tbuckley/cabot-search huggingface dataset:
KINECT 3: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial of Valbenazine for Tardive Dyskinesia
Authors: Robert A. Hauser, Stewart A. Factor, Stephen R. Marder, Mary Ann Knesevich, Paul M. Ramirez, Roland Jimenez, Joshua Burke, Grace S. Liang, Christopher F. O’Brien
Journal: American Journal of Psychiatry (2017)

Tardive dyskinesia is a persistent movement disorder induced by dopamine receptor blockers, including antipsychotics. Valbenazine (NBI-98854) is a novel, highly selective vesicular monoamine transporter 2 inhibitor that demonstrated favorable efficacy and tolerability in the treatment of tardive dyskinesia in phase 2 studies. This phase 3 study further evaluated the efficacy, safety, and tolerability of valbenazine as a treatment for tardive dyskinesia.This 6-week, randomized, double-blind, placebo-controlled trial included patients with schizophrenia, schizoaffective disorder, or a mood disorder who had moderate or severe tardive dyskinesia. Participants were randomly assigned in a 1:1:1 ratio to once-daily placebo, valbenazine at 40 mg/day, or valbenazine at 80 mg/day. The primary efficacy endpoint was change from baseline to week 6 in the 80 mg/day group compared with the placebo group on the Abnormal Involuntary Movement Scale (AIMS) dyskinesia score (items 1-7), as assessed by blinded central AIMS video raters. Safety assessments included adverse event monitoring, laboratory tests, ECG, and psychiatric measures.The intent-to-treat population included 225 participants, of whom 205 completed the study. Approximately 65% of participants had schizophrenia or schizoaffective disorder, and 85.5% were receiving concomitant antipsychotics. Least squares mean change from baseline to week 6 in AIMS dyskinesia score was -3.2 for the 80 mg/day group, compared with -0.1 for the placebo group, a significant difference. AIMS dyskinesia score was also reduced in the 40 mg/day group (-1.9 compared with -0.1). The incidence of adverse events was consistent with previous studies.Once-daily valbenazine significantly improved tardive dyskinesia in participants with underlying schizophrenia, schizoaffective disorder, or mood disorder. Valbenazine was generally well tolerated, and psychiatric status remained stable. Longer trials are necessary to understand the long-term effects of valbenazine in patients with tardive dyskinesia.
NLG-0301: An open-label, randomized phase 2B active control study of second-line tergenpumatucel-L immunotherapy versus docetaxel in patients with progressive or relapsed non-small cell lung cancer (NSCLC).
Authors: Ramaswamy Govindan, John Charles Morris, Gabriela R. Rossi, Nicholas N. Vahanian, Charles J. Link
Journal: Journal of Clinical Oncology (2014)

