tbuckley/cabot-search huggingface dataset:
Inhibition of the IGF pathway in metastatic castrate resistant prostate cancer (CRPC): Results from a phase II study of OSI-906 (linsitinib).
Authors: Jorge A. Garcia, Paul Elson, Matthew M. Cooney, Allison Janine Tyler, Victoria Rezash, Ernest C. Borden, Robert Dreicer
Journal: Journal of Clinical Oncology (2013)

e16022 Background: AR ligand independent pathways are responsible for the development of CRPC. IGF-1R and its ligands (IGF-1/IGF-2) play a key role in regulating growth, resistance to apoptosis, and invasion in PCa. IGF-1R is overexpressed in PCa and mediates resistance to ADT. Linsitinib is a small molecule potent dual inhibitor of IGF-1R and insulin receptor TK activity. To determine the activity of linsitinib in men with CRPC a Simon two-stage phase II study was conducted. Methods: Men with asymptomatic or mildly symptomatic Met CRPC were eligible. ECOG 0-1, adequate organ function, and no prior chemotherapy for CRPC were required. Pts received linsitinib at 150mg orally twice daily on a 28-day cycle. Endpoints included PSA response at 12 wks, safety, RECIST-defined response, time to PSA progression, and OS. Correlative studies explored the impact of linsitinib on AR signaling (androstenedione, DHEA, DHEA-sulfate, p-IGF-1R, p-IR), markers of PD (TGF-b1, IL-6, TNF-a, MCP-1), and CTC and CECs. Results: Eighteen pts were enrolled and completed 12 wks of therapy. Median age 68 (55-78); Median pre-treatment PSA was 55.23 (range 2.46-277.60); 41% of pts had bone-only disease, 29% soft-tissue only and 29% had both. Although transient PSA declines were noted (8/18), seventeen pts discontinued therapy sec PSA progression. RECIST-defined SD was observed in 8 pts. Pts received a median of 3 cycles of therapy (range 2-6+). Most common G1/2 AEs included AST/ALT changes observed in 41 and 18% of patients respectively, fatigue (59%); prolonged QT interval (35%) and nausea/vomiting (35%). No significant change in the number of CTC and CEC counts was observed. An association between pre-treatment PSA and pre-treatment CTC was observed (Spearman r=0.49, p=.04). No correlation between CTC changes and PSA progression was observed .Evaluation of other molecular markers of PD is underway. Conclusions: Treatment with linsitinib is safe however no PCa activity was seen. No changes in CTC/CECs were noted. Markers of PD might help elucidate potential mechanisms of escape to this alternative pathway in CRPC. Linsitinib plus an AA might provide synergistic activity in this setting. Clinical trial information: NCT01533246.
Breast cancer survivorship: State of the science.
Authors: Kathy Pan, Rowan T. Chlebowski
Journal: Journal of Clinical Oncology (2017)

