming Chen, Jason R. Westin, Sattva S. Neelapu
Journal: Blood (2018)
Cost burden of adverse effects associated with metastatic melanoma treatments in France.
Authors: Katja Vouk, Ursula Benter, Mayur Amonkar, Sylvie Pfersch, Laure Benjamin
Journal: Journal of Clinical Oncology (2014)

e17531 Background: Chemotherapy (CT), targeted therapy (TT), and immunotherapy (IT), which are commonly used in the treatment of metastatic melanoma (MM), frequently cause adverse effects (AEs). This study estimated the per-event costs and total cost burden associated with managing the most common and/or severe AEs for these 3 treatment categories from the French health insurance system perspective. Methods: The study involved a literature review to evaluate the incidence and types of AEs associated with the 3 treatment categories. A total of 29 AEs (CT:11; TT:11; and IT:7), all-severity grades (Gr) occurring in >20% or Gr 3/4 occurring in >5%, were selected. Medical resource use related to the management of AEs was assessed by conducting 2 blinded Delphi panel cycles, with 3 clinician interviews covering CT, 4 for TT, and 3 for IT. Published unit costs were used to estimate the costs per AE and then combined with AE incidence (assuming 1 occurrence/patient/cycle), treatment usage, and 1-year prevalence of MM at diagnosis (381 cases) to estimate the treatment burden in France for a single occurrence of each AE. Results: The top 2 cost-intensive AEs within each treatment category are presented in the Table. The top 5 AEs across all 3 treatment categories contributing most to the burden for the whole population (assuming single occurrence) were all Gr 3/4 and included SCC (mean total cost of €46,243), thrombocytopenia (€17,248), colitis (€14,916), neutropenia/leukopenia (€13,267), rash (€12,751), and diarrhea (€11,354). Conclusions: Costs associated with the management of AEs for MM therapies can be substantial. The total burden may be underestimated since it does not account for AE recurrence and excludes patients diagnosed with local disease but progressing to metastatic disease. Treatment category and Gr 3/4 adverse effects Cost of each occurrence, € Mean ± SD Range Chemotherapy Anaphylaxis 2728.01 ± 28.20 2708.07-2747.95 Peripheral neuropathy 1941.16 ± 2673.32 50.84-3831.48 Targeted therapy Squamous cell carcinoma (SCC) 1502.26 ± 2544.57 20.67-5301.47 Rash 1070.98 ± 1111.27 365.67-2729.01 Immunotherapy Colitis 3755.42 ± 342.55 3383.71-4058.37 Diarrhea 2699.91 ± 1098.41 2054.38-3968.18
A pilot study of pharmacokinetically guided dose management of capecitabine in CRC patients.
Authors: Katsuya Makihara, Hideyuki Mishima, Sayaka Azuma, Kazuyo Matsuyama, Katsuya Komori, Hiroko Hasegawa, Masayoshi Yasui, Masakazu Ikenaga, Toshimasa Tsujinaka
Journal: Journal of Clinical Oncology (2012)

510 Background: Pharmacokinetically (PK) guided dose adjustment of 5-fluorouracil (5-FU) has been reported better than body surface area based dosing of 5-FU. On the other hand, few articles have been reported about PK guided dose management of oral drug chemotherapy. The aim of this study is to assess the possibility of pharmacokinetically guided dose management of capecitabine with a nanoparticle antibody-based immunoassay for 5-FU (My5-FU R assay). Methods: Colorectal cancer patients receiving chemotherapy with FOLFOX, FOLFIRI, LV5FU2, Capecitabine, CapeOx (capecitabine plus oxaliplatin) were analyzed by My5-FU R assay. Blood samples were collected after 24 hours of 5-FU infusion or 2 hours after administration of capecitabine at day 7. Correlation between liquid chromatography-mass spectrometry (LC-MS) and My5-FU R assay of 5-FU were also examined. Results: A total of 50 patients were analyzed by My5-FU R assay. A linear relationship (r=0.9204) exists between LC-MS and My5-FU R assay. The area under the concentration curve of continuous 5-FU infusion were 15~56mg-h/L, and the concentrations of 5-FU after administration of capecitabine were 41~457 ng/mL. Severe side effects were observed in the patients with plasma concentration of 5-FU greater than 300 ng/mL 2 hours after administration of capecitabine. Conclusions: Plasma concentrations of 5-FU after administration of capecitabine were measurable by My5-FU R assay. The concentrations of 5-FU were lower in capecitabine than continuous 5-FU. The distribution of 5-FU was wider in capecitabine than continuous 5-FU. It is possible to manage dose of capecitabine pharmacokinetically.
The evidence‐based group‐level symptom‐reduction model as the organizing principle for mental health care: time for change?
Authors: Jim van Os, Sinan Guloksuz, Thomas Willem Vijn, Anton Hafkenscheid, Philippe Delespaul
Journal: World Psychiatry (2019)

The content and organization of mental health care have been heavily influenced by the view that mental difficulties come as diagnosable disorders that can be treated by specialist practitioners who apply evidence‐based practice (EBP) guidelines of symptom reduction at the group level. However, the EBP symptom‐reduction model is under pressure, as it may be disconnected from what patients need, ignores evidence of the trans‐syndromal nature of mental difficulties, overestimates the contribution of the technical aspects of treatment compared to the relational and ritual components of care, and underestimates the lack of EBP group‐to‐individual generalizability. A growing body of knowledge indicates that mental illnesses are seldom “cured” and are better framed as vulnerabilities. Important gains in well‐being can be achieved when individuals learn to live with mental vulnerabilities through a slow process of strengthening resilience in the social and existential domains. In this paper, we examine what a mental health service would look like if the above factors were taken into account. The mental health service of the 21st century may be best conceived of as a small‐scale healing community fostering connectedness and strengthening resilience in learning to live with mental vulnerability, complemented by a limited number of regional facilities. Peer support, organized at the level of a recovery college, may form the backbone of the community. Treatments should be aimed at trans‐syndromal symptom reduction, tailored to serve the higher‐order process of existential recovery and social participation, and applied by professionals who have been trained to collaborate, embrace idiography and maximize effects mediated by therapeutic relationship and the healing effects of ritualized care interactions. Finally, integration with a public mental health system of e‐communities providing information, peer and citizen support and a range of user‐rated self‐management tools may help bridge the gap between the high prevalence of common mental disorder and the relatively low capacity of any mental health service.