tbuckley/cabot-search huggingface dataset:
Meta-analysis of the impact of single agent daily prednisone on outcomes and toxicities in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Pooja Ghatalia, Gregory Russell Pond, Arnoud J. Templeton, Guru Sonpavde
Journal: Journal of Clinical Oncology (2015)

e16095 Background: Oral prednisone (P) has been commonly employed for the therapy of men with mCRPC. However, its clinical impact is unknown. We performed a pooled analysis of control arms of randomized trials which either did or did not administer single agent P. Methods: Randomized trials with a control arm including single agent placebo (or no anti-cancer therapy) or single-agent P (+/- placebo) were eligible for analysis. Patients receiving P in combination with other agents in the control arm were excluded. Trial characteristics and baseline demographics were collected from published manuscripts along with reported outcomes including overall survival (OS), progression free survival (PFS), prostate-specific antigen (PSA) response, RECIST response, and toxicities (i.e. all grades and grade ≥ 3). P specific toxicities were also collected including hyperglycemia, hypertension, hypokalemia, skeletal related events and edema. Impact of P was investigated for significance in bivariate models, adjusting for age, pre/post-docetaxel status, ECOG performance status (PS) and trial publication year. Trials were weighted based on sample size. Results: Eighteen trials were included in the analysis, within which nine had control arms that contained P (N = 2831) and nine did not (N = 2784). Age, pre/post-docetaxel status, PS and publication year were similar in both groups. No significant differences were identified for OS or toxicities of any grade. A significantly higher PSA response rate (18.8% vs. 2.5%, P= 0.023) and a trend for more frequent grade ≥ 3 fluid retention (1.0% vs. 0.4%, P= 0.097) was seen in the P group. In most bivariate analyses, P was significantly associated with PSA response. P was also significantly associated with PFS after adjusting for docetaxel status. Conclusions: Single agent P for mCRPC was not associated with extension of OS, but was associated with a higher PSA response rate and a potential extension in PFS. Overall and grade ≥ 3 toxicities were not significantly higher with P, although a trend for increased fluid retention was seen. With the exception of concurrent use with abiraterone or for palliative purposes, the routine use of P appears unnecessary.
Multicenter study assessing tumor molecular profiles in advanced pediatric solid tumors.
Authors: Katherine A. Janeway, Steven G. DuBois, Julia Lynne Glade Bender, AeRang Kim, Erin Parker, Alanna Church, Brian D. Crompton, Kimberly Stegmaier, Suzanne Shusterman, Wendy B. London, Neal Ian Lindeman, Lisa Diller, Carlos Rodriguez-Galindo, Marian H. Harris
Journal: Journal of Clinical Oncology (2014)

10011 Background: The role of molecular profiling in the clinical care of children with advanced solid tumors is unknown. Key questions are: do pediatric solid tumors have a sufficient rate of actionable alterations to warrant prospective assessment for clinical use; and, if potentially actionable alterations are identified are targeted drugs accessible for use in children with recurrent solid tumors? Methods: We conducted a multi-institution study to determine whether it is feasible to identify actionable alterations and make an individualized cancer therapy (iCat) recommendation using currently available clinical genomic technologies. Patients(pts) were eligible if they had a diagnosis of a high risk or recurrent/refractory solid tumor. Tumor profiling consisted of: a)mutation detection by either a Sequenom assay or targeted next-generation sequencing; b)copy number assessment by array CGH; and c)validation with IHC/FISH in some cases. Tumor profiling results were reviewed by a multi-disciplinary expert panel. iCat recommendations were made if an actionable alteration was present and if a targeted drug was available. Recommendations were tiered from 1 (strongest) to 5 (weakest) based upon strength of supporting evidence. Results: 100 pts were enrolled in 14 months. The most common diagnoses were neuroblastoma and Ewing sarcoma. 43% of pts had rare solid tumors. With 54 pts resulted and reviewed at the time of submission, profiling was technically feasible in 81%. Overall, 16 of 54 (30%) pts received an iCat recommendation (1 tier 1; 5 tier 3; 8 tier 4; 2 tier 5). The most common molecular aberrations in the 16 pts receiving an iCat recommendation were cancer-associated signaling pathway gene mutations (n=9), MYC/MYCN high copy number gain (n=4), and Cyclin D/CDK4/Rb pathway gene alterations (n=3). Additional pts had a potentially actionable alteration, but an iCat recommendation was not made due to lack of available drug. Conclusions: It is feasible to conduct a multi-institution clinical genomics study. A substantial proportion of relapsed, refractory pediatric solid tumors have actionable alterations. Additional research is required to determine whether applying genomics in this setting has an impact on pt outcome.
Clinical activity and safety of combination therapy with temsirolimus and bevacizumab for advanced melanoma: Phase II trial with correlative studies.
Authors: Craig L. Slingluff, Gina R. Petroni, Kerrington R. Molhoek, David L Brautigan, Kimberly A. Chianese-Bullock, Amber L Shada, Mark E Smolkin, Alison Gaucher, Cheryl F. Murphy, William W. Grosh, Geoffrey R. Weiss, Aubrey G Wagenseller, Anthony J. Olszanski, Lainie P. Martin, Sofia M Shea, Gulsun Erdag, Prahlad T Ram, Jeffrey E. Gershenwald, Michael J Weber
Journal: Journal of Clinical Oncology (2012)