45 Background: Only in the past decade has breast cancer survivorship earned formal recognition as a research discipline. Complicating survivorship research is the overlap between aging and treatment sequelae (Pan et al., Breast Cancer Res Treat 2016). The ACS/ASCO 2015 Breast Cancer Survivorship Care Guideline and the jointly sponsored 2016 Cancer Survivorship Symposium afforded an opportunity to review the “state of the science.” Methods: All 236 citations from the Guideline and all 250 abstracts from the Symposium were reviewed independently by two authors and prospectively categorized as follows: randomized trial; non-randomized study with controls; study without controls; review; and guideline. Additional categories were generated during the review process. Results: The Guideline most commonly cited reviews (n = 88, 37%), followed by 51 (22%) non-randomized, non-controlled studies and 37 (16%) randomized trials, which mostly addressed interventions for therapy sequelae such as lymphedema. Symposium abstracts most commonly described non-randomized, non-controlled studies (n = 113, 45%). Among 13 randomized trials (5%), 3 had not completed accrual; sample sizes were 60-467. 42 (17%) abstracts were identified as pilot studies and 17 (7%) as qualitative studies. 65 (26%) exclusively addressed breast cancer. Abstracts mostly covered health-related or psychosocial sequelae of therapy; however, some addressed overall survival or active cancer therapy. Conclusions: Much of the survivorship literature remains in the exploratory stage, consisting of non-controlled, pilot and qualitative studies. To optimally address survivorship issues, increasing incorporation of cancer-free, age-matched control populations is needed. [Table: see text]
A phase I study determining the safety and tolerability of combination therapy with pazopanib, a VEGFR/PDGFR/raf inhibitor, and GSK1120212, a MEK inhibitor, in advanced solid tumors enriched with patients with advanced differentiated thyroid cancer.
Authors: Shabina Roohi Ahmed, Nilofer Saba Azad, Douglas Wilmot Ball, Michelle A. Rudek, Barry Nelkin, David Cosgrove, Jing Gong, Daniel Finkelstein, Marianna Zahurak, Filip Janku, Melinda Downs, Ashley O'Connor, Susan Markus, Michael Anthony Carducci, Steven I. Sherman, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2012)

TPS3117 Background: Mutations of the RAS/RAF/MEK/ERK signaling pathway, especially RAS, BRAF and IGF-I/II receptor genes play a critical role in the development of many different types of cancers, including breast, colorectal, melanoma, NSCLC, and thyroid. Differentiated thyroid cancer (DTC) is the most common endocrine malignancy, but there is currently no approved therapy for advanced radioiodine-resistant disease. In DTC xenograft models, vertical inhibition of this pathway, achieved by targeting the vascular endothelial growth factor receptor (VEGFR) and MEK, has shown greater clinical efficacy than with either agent alone. Pazopanib (P) is a small molecule tyrosine kinase inhibitor that selectively inhibits VEGFR1-3, PDGFR-α, PDGFR-b, c-kit, and FGFR 1-3. Phase II data in advanced DTC from Bible, et al, indicate a 49% response rate with a PFS of 11.7 months in a patients with PD within 6 months. GSK1120212 (G) is a potent, highly selective, allosteric inhibitor of MEK1/2. In a phase I/II study, Infante et al. reported an ORR of 81% in BRAF mutant melanoma patients when G was combined with a RAF inhibitor. Methods: A phase I, open label, dose escalation trial with P+G is currently accruing pts with advanced malignancies. The study is a standard 3+3 design with an expansion cohort of 25 pts with advanced DTC for correlative endpoints and PK studies. Pts will be treated with P at 400 mg QD, 600 mg QD and 800 mg QD, with G held constant at 1 mg QD; G will then be escalated to 1.5 mg QD and 2 mg QD. Eligibility includes advanced solid tumor, good end organ function and performance status, and PD within 6 months in the expansion cohort. The primary objective is to determine the safety and tolerability of the combination and determine the MTD. Secondary objectives include assessing preliminary efficacy as defined by RECIST criteria and PFS, and exploration of PK/PD endpoints. Serial tumor biopsies will be evaluated for changes in signaling through p-ERK. RAS and RAF mutation sites will be sequenced in order to correlate with PD endpoints and disease response. Currently, DL1 has accrued with no DLTs.
In Reply
Authors: Laura Q.M. Chow, S. Gail Eckhardt
Journal: Journal of Clinical Oncology (2007)

