tbuckley/cabot-search huggingface dataset:
Using real-world data to develop clinical trial referral networks for metastatic renal cell carcinoma (mRCC).
Authors: Nobumasa Kawasaki, Tanya Partridge, Jeffrey Stewart, Charlotte Carey, Cyrille Leroy, Una Ria, J. Ignacio Úbeda, Lisette Wagenaar, Anirudh Singh Rathore, Erika Rovati, Jeffrey Hodge, Natalia Balko Kotchie
Journal: Journal of Clinical Oncology (2018)

e16556 Background: As of February 2018, there are 16 ongoing global Phase III clinical trials in mRCC (with 11 in the US) in the first-line setting involving 1300 sites and 9600 patients (pts). To improve access to trials, we developed an analytically driven referral network for first-line mRCC pts, leveraging existing relationships with principal investigators (PIs). This may save time and costs compared with opening new trial sites. Methods: We analyzed patient treatment pathways for mRCC using US medical and pharmacy claims data to profile suitable first line treatment pts based on diagnosis, surgical history and current treatment. This allowed us to identify real-world referral patterns across care settings and specialist types, enabling us to find the source of the PI’s patients by linking them back to the referring specialist. For each specialist, we studied the volume of post-surgery pts and quantified those not referred to the PI. These potential additional candidates for referral and enrolment were geographically mapped to prioritize the opportunity for each PI. Results: While the majority of specialists referring pts for mRCC clinical trials were hematologist/oncologists, many other PI specialties were involved (Table 1). The identification of non-referred, suitable pts emphasized the untapped potential of the PI network (where the referring physicians had only sent a small percentage of their RCC pts to a PI). Conclusions: Using US claims data, we identified patient referral patterns that vary by site. Understanding these patterns may enhance recruitment in Phase III mRCC trials. A similar exercise is underway in Europe. Table 1. PI patient referral network patterns mRCC patients PI 1 PI 2 Referring Physician’s Referral to PI # of currently referred pts 81 136 Hematology/Oncology 47% 12% Internal Medicine 20% 13% Family Medicine 15% 26% Urology 0% 39% Other 19% 10% Referring Physician's Total Available Pts # of total available pts 446 872 Hematologist/ Oncologist 79% 35% Internal Medicine 5% 7% Family Medicine 1% 1% Urology 0% 48% Other 15% 0%
Outcomes of adolescents and young adults (AYAs) compared to pediatric patients with acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL): Real world data from the SEER registry.
Authors: Syed Sameer Nasir, Smith Giri, Sarah Elizabeth Nunnery, Eric Wiedower, Michael Gary Martin
Journal: Journal of Clinical Oncology (2016)

e18506 Background: Studies on outcomes of AYAs with AML and APL are limited. We sought to compare outcomes of AYAs and pediatric patients (pts) with AML (pAML) and APL (pAPL) using the Surveillance Epidemiology and End Results (SEER) registry. Methods: We utilized SEER-18 registry to identify pediatric (0-18 years) and AYA (age 19-30 years) pts with AML and APL. Survival statistics were computed using Kaplan-Meier method and compared using Z-test for population proportions. Early mortality rate (EMR), defined as mortality within 1 month of diagnosis, was used as a surrogate for treatment related mortality. Kaplan Meier (KM) survival curves were plotted and compared using log-rank test. Multivariate analysis was done using logistic regression and Cox proportional hazard regression model. All p-values were two-sided using significance level of 0.05. Results: 6343 AML pts were identified, and 44.7% were AYAs. Most pts were categorized as AML, not otherwise specified (56%). EMR was lower in pAML as compared to AYAs (6.2% vs 9.2%; p < 0.01). 1-year overall survival (OS) (70.3% vs 62.1%; p < 0.01) and 5-year OS was higher in pediatric pts versus AYAs (48.2% vs 36.4%; p < 0.01). KM plot showed worse OS for AYAs versus pAML. 920 APL pts were identified, and 59.5% were AYAs. EMR in pAPL compared to AYAs was 11.4% vs 14.1% (p = 0.23). 1-year OS (83.8% vs 81.2%; p = 0.31) and 5-year OS rates were not significantly different (68.2% vs 73.1%; p = 0.11). KM plot also showed similar OS for AYAs and pAPL. EMR for both AYAs and pAPL pts (11.4% and 14.1%) was higher than AYAs and pAML (6.2% and 9.2%). In contrast, OS for AYAs and pAPL pts (5-year OS 68.2% and 73.1%) was better than AYAs and pAML (5-year OS 48.2% and 36.4%). Conclusions: Our population based analysis showed AYAs with AML have worse EMR and OS compared to pAML. In contrast, AYAs and pAPL pts, managed with similar treatment protocols have similar outcomes. This observation supports that standardizing treatment protocols for AYAs with AML similar to pediatric pts may reduce EMR and OS to the rates seen in pAML pts. To our knowledge this is the first study to compare survival outcomes for pediatric and AYA pts with AML and APL.
Effect of Group-Administered Behavioral Treatment on Urinary Incontinence in Older Women
Authors: Ananias C. Diokno, Diane K. Newman, Lisa K. Low, Tomas L. Griebling, Michael E. Maddens, Patricia S. Goode, Trivellore E. Raghunathan, Leslee L. Subak, Carolyn M. Sampselle, Judith A. Boura, Ann E. Robinson, Donna McIntyre, Kathryn L. Burgio
Journal: JAMA Internal Medicine (2018)