8530 Background: A CTEP-sponsored phase II trial was performed to evaluate safety and clinical activity of combination therapy with CCI-779 (temsirolimus) and bevacizumab in patients with advanced melanoma. Correlative studies assessed mTOR signaling in tumor biopsies and evidence of induced immunologic dysfunction systemically. Methods: 17 patients with stage III or IV melanoma were enrolled and treated with temsirolimus (25 mg IV weekly) and bevacizumab (10 mg/kg IV every 14d, starting d.8) for up to 13 months. Clinical response was determined by RECIST criteria. Adverse events were assessed (CTCAE v3.0). Blood was collected d.1, 2, and 23 (to assess immune function), and tumor biopsies were obtained (to assess protein kinase activity and melanoma cell proliferation). Results: Treatment-related grade 3 or 4 adverse events occurred in 5 and 1 patients, respectively; 1 patient developed reversible leukoencephalopathy. In 16 patients evaluable for clinical response, best overall response was a partial response (PR) in 3 patients (19%), stable disease at 8 weeks (SD) in 9 patients (56%), and progressive disease in 4 patients. Thus, disease control rate (DCR = PR + SD) was 75%. Ten of the patients had BRAF wild-type (BRAF wt ) melanomas: these accounted for the 3 PRs (30%), and a DCR of 100%. Maximal response duration has exceeded 3 years for a BRAF wt patient. mTOR signaling was inhibited in melanoma metastases, based on decreased phospho-S6 kinase after 24h temsirolimus. Ki67 + melanoma cells in tumor biopsies decreased significantly by day 23 (p = 0.007, F-test), most notably in clinical responders. There was no significant alteration of T cell and NK function with combination treatment, by ELIspot and cytotoxicity assays. Conclusions: Combination therapy with temsirolimus and bevacizumab is well-tolerated in patients with advanced melanoma and has intriguing clinical activity. The most notable responses were in patients with BRAF wt tumors, a population with no accepted effective targeted therapy. Decreases in Ki67 + melanoma cells may be associated with clinical response. The lack of immunologic dysfunction supports future combination with immune therapies.
Palliative sedation (PS) given to patients treated at the Fundación Santa Fe de Bogotá.
Authors: Milton Alberto Lombana Quinonez, Juan G. Santacruz, Luis Pino, Maria I. Camacho, Andres Acevedo, Maria J. Buendia, Ivonne Zamora, Ana Torres, Catalina Mendez, Andres Felipe Cardona Zorrilla
Journal: Journal of Clinical Oncology (2013)

9541 Background: Around 50% of advanced-stage cancer patients have inadequate control of symptoms during the final period of life; palliative sedation (PS) would seem to be appropriate in such scenario. Methods: A retrospective cohort analytical study was carried out for determining the effectiveness of PS, evaluating the non-reduction of the number of final days of life in patients suffering advanced-stage cancer. PS therapy consisted of using a continuous infusion of benzodiazepines, opioids, antipsychotics and/or anaesthetics. Results: The study included 145 patients recorded between July 2008 and October 2012. Median age was 68 years (24% of the patients being aged over 80). The main motives for considering PS were dyspnoea (30%), uncontrolled pain (25%), delirium (26%) and presenting more than one of these symptoms (19%). The drugs used were opioids (in 87% of the patients), benzodiazepines (54%) and anaesthetics (2%). Using PS led to symptoms becoming controlled in 79% of the cases compared to 53% without it; symptoms became controlled in 85% of the cases in less than 24 hours when PS was used compared to 15% when it was not used (p&lt;0.001). Mean overall survival (OS) was 6.8 days for those who received PS and 7.2 for those who did not (RR 0.94, 0.97-1.33 95%CI; p=0.72) and final days of life after starting PS was 2.2 days (&lt;1-16 days). Multivariate analysis showed that using PS (HR 1.49, 1.08-2.07 95%CI; p=2.04) and the presence of oedema (RR 0.79, 0.61-1.0 95%CI; p=0.01) modified the course of controlling symptoms. Conclusions: PS improved the time to controlled cancer symptoms in patients suffering terminal illness, and their presentation profile without modifying the OS.
Lanreotide autogel/depot (LAN) treatment for carcinoid syndrome (CS) symptoms: Patient-reported outcomes (PROs) from the SYMNET study.
Authors: Philippe B. Ruszniewski, Martyn E. Caplin, Juan W. Valle, Catherine Lombard-Bohas, Graeme John Poston, Petros Perros, Lubos Holubec, Gianfranco Delle Fave, Denis Michel Smith, Patricia Niccoli, Pascal Maisonobe, Philippe Atlan
Journal: Journal of Clinical Oncology (2014)