different neurotrophins.trkA is the receptor tyrosine kinase for NGF." 3,4 trkA mediates the survival-promoting and neurite growth-promoting effects of NGF during development and its later pain-provoking actions. 5 A lot has been written about chronic pain: synaptic events, axonal reflexes leading to wind-up processes, and the key roles played by AMPA receptors, NMDA and brain-derived neurotrophic factor receptors and mediators. 2NGF has also been proven to play a role in chronic pain, but unfortunately, research has hindered the recognition of the role of NGF as a key pain mediator until recently. 2So, drug-discovery approaches to NGF antagonists became the real target of several researchers.These recent findings suggest that there is an effective therapeutic need to prevent the activation of trkA by NGF.Namely, Hefti et al 2 remarked that this might be achieved by agents that remove free NGF by molecules that prevent NGF binding to trkA and by molecules that prevent activation of trkA.
Interim safety and efficacy results from a phase I/II study of vaccination with electrofused allogeneic dendritic cells/autologous tumor-derived cells in patients with stage IV renal cell carcinoma
Authors: D. E. Avigan, D. J. George, P. W. Kantoff, R. A. Figlin, D. W. Kufe, T. E. Olencki, M. J. Vasconcelles, B. S. Vasir, Y. Xu, R. M. Bukowski
Journal: Journal of Clinical Oncology (2004)

2526 Background: Vaccination with dendritic cell (DC)/tumor cell fusions can induce specific anti-tumor immunity in preclinical studies and has shown clinical activity. We report results of a fully enrolled, ongoing phase I/II study of electrofusion vaccine (EFV), comprised of allogeneic DCs (alloDC) and autologous tumor-derived cells administered subcutaneously to patients with Stage IV renal cell carcinoma (RCC). Methods: Tumors were processed and cryopreserved following acquisition from the primary or a metastatic site. Volunteer donor peripheral blood mononuclear cells were used to generate alloDC. At 6 week intervals, patients received up to 3 freshly prepared, irradiated EFV, within a constant dose range of 4 x 107 to 1 x 108 total cells. Study endpoints were safety, and tumor and immunologic response assessments. Results: Of the 30 enrolled patients, data are available on 21; 19 of the 21 were eligible for vaccination. The median age is 58 years (12 M, 9 F); mean number of metastatic sites is 2.4. Fifteen patients received prior treatments, including high dose IL-2. The mean fusion efficiency for 50 vaccine preparations is 20.7%, as determined by cell coexpression of specific DC and tumor markers. The only serious adverse event (excessive intraoperative bleeding) considered related to the study occurred during a tumor acquisition procedure. Adverse events assessed by the investigators as related to EFV and occurring in more than 1 patient were injection site reactions (n=5), fatigue (n=3) and coughing (n=3), all Common Toxicity Criteria grade I or II. Tumor responses to date (9 patients) are 1 partial response, 3 stable disease. Complete analyses of safety, immunologic reactivity (autologous tumor-induced delayed-type hypersensitivity and intracellular interferon γ production) and tumor response assessments will be presented. Conclusions: These interim data suggest a vaccination strategy employing alloDC electrofused with tumor-derived cells in patients with Stage IV RCC is feasible, well-tolerated and may show evidence of tumor response. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Dana-Farber Cancer Institute; Genzyme Corp. Genzyme Corp. Genzyme Corp. Genzyme
Reply
Authors: Pierre Nahon, Olivier Seror, Isabelle Durand‐Zaleski
Journal: Hepatology (2017)

