tbuckley/cabot-search huggingface dataset:
Multi-omic profiling of metastatic lesions to guide treatment selection: The Side Out 2 trial experience.
Authors: Mariaelena Pierobon, Nicholas J. Robert, Donald W. Northfelt, Mohammad Jahanzeb, Shukmei Wong, K. Alex Hodge, Jessica Aldrich, David W. Craig, Lance A. Liotta, Julia Dianne Wulfkuhle, Rosa Isela Gallagher, David Arguello, Amber Conrad, Ariane C. Kemkes, David M. Loesch, Linda Vocila, Bryant Dunetz, John D. Carpten, Emanuel Petricoin, Stephen Patrick Anthony
Journal: Journal of Clinical Oncology (2018)

1077 Background: The aim of this prospective pilot study, the Side Out 2 trial (NCT01919749), was to explore if treatment selection based on Multi-omic Profiling (MoP) provides clinical benefits superior to empiric treatment selection in progressive metastatic breast cancers (MBC). Methods: Fresh core biopsies were collected from the metastatic lesions of 32 MBC patients. Samples underwent genomic and proteomic profiling, including: exome sequencing, RNA-Seq, IHC, and quantitative phosphoprotein-based protein pathway activation mapping by Reverse Phase Protein Microarray (RPPA). Whole tissue lysates were used for the exome sequencing, RNA-Seq and IHC; the RPPA data were obtained from microdissected tumor epithelia. A sample size of 25 evaluable patients was determined a priori according to the exact single-stage design for phase II studies, using a type I error rate of 5% (one-sided) and a power of 90%. Clinical benefit was defined as Growth Modulation Index (GMI) ≥ 1.3 assuming that MoP selected therapy would warrant further investigation if ≥ 35% of the patients demonstrate a PFS ratio of ≥ 1.3. GMI was calculated as a ratio between PFS on MoP selected therapy versus PFS on prior therapy (PMID:25209003). Results: Between 2014 and 2016, four US sites enrolled 32 previously treated MBC patients. Of the 32 patients enrolled, 29 received treatment based on their MoP and 25 met the follow-up criteria established by the trial protocol. Of the 25 patients, 14 (56%) met or exceeded a GMI of 1.3. The most frequently selected treatments were irinotecan based on TOPO1 expression (n = 12; single agent n = 6) and capecitabine based on TS expression (n = 9; single agent n = 3). Of the 7 patients that received endocrine therapy, 3 were treated with exemestane+everolimus. Based on HER2 amplification/pathway activation, HER2 targeted agents were given to 4 patients. Conclusions: This study confirmed the unique role of MoP to select effective treatments for MBC. This approach provided clinical benefit for 56% previously treated MBC patients, which met the primary objective of the study. Thus, this approach merits further investigation. This study also suggests that irinotecan may be an under-developed drug for MBC patients. Clinical trial information: NCT01919749.
Experience sampling methodology in mental health research: new insights and technical developments
Authors: Inez Myin‐Germeys, Zuzana Kasanova, Thomas Vaessen, Hugo Vachon, Olivia Kirtley, Wolfgang Viechtbauer, Ulrich Reininghaus
Journal: World Psychiatry (2018)

In the mental health field, there is a growing awareness that the study of psychiatric symptoms in the context of everyday life, using experience sampling methodology (ESM), may provide a powerful and necessary addition to more conventional research approaches. ESM, a structured self-report diary technique, allows the investigation of experiences within, and in interaction with, the real-world context. This paper provides an overview of how zooming in on the micro-level of experience and behaviour using ESM adds new insights and additional perspectives to standard approaches. More specifically, it discusses how ESM: a) contributes to a deeper understanding of psychopathological phenomena, b) allows to capture variability over time, c) aids in identifying internal and situational determinants of variability in symptomatology, and d) enables a thorough investigation of the interaction between the person and his/her environment and of real-life social interactions. Next to improving assessment of psychopathology and its underlying mechanisms, ESM contributes to advancing and changing clinical practice by allowing a more fine-grained evaluation of treatment effects as well as by providing the opportunity for extending treatment beyond the clinical setting into real life with the development of ecological momentary interventions. Furthermore, this paper provides an overview of the technical details of setting up an ESM study in terms of design, questionnaire development and statistical approaches. Overall, although a number of considerations and challenges remain, ESM offers one of the best opportunities for personalized medicine in psychiatry, from both a research and a clinical perspective.
Pre-existing anti-polyethylene glycol antibody reduces the therapeutic efficacy and pharmacokinetics of PEGylated liposomes
Authors: Yuan-Chin Hsieh, Hsin-Ell Wang, Wen-Wei Lin, Steve R. Roffler, Ta-Chun Cheng, Yu-Cheng Su, Jia-Je Li, Chao-Cheng Chen, Chun-Han Huang, Bing-Mae Chen, Jaw-Yuan Wang, Tian-Lu Cheng, Fang-Ming Chen
Journal: Theranostics (2018)