TPS8133 Background: Tergenpumatucel-L immunotherapy consists of allogeneic lung cancer cells that have been genetically modified to express the carbohydrate α(1,3)Gal, to which humans have an inherent pre-existing immunity. It is αGal that is primarily responsible for the hyperacute rejection of foreign tissue via this potent immune defense mechanism in humans. Tergenpumatucel-L leverages this mechanism to educate the immune system towards components of the patients’ own tumor cells. In a Phase 2 study of tergenpumatucel-L, patients with evidence of immune activation after therapy (11/18 patients with elevated IFN gamma via ELISPOT) had a median survival of 21.9 months. 16 of 28 patients went on to salvage therapy after progression and 9 of these 16 had objective responses (5PR, 4SD) to the post immunotherapy chemotherapy. This study is designed to further evaluate this potential chemo-sensitization effect of tergenpumatucel-L. Methods: This Phase 2B study is an open label, multi center randomized trial of single agent tergenpumatucel-L versus docetaxel. Eligible patients have pathologically confirmed NSCLC and may have previously undergone surgery, radiotherapy, and ≤ 2 prior chemotherapy regimens for this diagnosis. 240 patients will be randomized in a 2:1:1 manner to docetaxel (75mg/m2 q3 weeks x 4 doses) versus tergenpumatucel-L (300 million cell intradermally weekly for 11 weeks and then q2 months for 5 additional doses) versus tergenpumatucel-L (300 million cell q2 weeks for 6 doses and then monthly for 10 months). Patients will be monitored and at progression may stay on study and receive gemcitabine or premetrexed if randomized to the docetaxel arm or docetaxel or gemcitabine or premetrexed if randomized to one of the tergenpumatucel-L arms. Patients randomized to immunotherapy may continue to receive tergenpumatucel-L while on salvage chemo until all 16 planned doses are administered. This design with the patients staying on trial after progression is intended to capture and evaluate the possible chemo-sensitization seen in previous trials. Primary endpoint is overall survival. Clinical trial information: NCT01774578.
Prognostic relevance of gene signatures in high-grade serous ovarian carcinoma.
Authors: Gottfried E. Konecny, Chen Wang, Boris Winterhoff, Judy Dering, Charles Ginther, Hsiao-Wang Chen, Habib Hamidi, Karl C. Podratz, William Cliby, Sean Christopher Dowdy, Paul Haluska, Lynn C. Hartmann, Kimberly Kalli, Ellen L. Goode, Dennis J. Slamon
Journal: Journal of Clinical Oncology (2013)

5510 Background: Transcriptional profiling of ovarian cancers has proven to be complex. As such it has been difficult to validate existing signatures across studies. Cancer Genome Atlas (TCGA) researchers have identified four molecular subtypes of high-grade serous ovarian cancer (HGSOC). However, survival duration did not differ significantly for the TCGA subtypes. Potential limitations of the TCGA data include short clinical follow-up (45% were alive at the time of last follow-up) and the need to unify gene expression measures from multiple platforms. Methods: Clinically annotated stage-II–IV HGSOC samples (n = 175) with &gt;70% tumor cell content were profiled using the Agilent Whole Human Genome 4 x 44K chip. To identify subtypes non-negative matrix factorization (NMF) of mRNA expression was performed using ~2000 genes with the highest variability across patients. In parallel differentially expressed genes were identified using the Rosetta Similarity Search Tool as well as analysis of variance based on genes known to be involved in epithelial to mesenchymal transition. Results: Median follow-up time was 35 months (range, 0–202 months, 12% were alive at the time of last follow-up). NMF clustering confirmed four HGSOC subtypes (immunoreactive, differentiated, proliferative, and mesenchymal) on the basis of gene content in the clusters. Pathway signatures with therapeutic potential were identified for individual or multiple subtypes. Survival differed significantly between the four molecular subgroups in univariate (Hazard Ratio [HR] 2.4, 95% CI 1.5-4.1, p = 0.007) and multivariate (HR 2.3, 95% CI 1.3-4.0, p = 0.003) analyses when accounting for age, stage, grade, and postoperative residual tumor. Using the supervised clustering approach two distinct molecular subtypes of HGSOC based on epithelial and mesenchymal gene expression signatures were identified with significantly different survival outcomes. Conclusions: Here we independently validate and expand upon the molecular TCGA classification of HGSOC. The potential of these two prognostic classifiers may lie in their ability to recognize categories of patients that are more likely to respond to particular therapies.
Predictive value of circulating tumor cells positive for VEGFR expression in patients with advanced colorectal cancer undergoing treatment with FOLFOX plus bevacizumab.
Authors: M. Jose Serrano, Francisco Gabriel Ortega, jose Antonio Lorente, Mayte Delgado, Jose Luis Puche
Journal: Journal of Clinical Oncology (2014)