Urinary incontinence (UI) guidelines recommend behavioral interventions as first-line treatment using individualized approaches. A one-time, group-administered behavioral treatment (GBT) could enhance access to behavioral treatment.To compare the effectiveness, cost, and cost-effectiveness of GBT with no treatment for UI in older women.Multisite randomized clinical trial (the Group Learning Achieves Decreased Incidents of Lower Urinary Symptoms [GLADIOLUS] study), conducted from July 7, 2014, to December 31, 2016. The setting was outpatient practices at 3 academic medical centers. Community-dwelling women 55 years or older with UI were recruited by mail and screened for eligibility, including a score of 3 or higher on the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF), symptoms of at least 3 months' duration, and absence of medical conditions or treatments that could affect continence status. Of 2171 mail respondents, 1125 were invited for clinical screening; 463 were eligible and randomized; 398 completed the 12-month study.The GBT group received a one-time 2-hour bladder health class, supported by written materials and an audio CD.Outcomes were measured at in-person visits (at 3 and 12 months) and by mail or telephone (at 6 and 9 months). The primary outcome was the change in the ICIQ-SF score. Secondary outcome measures assessed UI severity, quality of life, perceptions of improvement, pelvic floor muscle strength, and costs. Evaluators were masked to group assignment.Participants (232 in the GBT group and 231 in the control group) were aged 55 to 91 years (mean [SD] age, 64 [7] years), and 46.2% (214 of 463) were African American. In intent-to-treat analyses, the ICIQ-SF scores for GBT were consistently lower than control across all time points but did not achieve the projected 3-point difference. At 3 months, the difference in differences was 0.96 points (95% CI, -1.51 to -0.41 points), which was statistically significant but clinically modest. The mean (SE) treatment effects at 6, 9, and 12 months were 1.36 (0.32), 2.13 (0.33), and 1.77 (0.31), respectively. Significant group differences were found at all time points in favor of GBT on all secondary outcomes except pelvic floor muscle strength. The incremental cost to achieve a treatment success was $723 at 3 months; GBT dominated at 12 months.The GLADIOLUS study shows that a novel one-time GBT program is modestly effective and cost-effective for reducing UI frequency, severity, and bother and improving quality of life. Group-administered behavioral treatment is a promising first-line approach to enhancing access to noninvasive behavioral treatment for older women with UI.ClinicalTrials.gov identifier: NCT02001714.
Errors in Meta-analysis of Trial Comparing Effectiveness and Safety of Cognitive Behavioral Therapy With Pharmacotherapy for Childhood Anxiety Disorders
Authors: Zhen Wang
Journal: JAMA Pediatrics (2018)

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Abstract 19161: cAMP Regulated Transcriptional Coactivator 1 - A Novel Player in Cardiac Hypertrophy
Authors: Karoline M Morhenn, Thomas Quentin, Sabine Schroeder, Anja Pahl, Michael Steinmetz, Birgit Geertz, Thomas Eschenhagen, Saskia Schlossarek, Lucie Carrier, Jean-René Cardinaux, Wolfram-Hubertus Zimmermann, Susanne Lutz, Elke Oetjen
Journal: Circulation (2015)