Potential conflict of interest: Dr. Seror consults for and received grants from Angiodynamics, General Electric, and Olympus Celon. Dr. Durand‐Zaleski consults for AbbVie and MSD. The authors did not receive funding for this study. All authors are employees of public hospitals, universities, or public research institutions. REPLY: 1 Dr Braillon highlights classical methodological issues discussed in the hepatology community regarding both utility of hepatocellular carcinoma (HCC) screening and risk factors for this tumor. Prospective cohorts of patients with cirrhosis included in HCC surveillance programs are currently the only reliable source of information. A randomized trial (RCT) assessing benefits of screening is indeed impractical and unethical, given that it has been shown that patients favor surveillance over randomization once informed consent has been provided.1 Furthermore, recent studies included analysis of lead time bias and have suggested a survival benefit in case of HCC screening,2 which is as close as we can get to robust evidence in the absence of RCT. As well, prospective cohorts have not confirmed alarming reports regarding direct antivirals, nor highlighted smoking habit as an established HCC risk factor,3 explaining why international recommendations do not endorse smoking cessation for HCC prevention. Dr. Braillon's skepticism is strengthened by his believing that 90 days of mean doubling growing time for HCC is an "incredible speed." However, results of several studies using different robust methodological approaches converged to a mean doubling time around 3 months.4 Finally, Markov models have been used for the past 40 years with over 400 publications in hepatology that have provided policy makers with estimates of the long‐term medical benefits as well as of the uncertainty surrounding those benefits. Our results show that the probability of patients benefiting from screening is 100%, which makes a strong case for implementing a policy.5 We thus believe that despite a "nonideal level of evidence," doubters should cautiously develop their theoretical arguments given that implementation of curative procedures in the largest rates of patients is the most reliable way to improve HCC prognosis. Meanwhile, reporting that HCC surveillance is cost‐effective5 is hopefully good news for believers, mostly patients and physicians who struggle every day with this deadly cancer.
A seasonal pattern of presentation in younger patients with de novo acute myeloid leukemia (AML).
Authors: Benjamin Jacob Drapkin, Hossein Sadrzadeh, Andrew Mark Brunner, Lillian Werner, Loren Babirak, Eyal C. Attar, Karen K. Ballen, Steven L McAfee, Philip C. Amrein, Yi-Bin Albert Chen, Richard M. Stone, Amir Tahmasb Fathi
Journal: Journal of Clinical Oncology (2012)

6617 Background: Seasonal variation in AML has been studied in a wide variety of populations and locations, with primarily negative results. These investigations may have been undermined by the heterogeneity of the disease, as de novo and secondary AML can vary in disease presentation and trajectory, likely reflecting distinct pathogenesis.We investigated seasonal variation in the incidence of AML diagnosed at Massachusetts General Hospital (MGH) from 1992 through 2011, focusing on de novo disease among younger patients. Methods: We assembled a database of 511 biopsy-proven cases of adult-onset AML (age &gt; 18 years), from the MGH electronic medical record, using a systematic search algorithm with IRB approval. We subdivided this database into three cohorts: (1) de novo AML diagnosed prior to age 50 (2) de novo AML diagnosed after age 50, and (3) secondary AML, preceded by chemotherapy, myelodysplasia or myeloproliferative disease. Diagnosis dates were grouped into quarters (Jan-Mar, Apr-Jun, Jul-Sep, Oct-Dec). Divergence of quarterly incidence from a null hypothesis of uniformity was evaluated by chi square analysis. Results: Among patients under 50-years-old with de novo AML, we found a 44% increase in incidence between October and December (Table, p=0.04). There was no significant variation throughout the rest of the calendar year. Furthermore, the incidence of both de novo AML diagnosed after age 50 and secondary AML conformed to a uniform quarterly distribution. As expected, the majority of AML patients under age 50 demonstrated intermediate-risk cytogenetics, most frequently normal karyotype. Conclusions: We found a significantly increased incidence of de novo AML in younger patients between the months of October and December, diagnosed at MGH from 1992 through 2011. This may reflect a local environmental or infectious exposure that is not relevant to the pathogenesis of AML in older patients or those in whom AML develops due to prior therapy or previous hematological disorder. Investigation of this exposure is ongoing. [Table: see text]
Maturing of the nuclear receptor family
Authors: Mitchell A. Lazar
Journal: Journal of Clinical Investigation (2017)