e22026 Background: The Metastasis process is associated with the presence of Circulating Tumor cells (CTCs) in peripheral blood of colon cáncer patients. However, biologic characteristics of CTC and primary tumor can diverge. These discrepancies can be responsible for treatment failures and subsequent relapse in colon cancer. VEGFR plays an important role in angiogenesis and an important therapeutic target. CTCs can express VEGFR. Thus, could be interesting analyze VEGFR expression in CTCs for monitoring of patients undergoing Bevacizumab treatment. Methods: Prospective observational study over 50 patients with metastatic colorectal cancer. Peripheral blood was analyzed before and after treatment, for VEGFR-2 expression in the CTCs. Changes in CTC levels were correlated with , clinicopathologic characteristics. The Pathologic response was evaluated to 6, 12 and 24 week after FOLFOX6+Bevacizumab treatment and correlated with the presence of CTCs at baseline. An Immunomagnetic positive selection method and Inmunocytochemistry method were used to isolated and detected respectively CTCs . After verifying the presence of cells positive for cytokeratin , VEGFR-2 detection was performed. Results: Positive Cytoqueratin CTCs were detected at baseline in 40% of patients. Two differents subpoplation of CTC were identified: CTCck+vegfr+ and CTCck+vegfr-. 75% of patients withCK+ were positive for VEGFR expression. 25% of CK positive samples were negatives to VEGFR. The observed results showeda lack of response to Folfox6+Bevacizumab treatment in all patients with CTCck+vegfr- , while the CTCck+vegfr+ population showed response to Folfox6+Bevacizumab treatment. Conclusions: These data provide evidence of the importance of characterization of CTCs for monitoring of treatment response in colon cáncer patients These finding require more validation, but suggest that subpopulations of CTCs may provide early indication of response to Bevacizumab therapy.
Mediating role of emotional symptoms on assessment of health-related quality of life of adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
Authors: I-Chan Huang, Tara M. Brinkman, Gregory T. Armstrong, Leslie L. Robison, Kevin R. Krull
Journal: Journal of Clinical Oncology (2014)

10092 Background: Factors that may mediate or influence how cancer survivors endorse health-related quality of life (HRQOL) items are not well studied. This study compared HRQOL between adult survivors of childhood cancer and siblings by accounting for the mediating effect and measurement non-invariance related to emotional symptoms. Methods: 7,103 cancer survivors and 390 siblings in the Childhood Cancer Survivor Study completed the SF-36 measuring eight domains of HRQOL. Symptoms of anxiety, depression and somatization were measured using the Brief Symptom Inventory-18. Multiple Indicators & Multiple Causes model was used to identify measurement non-invariance related to emotional symptoms in the SF-36 items. Structural equation modeling was performed to test direct and indirect effects of cancer experience on HRQOL accounting for the mediating role of emotional symptoms. Results: 10, 12, and 14 items of the SF-36 were identified with measurement non-invariance related to anxiety, somatization and depression, respectively. Survivors reported poorer HRQOL in all domains than siblings did (all p's<0.05), except for pain (p>0.05). Poorer physical functioning was significantly explained by direct effect of cancer experience (p<0.05) and indirect effect of cancer experience through emotional symptoms (p<0.05). However, poorer HRQOL in other domains was greatly explained by the mediating role of emotional symptoms, indicating indirect effect (p<0.05) rather than direct effect (p>0.05). Indirect effects explained 40-70% of total effects in the association of cancer experience and HRQOL. Adjusting for measurement non-invariance for the SF-36 items did not change the association of cancer experience with HRQOL compared to not adjusting for non-invariance. Conclusions: Childhood cancer survivors reported poorer HRQOL than siblings. The differences appear due, in part, to measurement non-invariance related to emotional symptoms that influence perceptions of HRQOL, and the mediating effect of emotional symptoms on HRQOL. Evaluating emotional health is an important component in survivorship care toward improving their HRQOL.
INCICENCIA, CARACTERISTICAS ENDOSCOPICAS, HISTOLÓGICAS Y EPIDEMIOLOGICAS DEL CANCER COLORRECTAL DE INTERVALO EN UN HOSPITAL DE TERCER NIVEL
Authors: S Frago Larramona, P Camo Monterde, EM Sierra Moros, MT Soria San Teodoro, LM Ruiz Belmonte
Journal: Endoscopy (2015)