Maladaptive cardiac hypertrophy leads to heart failure, a common cause for hospitalization. Chronic β-adrenergic, PKA dependent signaling and calcineurin contribute to hypertrophy. These signals converge in many tissues on the cAMP Regulated Transcriptional Coactivator 1 (CRTC1). We studied if CRTC1 promotes the development of maladaptive cardiac hypertrophy in human and murine hearts. In cardiomyocytes, treatment with β-adrenoceptor agonist isoprenaline dephosphorylated, thus activated 59 ± 5 % of total CRTC1, as seen by immunoblot (n = 3-4). Activation was prevented by propranolol. CRTC1 was not activated by endothelin or angiotensin II. CRTC1 protein content was enhanced in human and murine heart tissue under conditions of acquired and inherited maladaptive hypertrophy, seen by immunoblot (n = 7-8). Crtc1 -deficient mice (KO) showed a higher ratio of heart weight to tibia length than their wild-type littermates (WT) (8.6 ± 0.4 mg/mm vs. 10.9 ± 0.8 mg/mm in WT and KO, respectively, n = 12) and increased myocyte size (516 ± 8 μm 2 vs. 590 ± 11 μm 2 in WT and KO, respectively, n = 3 hearts). Echocardiographically assessed, the ejection fraction, fractional area shortening and cardiac output were reduced by 47 ± 8 %, 49 ± 12 % and 42 ± 9 %, respectively, in KO mice (n = 6-9). mRNA levels of Nppa , Nppb , Acta1 , Myh7 and the pro-fibrotic Ctgf did not differ between WT and KO mice (n = 12-15). By reducing G αq -protein induced signals in the heart, the Regulator of G-Protein Signaling 2 (RGS2) reduces hypertrophy. In KO mice the Rgs2 mRNA and protein levels were reduced by 26 ± 10 % and by 38 ± 8 %, respectively (n = 8-10). In a luciferase reporter gene assay overexpression of CRTC1 stimulated Rgs2 promoter transcriptional activity 1.8 fold (± 0.1); mutation of the CRTC1-interaction site, the cAMP-response element, prevented CRTC1-induced transcriptional activity (n = 6). In addition, chromatin immunoprecipitation showed the recruitment of endogenous CRTC1 to the Rgs2 promoter in cardiac tissue. In conclusion, our data indicate that increased CRTC1 protein content in maladaptive cardiac hypertrophy is a compensatory mechanism to delay disease progression, in part by upregulation of RGS2. Thus, CRTC1 represents a novel player of cardiac hypertrophy.
Establishment of patient-derived renal cell carcinoma (RCC) models based on orthotopic xenografts (PDX) and cancer stem cell (CSC) isolation to provide prognostic and predictive information.
Authors: Simona di Martino, Gabriele de Luca, Ludovica Grassi, Giulia Federici, Laura De Salvo, Anna Laura Di Pace, Antonio Addario, Giovanni Muto, Manuela Costantini, Mauro Biffoni, Michele Signore, Isabella Sperduti, Steno Sentinelli, Michele Milella, Francesco Cognetti, Michele Gallucci, Ruggero De Maria, Desiree Bonci
Journal: Journal of Clinical Oncology (2017)

e16055 Background: The introduction of VEGF/VEGFR- and mTOR, and immune checkpoint-targeted agents has radically changed metastatic RCC treatment; however, predictive biomarkers are still lacking and the potential for curative impact of such treatments in earlier disease stages is hotly debated. To identify potential diagnostic, prognostic, and predictive biomarkers, we developed patient-derived preclinical RCC models based on PDX obtained from freshly dissociated cancer tissues and combining isolation of cell populations endowed with self renewal and multi-lineage differentiation abilities (CSC). Methods: 182 surgical RCC specimens (clear cell, n = 110; papillary type I/II, n = 23, chromophobe/oncocytoma, n = 26, other, n = 23; stage I-III, n = 124, stage IV, n = 28, n/a n = 30) were collected; tumor spheroids were obtained and characterized in 57 cases, using a stem-cell isolating medium supplemented with EGF/b-FGF; 30 cancer samples were orthotopically injected in immunocompromised mice and were able to engraft in 67% of cases (G3-G4 cases more frequently than G1-G2 cases, p = 0.04). Results: PDX tumors recapitulated histological appearance, sarcomatoid features when they were present, and tumor heterogeneity of their human counterpart; interestingly, PDX engraftment was significantly correlated with shorter DFS in the corresponding patient population (p = 0.12). We conducted proteomic analysis by Reverse Phase Protein Array (RPPA) in 21 patient-derived CSC models in vitro: a panel of established (HIF, VEGFR, mTOR) and novel (EGFR(Y1148)), AKT, PI3K) oncogenic signals were deregulated in our isolated cell populations; molecular endpoints were correlated with grading and with angiogenesis and mTOR pathways (p &lt; 0.05). Data analysis is ongoing to ascertain whether specific RPPA-signatures can potentially complement clinical prognostic information and suggest candidate biomarkers and potential targets for therapy. Conclusions: In the era of personalized therapy, the combined use of PDX and RPPA from tumor specimens may be very useful for drug testing and patient stratification in RCC.
Functional independence in adult survivors of pediatric CNS tumors: A report from the St. Jude lifetime cohort study.
Authors: Tara M. Brinkman, Kirsten K. Ness, Zhenghong Li, Kevin R. Krull, Amar J. Gajjar, Thomas E. Merchant, Fredrick Boop, Paul Klimo, Raja B. Khan, Deokumar Srivastava, Leslie L. Robison, Melissa M. Hudson, Gregory T. Armstrong
Journal: Journal of Clinical Oncology (2016)