Members of the nuclear receptor (NR) superfamily of ligand-regulated transcription factors play important roles in reproduction, development, and physiology. In humans, genetic mutations in NRs are causes of rare diseases, while hormones and drugs that target NRs are in widespread therapeutic use. The present issue of the JCI includes a series of Review articles focused on specific NRs and their wide range of biological functions. Here I reflect on the past, present, and potential future highlights of research on the NR superfamily.
Expression of PI3k, akt, p-akt, bad, and p-bad in radiosensitivity induced by aresenic trioxide in human esophageal carcinoma.
Authors: Hui Zhang, Ying Wang, Sue Cao, Sheng Lu, Yanhui Cui, Ping Lu, Zhanhui Miao
Journal: Journal of Clinical Oncology (2014)

e15039 Background: Esophageal cancer is one of the common malignant digestive tract tumors. Increasing the radiation sensitivity to tumor cells is a potential method to improve the efficacy of radiotherapy. As2O3 not only can remarkably inhibit the proliferation and increase the apoptosis to implement the sensitization in solid tumor cells, but also induce the tumor cells to be arrested in G/M phase. Phosphatidylinositol-3kinase (P13K/Akt) signaling pathways are particularly important, which is closely related to promoting the cell proliferation, inhibiting apoptosis, metastasis and radiation resistance. Hence, our study was to explore the mechanism of radiosensitivity induced by As2O3 in esophageal carcinoma cells (EC-1 cells). Methods: The experiment was divided into 4 groups: blank control group (C), radiation therapy group (R), arsenic trioxide group (As2O3) and As2O3 group + R group (Co-treat). The expression of the PI3k, Akt, p-Akt, Bad and p-Bad of the PI3k/Akt signaling pathway components was determined by western blot. Results: Western blot results showed that the expression levels of p-Akt and p-Bad declined in EC-1 cells treated with As2O3 or Co-treat compared with C (p<0.05). The expression of p-Akt and p-Bad decreased remarkably in EC-1 cells treated with Co-treat compared with R alone, with statistical significance (p<0.05). The expression levels of PI3k, Akt and Bad had no obvious differences in EC-1 cells treated with R, As2O3 or Co-treat compared with C and Co-treat compared with As2O3 or R alone, without statistical significance (p>0.05). Conclusions: As2O3 can improve the radiotherapy sensitization probably through down-regulating expression of p-Akt and p-Bad. PI3K/Akt signaling pathways are possibly one of the radiotherapy sensitization mechanism induced by As2O3in EC-1 cells.
4EVER: Assessment of circulating tumor cells with a novel, filtration-based method, in a phase IIIb multicenter study for postmenopausal, HER2- negative, estrogen receptor-positive, advanced breast cancer patients.
Authors: Peter A. Fasching, Walter Gumbrecht, Tanja N Fehm, Lothar Haeberle, Mathias Muth, Daniel Sickert, Michael Pugia, Katja Friedrich, Mark Matzas, Diana Lueftner, Matthias W. Beckmann, Peyman Hadji, Julia Kreuzeder, Michael P Lux, Wolfgang Janni, Andreas Schneeweiss, Erik Belleville, Thomas Decker, Eva-Maria Grischke, Hans Tesch
Journal: Journal of Clinical Oncology (2013)