Rationale: Increasing frequency of human exposure to PEG-related products means that healthy people are likely to have pre-existing anti-PEG antibodies (pre-αPEG Ab).However, the influence of pre-αPEG Abs on the pharmacokinetics (PK) and therapeutic efficacy of LipoDox is unknown.Methods: We generated two pre-αPEG Ab mouse models.First, naïve mice were immunized with PEGylated protein to generate an endogenous αPEG Ab titer (endo αPEG).Second, monoclonal αPEG Abs were passively transferred (αPEG-PT) into naïve mice to establish a αPEG titer.The naïve, endo αPEG and αPEG-PT mice were intravenously injected with 111 in-labeled LipoDox to evaluate its PK.Tumor-bearing naïve, endo αPEG and αPEG-PT mice were intravenously injected with 111 in-labeled LipoDox to evaluate its biodistribution.The therapeutic efficacy of LipoDox was estimated in the tumor-bearing mice.Results: The areas under the curve (AUC)last of LipoDox in endo αPEG and αPEG-PT mice were 11.5-and 15.6-fold less, respectively, than that of the naïve group.The biodistribution results suggested that pre-αPEG Ab can significantly reduce tumor accumulation and accelerate blood clearance of 111 In-labeled LipoDox from the spleen.The tumor volumes of the tumor-bearing endo αPEG and αPEG-PT mice after treatment with LipoDox were significantly increased as compared with that of the tumor-bearing naïve mice.Conclusions: Pre-αPEG Abs were found to dramatically alter the PK and reduce the tumor accumulation and therapeutic efficacy of LipoDox.Pre-αPEG may have potential as a marker to aid development of personalized therapy using LipoDox and achieve optimal therapeutic efficacy.
Association of Obesity in Early Adulthood and Middle Age With Incipient Left Ventricular Dysfunction and Structural Remodeling
Authors: Satoru Kishi, Anderson C. Armstrong, Samuel S. Gidding, Laura A. Colangelo, Bharath A. Venkatesh, David R. Jacobs, J. Jeffery Carr, James G. Terry, Kiang Liu, David C. Goff, João A.C. Lima
Journal: JACC Heart Failure (2014)
Antigen-Specific CD8 Lytic Phenotype Induced by Sipuleucel-T in Hormone-Sensitive or Castration-Resistant Prostate Cancer and Association with Overall Survival
Authors: Emmanuel S. Antonarakis, Eric J. Small, Daniel P. Petrylak, David I. Quinn, Adam S. Kibel, Nancy N. Chang, Erica Dearstyne, Matt Harmon, Dwayne Campogan, Heather Haynes, Tuyen Vu, Nadeem A. Sheikh, Charles G. Drake
Journal: Clinical Cancer Research (2018)

Purpose: Sipuleucel-T is FDA approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) based on the IMPACT trial showing a 4.1-month benefit in median overall survival (OS) for patients receiving sipuleucel-T versus control. Although efficacy of sipuleucel-T is well established, its mechanism remains incompletely understood.Patients and Methods: Patient samples from three sipuleucel-T trials were assessed for peripheral cellular immune responses to the immunogen PA2024 and the target antigen prostatic acid phosphatase (PAP). PAP- and PA2024-specific proliferative and cytolytic responses were characterized to delineate sipuleucel-T-induced immune responses. To quantify potential cytotoxic T lymphocyte (CTL) activity, cell-surface CD107a expression on PAP- or PA2024-specific CD8+ T cells was measured in sipuleucel-T-treated patient and healthy volunteer samples.Results: Increased PA2024-specific CD4+ (P = 0.030) and CD8+ (P = 0.052) T-cell proliferation from baseline to week 6 was observed (N = 14) post-sipuleucel-T, with greater magnitude of PA2024-specific responses compared with PAP. PAP- and PA2024-CTL activity (CD107a positivity) significantly increased at weeks 6 and 26 after sipuleucel-T treatment (P < 0.0001; N = 22). At 26 weeks post-sipuleucel-T, OS correlated with the magnitude of PAP (Pearson R, 0.52; P = 0.013) or PA2024 (Pearson R, 0.67; P = 0.0006) CTL activity. Higher PA2024-CTL activity at week 26 was significantly associated with longer OS using tertile analysis (P = 0.0005; N = 22), with PA2024 responses correlating with PAP responses at week 26 (R = 0.90; P = 1.53E-08).Conclusions: This study is the first to report PAP-specific CD8+ T-cell responses elicited by sipuleucel-T treatment. Increased and persistent potential PA2024-specific CTL activity correlated with PAP-specific CTL activity and associated with improved OS following sipuleucel-T treatment. Clin Cancer Res; 24(19); 4662-71. ©2018 AACR.
Phase I Trials of Anti-ENPP3 Antibody–Drug Conjugates in Advanced Refractory Renal Cell Carcinomas
Authors: John A. Thompson, Robert J. Motzer, Ana M. Molina, Toni K. Choueiri, Elisabeth I. Heath, Bruce G. Redman, Randeep S. Sangha, D. Scott Ernst, Roberto Pili, Stella K. Kim, Leonard Reyno, Aya Wiseman, Fabio Trave, Banmeet Anand, Karen Morrison, Fernando Doñate, Christian K. Kollmannsberger
Journal: Clinical Cancer Research (2018)