Introducción: El cáncer colorrectal de intervalo (CCRI) es aquel carcinoma colorrectal (CCR) que se diagnostica dentro de los 3 – 5 años siguientes a una colonoscopia. Su incidencia se estima entre el 2.9% y el 7.9%.
Is guideline-adherent adjuvant treatment an equivalent option for elderly patients who cannot participate in adjuvant clinical breast cancer trials? A retrospective multicenter cohort study of 4,142 patients.
Authors: Lukas Schwentner, Reyn Van Ewijk, Theresa Gundelach, Jochem König, Rolf Kreienberg, Wolfgang Janni, Maria Blettner, Achim Wöckel
Journal: Journal of Clinical Oncology (2014)

1063 Background: It is well accepted that innovation in oncology is transported through randomized clinical trials (CT). However, elderly patients (>65) are usually excluded from CT. Therefore this study tries to answer the following questions: (1) Is there a difference in outcome parameters comparing study participants (PA) and elderly patients who are not able to participate? (2) Is guideline adherent treatment an equivalent option for elderly patients (>65)? Methods: This German multi-center [17 participating hospitals all are certified as breast cancer centers] retrospective cohort study called BRENDA included study participants <65 (PA) and elderly breast cancer patients >65 (E) obtained from 1992 until 2008. The definition of guideline adherence was based on internationally validated guidelines. Results: After adapting the exclusion criteria we included 960 (23.2%) PA and 3.182 (76.8%) E >65. E >65 demonstrate a significantly inferior RFS [RFS: p<0.001; HR=1.67 (95% CI: 1.32-2.11)] and OS [OS: p<0.001; HR=1.98 (95% CI: 1.50-2.62)] compared to PA <65. Within the E group 1.868 (58.7%) patients received guideline adherent adjuvant treatment. However when comparing PA <65 versus guideline conform E >65 we are not able to demonstrate a significant difference in RFS [RFS: p=0.218; HR=1.17 (95% CI: 0.91-1.50)] and OS [OS: p=0.054; HR=1.34 (95% CI: 1.00-1.81)]. However non-guideline adherent E >65 demonstrated significantly inferior survival parameters [RFS: p<0.001; HR=2.10 (95% CI: 1.61-2.62)] [OS: p<0.001; HR=2.50 (95% CI: 1.87-3.33)] compared to PA. Conclusions: Guideline adherent adjuvant treatment is an equivalent option for elderly patients who are excluded from participation in clinical trials. There is a strong association between guideline adherence and improved outcome parameters in elderly breast cancer patients.
<i>In utero</i> presentation of aggressive systemic mastocytosis in a neonate
Authors: A. Huang, N. Fiadorchanka, K. Brar, J.L. Balderacchi, S.A. Glick
Journal: British Journal of Dermatology (2017)

Mastocytosis is a clinically heterogenous disease characterized by mast cell hyperplasia in skin, bone marrow and/or visceral organs. Cutaneous mastocytosis is more frequently observed in children, whereas indolent systemic mastocytosis is more commonly observed in adults. Aggressive systemic presentation, particularly of the neonate, is exceptionally rare. We present a rare case of congenital aggressive systemic mastocytosis. The patient was a 37‐week‐old male, born by caesarean section owing to hepatosplenomegaly and ascites diagnosed in utero, who exhibited extensive cutaneous and systemic manifestations of mastocytosis at birth. Mutation analysis of c‐KIT identified D816V mutation in exon 17. Although initial bilateral bone marrow aspirates demonstrated no mast‐cell infiltrates or haematological neoplasm, subsequent bone‐marrow biopsies postmortem exhibited multifocal mast‐cell aggregates. Clinical course was complicated by bacteraemia and cardiorespiratory failure, leading to death at 10 weeks.
Taking Stock of Retinal Gene Therapy: Looking Back and Moving Forward
Authors: Jean Bennett
Journal: Molecular Therapy (2017)