591 Background: The presence of circulating tumor cells (CTCs) has been shown to be of prognostic relevance for patients with early and advanced breast cancer (BC). The usefulness of CTC assessments depends on accurate cell counts and corresponding analysis of molecular targets. The aim of this sub study was to assess the feasibility of a novel, integrated CTC platform for automated cellular protein and nucleic acid analysis in a prospective multi-center study. Methods: The German 4EVER study included patients with postmenopausal, metastastic, ER positive, HER2 negative BC, who progressed after therapy with a non-steroidal aromatase inhibitor and were treated with exemestane and the mTOR inhibitor everolimus. Baseline blood samples (TransFix vaccum tubes, Cytomark, Caltag Medsystems Ltd.) were used for CTC analysis and processed on the modified Versant kPCR Sample Prep system using 8µm pore size Whatman Nuclepore track-etched membranes (GE Healthcare Piscataway, NJ). After CTC capture, immunostaining was performed for Cytokeratin 8/18/19 and CD45. CTCs were detected by image analytics after fluorescence scanning microscopy using a dedicated software solution implemented by Siemens. The data is summarized and correlated with baseline clinical characteristics. Results: CTC counts and clinical data were available for 111 blood samples (91.7%). CTCs were found in 75 patients (67,6%), 13 patients having 1 CTC, 38 having 2-9 CTCs and 24 patients having 10 or more CTCs. In an exploratory analysis the presence of CTCs was correlated with baseline patient and tumor characteristics. There were no associations with primary TNM stage, hormone receptor status or tumor type. Conclusions: CTC assessment with this novel filtration based method was feasible in a multi-center study setting. The CTC positivity rate was within the expected range. The follow-up of this study will give first insights, how the CTC measures of this platform can be used as a prognostic tool. As this CTC assessment platform was developed to perform additional automated cellular protein and nucleic acid analysis, the usefulness might derive from these analytic tools as well. Clinical trial information: NCT01626222.
Prevalence of <i>BRCA1</i> and <i>BRCA2</i> mutations in patients fulfilling HBOC criteria in South Brazil.
Authors: Barbara Alemar, Cleandra Gregorio, Osvaldo Artigalas, Cristina Netto, Patricia Ashton-Prolla
Journal: Journal of Clinical Oncology (2015)

e12529 Background: In Brazil breast cancer (BC) is a public health care problem due to its high incidence and mortality rates. Approximately 5% of BC and 15% of ovarian cancers (OC) are attributable to germline mutations in the BRCA1 and BRCA2 genes, whose mutational prevalence among patients fulfilling Hereditary Breast and Ovarian cancer (HBOC) genetic testing criteria are largely unknown in South Brazil. Methods: We enrolled 127 women from three medical genetics centers from the Southernmost Brazilian state, Rio Grande do Sul. All patients fulfilled NCCN HBOC criteria and underwent complete sequencing of BRCA1/2. In a subset of patients, gene rearrangement screening by MLPA was also done. Results: Most of the patients were diagnosed first with BC (73%) or OC (11%) and the mean age at diagnosis was 43 years (range 23-75). BRCA mutations were detected in 25 of 127 patients (19.7%). Among the 18 (14.17%) BRCA1 mutation carriers, we identified 14 different mutations; among the 7 (5.5%) BRCA2 mutation carriers, 6 different mutations were detected. In 64 out 102 mutation-negative patients by sequencing, MLPA was performed and gene rearrangements in BRCA1 (del exon 8, del exon 9) were identified in 2 cases (3.1% of tested cases). Conclusions: Mutation prevalence among these HBOC probands was lower than described in the international literature suggesting that population specific phenotypic aspects of HBOC syndrome may be at play in the region. Studies on a larger cohort should be undertaken to confirm these findings and genetic testing criteria should be revised for the Brazilian population. BRCA1 gene mutations in 127 HBOC patients in Southern Brazil. Mutation N° of carriers Prevalence (%) BRCA1 c.66_67delAG (185delAG) 1 0,79 c.791_794delGTTC 1 0,79 c.1612C>T 1 0,79 c.1687C>T 2 1,57 c.3331_3334delCAAG 1 0,79 c.3534delC 1 0,79 c.3598C>T 1 0,79 c.4183C>T 1 0,79 c.4484G>C 1 0,79 c.5062_5064delGTT 2 1,57 c.5173_5176delGAAA 1 0,79 c.5177_5180delGAAA 1 0,79 c.5251C>T 1 0,79 c.5263_5264insC (5382insC) 3 2,36 Total N° of carriers 18 14,17 BRCA2 c.2805_2808delTAAA 1 0,79 c.2808_2811delACAA 2 1,57 c.4829_4830delTG (5057delTG) 1 0,79 c.5351_5352insA 1 0,79 c.5946_5946delT 1 0,79 c.8878C>T 1 0,79 Total N° of carriers 7 5,51 Total BRCA1/2 25 19,69