Purpose: To determine the safety, pharmacokinetics, and recommended phase II dose of an antibody-drug conjugate (ADC) targeting ectonucleotide phosphodiesterases-pyrophosphatase 3 (ENPP3) conjugated to monomethyl auristatin F (MMAF) in subjects with advanced metastatic renal cell carcinoma (mRCC).Patients and Methods: Two phase I studies were conducted sequentially with 2 ADCs considered equivalent, hybridoma-derived AGS-16M8F and Chinese hamster ovary-derived AGS-16C3F. AGS-16M8F was administered intravenously every 3 weeks at 5 dose levels ranging from 0.6 to 4.8 mg/kg until unacceptable toxicity or progression. The study was terminated before reaching the MTD. A second study with AGS-16C3F started with the AGS-16M8F bridging dose of 4.8 mg/kg given every 3 weeks.Results: The AGS-16M8F study (n = 26) closed before reaching the MTD. The median duration of treatment was 12 weeks (1.7-83 weeks). One subject had durable partial response (PR; 83 weeks) and 1 subject had prolonged stable disease (48 weeks). In the AGS-16C3F study (n = 34), the protocol-defined MTD was 3.6 mg/kg, but this was not tolerated in multiple doses. Reversible keratopathy was dose limiting and required multiple dose deescalations. The 1.8 mg/kg dose was determined to be safe and was associated with clinically relevant signs of antitumor response. Three of 13 subjects at 1.8 mg/kg had durable PRs (range, 100-143 weeks). Eight subjects at 2.7 mg/kg and 1.8 mg/kg had disease control >37 weeks (37.5-141 weeks).Conclusions: AGS-16C3F was tolerated and had durable antitumor activity at 1.8 mg/kg every 3 weeks. Clin Cancer Res; 24(18); 4399-406. ©2018 AACR.
Alignment of parent- and child-reported outcomes and histology in eosinophilic esophagitis across multiple CEGIR sites
Authors: Seema S. Aceves, Eileen King, Margaret H. Collins, Guang-Yu Yang, Kelley E. Capocelli, J. Pablo Abonia, Dan Atkins, Peter A. Bonis, Christina L. Carpenter, Evan S. Dellon, Michael D. Eby, Gary W. Falk, Nirmala Gonsalves, Sandeep K. Gupta, Ikuo Hirano, Kendra Kocher, Jeffrey P. Krischer, John Leung, Jessi Lipscomb, Paul Menard-Katcher, Vincent A. Mukkada, Zhaoxing Pan, Jonathan M. Spergel, Qin Sun, Barry K. Wershil, Marc E. Rothenberg, Glenn T. Furuta, Ashley Arrington, Jeanie Bailey, John Besse, Wendy M. Book, Deirdre Burke, Jacquelyn Covington, Maureen DeMarschall, Ranjan Dohil, Allison Dubner, Heather Foote, Shaobo Guan, Alicia Hurnton, Ellyn Kodroff, Jonathan Kuhl, Shay Kyle, Megan Lewis, Denise Mack, Sarah McGee, Melissa Mingler, Susan Moist, Amanda Muir, Heidi Poppendeck, Philip Putnam, Cathy Reidy, Amanda K. Rudman-Spergel, Kathleen Sable, Melissa Scott, Mary Jo Strobel, Katherine Thompson, Joshua Wechsler
Journal: Journal of Allergy and Clinical Immunology (2018)
Clusters de doença dos legionários associados a viagens, em França, Setembro 2001 - Agosto 2003
Authors: B Decludt, C Campese, D Che, S Jarraud, J Etienne
Journal: Eurosurveillance (2004)