Over the past 20 years, there has been tremendous progress in retinal gene therapy. The safety and efficacy results in one early-onset severe blinding disease may lead to the first gene therapy drug approval in the United States. Here, we review how far the field has come over the past two decades and speculate on the directions that the field will take in the future.
Retreatment with pemetrexed-based chemotherapy in advanced nonsquamous NSCLC patients.
Authors: Minglei Zhuo, Jie Wang, Tongtong An, Zhijie Wang, Jun Zhao, Meina Wu, Jianchun Duan, Yuyan Wang, Hua Bai, Shuhang Wang
Journal: Journal of Clinical Oncology (2013)

e19061^ Background: Retreatment of pemetrexed based chemotherapy (PBC) has been reported in MPM previously, but it is not investigated in non-squamous NSCLC (NS-NSCLC). Methods: We retrospectively enrolled 26 advanced NS-NSCLC patients who had received retreatment of PBC when their response to initial PBC were PR or SD. Chemotherapy regimens administered as retreatment were single pemetrexed (500 mg/m 2 every 3 weeks) or pemetrexed with a platinum. Response was evaluated according to RECIST. Toxicity was evaluated according to NCI-CTC version 3.0. PFS and OS were computed by Kaplan-Meier. Statistical analyses were performed with SPSS13.0. Results: In retreatment, most adverse effects (AE) were tolerable but doublet regimen was associated with higher AE including bone marrow depression and fatigue. In patients who received retreatment of PBC, objective response rate (ORR) and disease control rate (DCR) was 12% (3/26) and 73% (19/26) respectively. Patient with PFS≥10 months in initial PBC therapy would have a longer PFS in retreatment comparing with those PFS &lt;10 months (6.0 vs 3.1 month, p = 0.004); patients with therapy-free interval (TFI) ≥6 months after initial PBC therapy also have a longer PFS in retreatment comparing with those interval &lt;6 months (7.0 vs 3.0 month, p = 0.001). The OS also tend to be longer but not reach statistic significance. The response of first round PBC therapy (PR vs. SD) was not a factor affecting the PFS in retreatment. Conclusions: Patients with PFS over 10 months or TFI over 6 months after first round of PBC could benefit from retreatment of PBC.
Clinical significance of type 1 insulin-like growth factor receptor and insulin-like growth factor binding protein-3 expression in squamous cell carcinoma of head and neck
Authors: H. Jun, M. Chang, Y. Ko, Y. Ahn, H. Jeong, Y. Son, J. Baek, Y. Park, K. Park, M. Ahn
Journal: Journal of Clinical Oncology (2009)

6036 Background: Type 1 insulin-like growth factor receptor (IGF-1R) plays an important role in the growth and apoptosis of cancer cell. The activities of IGF-1R are modulated by a family of high-affinity insulin-like growth factor binding proteins (IGFBPs), of which IGFBP-3 is the major serum carrier protein. The expression and significance of IGF-1R and IGFBP-3 in squamous cell carcinoma of the head and neck (SCCHN) is unknown. Methods: This study explored immunohistochemical expression of IGF-1R and IGFBP-3 in tumor samples from 131 patients with surgically resected SCCHN. Results: The positive expression of IGF-1R and IGFBP-3 was observed in 96 (73.3%) and 117 (89.3%) patients. There were no significant differences in baseline characteristics between the positive and negative expressed groups of IGF-1R and IGFBP-3. With the median follow up of 53.5 months, 3 year progression free (PFS) and overall (OS) survival rate was 64.0% and 72.9%, neither IGF-1R nor IGFBP-3 expression had prognostic values in the whole cohort. Thirty-seven (67.3%) of 55 stage IV patients demonstrated IGF-1R positivity. The subgroup analysis of in stage IV patients showed the poor PFS ( = 0.029) and OS (pp = 0.025) in IGF-1R positive groups. In a multivariate analysis using IGF-1R expression and other clinicopathological parameters, the IGF-1R expression was remained as an independent factor for PFS (p = 0.037, HR = 2.816, 95% C.I. 1.065 - 7.446) and OS (p = 0.034, HR = 3.169, 95% C.I. 1.089 - 9.225). Conclusions: Our work exhibited that IGF-1R expression is frequent in SCCHN patients and related with poor survival in advanced stage, this could support the attempts using the IGF-1R inhibitor for treatment of SCCHN. No significant financial relationships to disclose.
Phase II study of AVR118 in the management of cancer related anorexia/cachexia
Authors: J. T. D'Olimpio, M. R. Chasen, R. Sharma, M. Diego, V. Gullo, N. MacDonald
Journal: Journal of Clinical Oncology (2009)