10524 Background: Beyond survival, attainment of functional independence is the primary goal for adult survivors of pediatric CNS tumors. However, the prevalence of and risk factors for non-independence have not been examined. Methods: Functional independence was assessed in 306 survivors (95 astrocytoma, 77 medulloblastoma/PNET, 35 ependymoma, 99 other) with mean [SD] current age = 26.3 years[5.1] and years since diagnosis = 17.6[5.0]. Six indicators were used to identify classes of independence using latent class analysis: employment, independent living, assistance with personal care and routine needs, driving ability and marital status. Physical performance impairments were defined as scores <10th percentile of normative data. Quality of life was measured using the SF-36. Multinomial logistic regression estimated odds ratios (OR) and 95% confidence intervals (CI) for associations with functional independence. Treatment models were adjusted for age, sex, age at diagnosis, tumor location, and surgical resection. Physical performance models were adjusted for age, sex, race, IQ, and chronic health conditions (cardiac, pulmonary, endocrine, neurologic). Results: Three classes of functional independence were identified: 1) independent (40%), 2) moderately independent (34%), and non-independent (26%). In multivariable treatment models, craniospinal irradiation (OR=4.9, 95%, 2.0-11.9) and younger age at diagnosis (OR=0.81, 95% CI, 0.74-0.88) were associated with increased risk of non-independence. After covariate adjustment, limitations in aerobic capacity (OR = 6.2; 95% CI, 2.1-18.5), balance (OR = 3.1; 95% CI, 1.2-7.7), strength (OR = 4.6; 95% CI, 1.2-18.2), and adaptive abilities (OR = 13.3; 95% CI, 4.2-42.4) were associated with increased odds of non-independence. Non-independent survivors reported worse physical (OR=2.7, 95% CI, 1.5-5.2), social (OR=1.5, 95% CI, 1.0-2.9), and emotional (OR=1.4, 95% CI, 1.0-2.0) quality of life than functionally independent survivors. Conclusions: A substantial proportion of pediatric CNS tumor survivors are unable to function independently as adults. Interventions targeting physical performance deficits are needed.
Schwann cell–derived periostin promotes autoimmune peripheral polyneuropathy via macrophage recruitment
Authors: Denise E. Allard, Yan Wang, Jian Joel Li, Bridget Conley, Erin W. Xu, David Sailer, Caellaigh Kimpston, Rebecca Notini, Collin-Jamal Smith, Emel Koseoglu, Joshua Starmer, Xiaopei L. Zeng, James F. Howard, Ahmet Hoke, Steven S. Scherer, Maureen A. Su
Journal: Journal of Clinical Investigation (2018)

Chronic inflammatory demyelinating polyneuropathy (CIDP) and Guillain-Barre syndrome (GBS) are inflammatory neuropathies that affect humans and are characterized by peripheral nerve myelin destruction and macrophage-containing immune infiltrates. In contrast to the traditional view that the peripheral nerve is simply the target of autoimmunity, we report here that peripheral nerve Schwann cells exacerbate the autoimmune process through extracellular matrix (ECM) protein induction. In a spontaneous autoimmune peripheral polyneuropathy (SAPP) mouse model of inflammatory neuropathy and CIDP nerve biopsies, the ECM protein periostin (POSTN) was upregulated in affected sciatic nerves and was primarily expressed by Schwann cells. Postn deficiency delayed the onset and reduced the extent of neuropathy, as well as decreased the number of macrophages infiltrating the sciatic nerve. In an in vitro assay, POSTN promoted macrophage chemotaxis in an integrin-AM (ITGAM) and ITGAV-dependent manner. The PNS-infiltrating macrophages in SAPP-affected nerves were pathogenic, since depletion of macrophages protected against the development of neuropathy. Our findings show that Schwann cells promote macrophage infiltration by upregulating Postn and suggest that POSTN is a novel target for the treatment of macrophage-associated inflammatory neuropathies.
Evaluation of genomic alterations in primary small cell carcinoma of the ovary (SCCO).
Authors: George Yaghmour, Omer HASSAN Jamy, Philippe Prouet, Manjari Pandey, Michael Gary Martin
Journal: Journal of Clinical Oncology (2016)