Os clusters de doenca dos legionarios associados a viagens requerem uma atencao especial, sendo detectados pelo sistema nacional frances de vigilância e pela rede europeia EWGLINET. Entre Setembro de 2001 e Agosto de 2003, identificaram-se 37 clusters de casos em locais turisticos de Franca: 27 hoteis e 10 parques de campismo. A distribuicao dos casos clinicos por cluster foi a seguinte: 30 clusters com dois casos (81%), seis clusters com tres casos (16%) e um cluster com quatro casos (3%), perfazendo um total de 82 casos. Foram realizadas investigacoes ambientais pelas autoridades de saude locais em 36 dos 37 clusters e foram recolhidas amostras de agua em 35 clusters. Dezasseis locais investigados (46%) deram um resultado positivo para Legionella pneumophila com uma concentracao superior a 103 ufc/litro. Em todos os locais onde a avaliacao do risco foi considerada inapropriada, foram tomadas imediatamente medidas de controlo. Seis hoteis foram encerrados logo apos os alertas de clusters. A comparacao das estirpes clinicas e ambientais, feita por electroforese de campo pulsado (PFGE), foi possivel em tres clusters, encontrando-se perfis genomicos identicos Durante estes dois anos de vigilância, os resultados indicam que houve risco de exposicao a Legionella em numerosos locais. Isto confirma a importância da rede europeia de vigilância e da notificacao rapida de todos os casos a mesma (EWGLINET).
More Research Needed on the Association Between Genotype and Antidepressant Response: Response to Fabbri et al.
Authors: Chloe P. O’Connell, Andrea N. Goldstein-Piekarski, Charles B. Nemeroff, Alan F. Schatzberg, Charles Debattista, Tania Carrillo-Roa, Elisabeth B. Binder, Boadie W. Dunlop, W. Edward Craighead, Helen S. Mayberg, Leanne M. Williams
Journal: American Journal of Psychiatry (2018)
Adult cancer survivorship referrals for hereditary cancer genetic testing.
Authors: Farzana L. Walcott, Rebecca Davidson Kaltman, Elizabeth Hatcher, Cam Ha, Tara Biagi, Elizabeth Stark, Allison McHenry, April Barbour
Journal: Journal of Clinical Oncology (2018)

183 Background: Genetic testing for hereditary cancer syndromes is underutilized among cancer patients. Cancer survivorship clinics may identify individuals at risk for hereditary cancer. We present the number of referrals from George Washington (GW) Adult Cancer Survivorship Clinic (ACS) to the GW Ruth Paul Hereditary Cancer Program (RPHCP) to demonstrate the feasibility of identifying high risk individuals in cancer survivorship. Methods: We reviewed the number of patients seen at the GW ACS and subsequent referrals to the GW RPHCP for genetic counseling/testing. An IRB approved research registry was used for retrieval of the data. The ACS clinic is staffed by a physician internist trained in clinical cancer genetics and a nurse practitioner trained in cancer survivorship. Results: 261 patients were seen in ACS from January 1, 2016, to September 30, 2017. Twenty patients (7.6%) were referred to RPHCP based on personal/family cancer history. Three patients were not consented for the research registry, leaving a total of 17 patients for this analysis. Fifteen (88.2%) patients were referred by the physician and 2/17 (11.7%) were referred by the nurse practitioner. Sixteen patients had genetic testing (94.1%) and results were: 5/16 (31.2%) positive, 6/16 (37.5%) negative, and 3/16 (18.7%) had a variant of unknown significance (VUS). Results on 2 patients are pending. One patient deferred testing. Of the 17 patients referred, 14/17 (82.3%) had personal/family history of cancer and had seen an oncologist. Cancer sites and germline mutations identified were: bilateral breast cancer and bladder cancer (BRCA2), prostate cancer (MUTYH), breast and ovarian cancer (BRCA1), endometrial cancer (APC). One patient without cancer was referred by an oncologist for a previously identified familial MLH1 mutation, and was positive. Conclusions: Cancer survivorship clinics may identify individuals appropriate for genetic testing for hereditary cancer syndromes. This is likely an underestimate as not all cancer patients are seen in survivorship clinic. Systematic capture of personal and family history of cancer in cancer survivors may enhance utilization of genetic testing services among cancer survivors and identification of high risk individuals.
A phase II study of atezolizumab (Atezo) combined with pertuzumab (P) and high-dose trastuzumab (H) for the treatment of central nervous system (CNS) metastases in patients with Her2-positive (HER2+) metastatic breast cancer (MBC).
Authors: Romualdo Barroso-Sousa, William Thomas Barry, Priya Kumthekar, Hao Guo, Kelly M. Silvestri, Ian E. Krop, Eric P. Winer, Sara M. Tolaney, Nancy U. Lin
Journal: Journal of Clinical Oncology (2018)