e20631 Background: AVR118 represents a new class of cytoprotective drugs in managing symptoms associated with anorexia\/ cachexia. In a previous study in patients with advanced HIV-AIDS, an improvement in appetite, strength and alertness was noted. The precise mechanism of action is not understood, but activity may be related to AVR118's adenosine based components. Other active components include guanosine and branched chain amino acids leucine and valine. Objective: To determine the effect of AVR118 on appetite, early satiety and nutritional intake in patients with advanced cancer. Secondary endpoints include changes in performance status, lean muscle mass and quality of Life (QOL). Methods: Eligible adult patients received 4.0 ml of AVR118 subcutaneous daily injections. Patients underwent bi-monthly evaluations during the 28 day initial treatment (phase A) Evaluations included Karnofsky performance status, Edmonton Symptoms Assessment Scale (ESAS), Patient Generated Subjective Global Assessment (PG-SGA), Simmonds Functional Assessment, Dyspepsia Symptom Severity Index, Weight, Lean Body Mass, skin fold thickness and grip strength. Patients who benefited from phase A could elect to continue with therapy (phase B). Results: Currently, of 16 enrolled patients 7 have completed phase A. All 7 patients chose to continue with AVR118 treatment (phase B). Improvements in anorexia and PG-SGA scores were seen in 7/7 and 6/7 patients respectively. Weight stabilization or gain was observed in 5/7 patients. All other parameters showed no significant difference. There was AVR118 has been well tolerated and no serious side effects have been reported. Conclusions: Based on these positive results, the primary endpoints have been achieved and the study will be expanded from 14 to 30 patients. [Table: see text]
Exploring the relationship between mentoring and doctors’ health and wellbeing: a narrative review
Authors: Gemma Wilson, Valerie Larkin, Nancy Redfern, Jane Stewart, Alison Steven
Journal: Journal of the Royal Society of Medicine (2017)

The health and wellbeing of doctors are crucial, both for the individuals themselves and their ability to deliver optimum patient care. With increased pressures on healthcare, support mechanisms that attend to doctors’ health and wellbeing may require greater emphasis to safeguard those working in frontline services. To inform future developments, this systematic narrative review aimed to identify, explore and map empirical and anecdotal evidence indicating the relationships between mentoring activities and the health and wellbeing of doctors. Twelve databases were searched for publications printed between January 2006 and January 2016. Articles were included if they involved doctors’ engagement in mentoring activities and, either health or wellbeing, or the benefits, barriers or impact of mentoring. The initial search returned 4669 papers, after exclusions a full-text analysis of 37 papers was conducted. Reference lists and citations of each retrieved paper were also searched. Thirteen papers were accepted for review. The Business in the Community model was used as a theoretical framework for analysis. Mentoring influenced collegiate relationships, networking and aspects of personal wellbeing, such as confidence and stress management, and was valued by doctors as a specialist support mechanism. This review contributes to the evidence base concerning mentoring and doctors’ health and wellbeing. However, it highlights that focused research is required to explore the relationship between mentoring, and health and wellbeing.