e17053 Background: As we have previously reported, SCCOis a rare, aggressive form of ovarian cancer associated with poor outcomes (Jamy 2015). In an effort to identify new treatment options, we utilized comprehensive genomic profiling to assess the potential for novel therapies in SCCO. Methods: Under an IRB approved protocol, we identified patients (pts) with SCCO, SCCO-HT (hypercalcemic type), neuroendocrine tumors of the ovary (NET-O) and small cell carcinoma of the lung (SCLC) profiled by Caris (company info) between 2007-2015. Tumors were assessed with up to 21 IHC stains, in situ hybridization of cMET, EGFR, HER2 and PIK3CA, and next generation sequencing (NGS) as well as Sanger sequencing of selected genes. Results: 46 pts with SCCO (10 SCCO, 18 SCCO-HT, 18 NET-O) were identified as well as 58 pts with SCLC. While small numbers prohibited comparisons SCCO patients were numerically younger (median 42 [range 12-75], SCCO-HT pts 26 [8-40] and NET-O pts 62 [13-76]) than SCLC pts 66 [36-86]. SCCO pts were numerically more likely to be metastatic (70%) than SCCO-HT (50%) or NET-O (33%) pts but at a similar rate to SCLC pts (65%). PD1 expression varied across tumor type with SCCO (100%), SCCO-HT (50%), NET-O (33%) vs SCLC (42%). PDL1 expression also varied with SCCO (50%), SCCO-HT (20%), NET-O (33%) and SCLC (0%). No amplifications were identified in cMET, EGFR, or HER2 and only 1 was found in PIK3CA (NET-O). Actionable mutations were rare with 50% of SCCO pts having a BRCA2 mutation and 29% of pts with NET-O having PIK3CA mutations. No other actionable mutations were identified. Conclusions: SCCO/NET-O represent rare and difficult to treat malignancies. While randomized trials will be difficult these tumors may respond to biomarker guided checkpoint or PARP inhibitors.
A multiplexed NGS solution to evaluate potential tumor immune response and objectively stratify tumors by histopathology from FFPE samples.
Authors: Ann Mongan, Sophie Rozenzhak, Geoff Bien, Takayuki Yoshino, Wataru Okamoto, Hiroyoshi Nishikawa, Warren Tom, Jianping Zheng, Tim Looney, Fiona Hyland
Journal: Journal of Clinical Oncology (2016)

e14566 Background: The emergent T cell checkpoint therapy has offered durable and potential curative results for many NSCLC and melanoma patients. Nevertheless, fewer than half of subjects in trials exhibited positive response (Sharma, 2015). These results greatly illustrate the necessity for a better understanding of tumor microenvironment, tumor-lymphocyte interactions, and biomarkers that could predict drug sensitivity. In particular, PD-L1 expression has been reported to be a promising marker of response for PD-L1 therapies. However, standard methods for assessing PD-L1 protein level via immunohistochemistry have been shown to be inefficient and highly variable (McLaughlin, 2015) depending on selected antibodies, staining techniques, and site of tumors (Meng, 2015). Furthermore, as investigators are often also interested in measurements of additional biomarkers such as IFNg as well as markers of immune response, a gene panel approach offers a convenient solution to objectively quantify expression levels of these informative markers. Methods: Here we describe the identification and characterization of a research panel of approximately 200 genes designed to evaluate the expression of immune checkpoint pathway, level of tumor infiltrating lymphocytes, T cell regulation, interferon signaling, and presence of various lymphocyte subsets. Results: Our preliminary data shows that expression of the selected genes can stratify non-small cell lung cancer FFPE samples by histopathology (adenocarcinoma vs. squamous cell carcinoma). Furthermore, quantitative read out of the IFNg is clear and unambiguous for IFNg positive and negative controls. Gene expression was measured by NGS. Technical replicates were found to have > 0.99 correlation among each other. Assays on this research panel* were also found to be robust with respect to low input amount (1-10 ng RNA). Conclusions: We found a gene panel approach is a suitable tool to evaluate the expression of immune checkpoint pathway and level of tumor infiltrating lymphocytes, thereby offering insights into drug sensitivity *For Research Use Only. Not for use in diagnostic procedures.
An attempt to better understand radiation recall events: A literature review.
Authors: Amin Benyounes, Amrit Pathak, Ethan Louis Binder, Petr Frantisek Hausner
Journal: Journal of Clinical Oncology (2018)

e22109 Background: Radiation recall is an inflammatory reaction at a previously irradiated site triggered mostly by an antineoplastic agent. The mechanism of this reaction is poorly understood. We hereby report the results of a literature review of all case reports and case series published. Methods: Data were collected by search of Pubmed. The search term