TPS1100 Background: There is no clear standard of care to address the management of refractory CNS metastases in HER2+ MBC. The ongoing study (NCT03417544) is evaluating the efficacy of the combination of Atezo with P and high-dose H for the treatment of CNS metastases in patients (pts) with HER2-positive MBC. Methods: This is a phase II, single arm, multi-center trial assessing the efficacy of Atezo with Pertuzumab plus high-dose H for the treatment of CNS metastases in HER2+ MBC. Participants will receive Atezo [1200mg every 3 weeks (q3w)], P (840-mg loading dose, then 420mg q3w), and high-dose H (6 mg/kg weekly for 24 weeks, and then q3w). Eligibility Criteria include pts with HER2+ MBC, at least one measurable CNS metastasis (≥10 mm), unequivocal evidence of new and/or progressive CNS metastases, and left ventricular ejection fraction (LVEF) ≥ 50%. Exclusion criteria include CNS complications for whom urgent neurosurgical intervention is needed; known leptomeningeal/brainstem metastases; and treatment with dexamethasone > 2mg/day or bioequivalent within 7 days of initiating therapy. The primary endpoint is objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Secondary endpoints include the duration of CNS response, bi-compartmental progression-free survival according to RANO-BM, and the extracranial ORR according to RECIST 1.1. Tumor biopsies, peripheral blood, and cerebrospinal fluid will be obtained at baseline, on treatment and at progression. In the first stage, 19 pts will be enrolled. If there are at least 4 CNS responses, accrual will continue to the second stage where up to 14 additional pts will be enrolled. If at least 8 of these 33 pts have CNS response, the regimen will be considered worthy of further study. With this design, if the true response rate is 15%, the chance the regimen is declared worthy of further study is less than 10% (exact alpha = 0.096). If the true response rate is 35%, the chance that the regimen is declared worthy of further study is 90.4%. The trial opened in February 2018, with a target accrual of 33 pts. Clinical trial information: 03417544.
Serial concept mapping: A tool to assess the evolution of medical student learning about cancer survivorship.
Authors: Miklos C. Fogarasi, Roy P Eichengreen
Journal: Journal of Clinical Oncology (2018)

21 Background: Concept mapping (CM) fosters meaningful learning yet its use in cancer education is rare. Serial CM as a learning tool may offer novel ways to promote critical thinking about complex medical issues. We introduced CM in our Cancer Survivorship (CS) elective to study the evolution of students’ conceptual learning, to offer feed-back and as a tool for inter-professional and team-based education. Methods: The study was funded by an institutional grant and received IRB exemption. Eleven 2 nd year medical students and 2 pre-med students enrolled. Oncologist-lead classes were co-facilitated by a primary care physician, a survivor, caregivers or other health care professionals. Students were trained using cMAPTools on week 1 and applied domains of the Quality of Life (QoL)-CS tool by City of Hope to their CMs. Feedback given after each round of mapping assessed adequate use of CS concepts and creation of meaningful linkages. Results: Map #1 (week 1) tested baseline perceptions. These maps displayed a wide-range of complexity, a largely non-hierarchical structure with rare connections and a sense of overload by the scope of CS issues. Map #2 (week 4) explored physical and spiritual challenges of CS from a primary care physician and a cancer survivor. Here improved maps presented concepts more clearly but linear thinking with limited crosslinks was still observed. Map #3 (week 8) about social aspects of CS followed lively sessions with a social worker and family caregivers. Emerging cross-links reflected a deeper understanding of survivor issues. Final CMs will be based on interviewing a panel of survivors and should aid students in creating a thorough Survivorship Care Plan. Team-based and inter-professional maps were well received. Conclusions: Serial concept mapping exposes progressive understanding of Survivorship issues during a one-semester elective. CM facilitates the learning of relationships among complex survivorship topics. Inter-professional and team-based CM is feasible. By mapping issues to QoL domains, students practice patient-centered critical thinking. Challenges include low reproducibility due to changing concepts, and limited practicality once concepts grow too large.