4111^ Background: Somatostatin analogs can provide CS symptom relief, but associated PROs in clinical practice, in particular patient (pt) treatment satisfaction, are less clear. Methods: SymNET was a large multinational observational study of PRO after >3 months’ LAN for CS-related diarrhea (NCT01234168). At a routine clinic visit (CV), 273 pts reported their satisfaction with diarrhea control (primary endpoint) on a 5-point Likert scale. Secondary endpoints included health-related quality of life (HRQoL) assessed with EORTC QLQ-C30 and G.I.NET 21 questionnaires completed by pts. HRQoL scores were transformed for some items/scales so that all had a range 0–100. Summary statistics were derived from evaluable data (enrolled population). Results: 58% (157/273) of pts were >60 yrs, 66% (176/267) had small-bowel primary tumors, and 80% (217/271) had liver metastases. At the CV, median LAN treatment duration was 11 months and 76% (203/268) [95% CI: 70–81%] were satisfied with diarrhea control (primary endpoint). QLQ-C30: problematic symptoms were fatigue, insomnia, diarrhea and, to a lesser extent, pain; in contrast, the majority of pts had no problems with other symptoms, levels of functioning were high, and global QoL only slightly lower (Table). G.I.NET 21: problematic symptoms were disease-related worries, social function, and muscle/bone pain and, to a lesser extent, gastrointestinal and endocrine symptoms; the majority of pts had no problems with other symptoms, including treatment-related effects. Conclusions: High levels of pt satisfaction with LAN for CS-related diarrhea were generally accompanied by high levels of HRQoL functioning. These data show HRQoL levels that are currently attained in a real-world setting and may help guide future efforts in CS management. Clinical trial information: NCT01234168. Functioning scales (higher score=better QoL) Median score Physical 85 Role; cognitive; social 83 Emotional 75 Global QoL 67 General symptoms scale (lower score=better symptoms) Nausea and vomiting 0 Pain 17 Fatigue 33 Specific symptoms scale (lower score = better symptoms) Dyspnea; appetite loss; constipation; financial difficulties 0 Insomnia; diarrhea 33
Use of granulocytes concentrates from a single high yield apheresis to support more than one patient.
Authors: Fleur M Aung, Benjamin Lichtiger, Virgil Reddy, Chitra Hosing
Journal: Journal of Clinical Oncology (2012)

6622 Background: Allogeneic granulocyte transfusion therapy is sometimes the only therapeutic option in immunocompromised neutropenic leukemic/HSCT patients with life threatening bacterial and fungal infections. Collection of larger cell doses of granulocyte concentrates (GC) by automated apheresis following G-CSF/steroids administration has renewed interest and its use has grown steadily. Methods: Donors were recruited from family/friends of the patients and informed consent was obtained. GCs were collected via donor stimulation with a single subcutaneous dose of G-CSF (600 mcg). First time donors received an oral dose of dexamethasone (8 mg). GCs were harvested by Hetastarch-assisted leukapheresis 12 hours later via peripheral venous access with the continuous flow cell separator Spectra (COBE Caridian BCT, Lakewood, CO). Results: GCs were collected from 93 donors (67M: 26F; age median 40 (19-73 years) and 1 ½ x blood volume processed median 7048 (3212-8085 mL). The pre/post wbc were median 8.1 (4.1-22.8)/ 42.7 (22.4-77.5). The volume collected was based on the post G-CSF wbc count (&gt; 35 K/UL - 800 mL; &lt;35 K/UL between 600-700 mL). The original yield (10 x10e) was median 9.7 (5.1-17.2 units), volume median 718 (538-860 mL) and WBC median 132.7 (84.2 -241.6 K/UL per bag). The Split GCs were median 4.48 (2.70-7.72 units), with neutrophils median 87% (54-97% per bag). GCs were transfused to 51 patients (31M: 20F; age median 58 [19-83 years]) who received median 3.5 (1-18 split units), containing wbcs median 10734.69 [5778-42 -162698.09 (x10^3/uL)/unit) and achieved a WBC increment median 0.2 (0.0-8.3K/UL). Conclusions: The GCs were split due to the primary care team's reluctance to transfuse the entire volume of the product due to volume restrictions or for some other medical reason. The same rationale to split platelets from high yield single apheresis was used to split our GC products. We found that GCs from each donor was utilized maximally and also brought partial relief to other patients who lacked donors. We would like to make the case that when adequate numbers of GCs are collected it may be feasible to split the unit. This may offer a glimmer of hope to other patients in need of GCs who lack a donor network support.
Association of Gastric Acid Suppression With Recurrent <i>Clostridium difficile</i> Infection
Authors: Raseen Tariq, Siddharth Singh, Arjun Gupta, Darrell S. Pardi, Sahil Khanna
Journal: JAMA Internal Medicine (2017)

Gastric acid suppression has been associated with an increased risk of primary Clostridium difficile infection (CDI), but the risk of recurrent CDI in patients taking gastric acid suppressant medications is unclear.To perform a systematic review and meta-analysis to evaluate the association between gastric acid suppressants and recurrent CDI.MEDLINE, EMBASE, the Cochrane Central Register, the Cochrane Database, and Web of Science were searched from January 1, 1995, to September 30, 2015, for studies assessing the association between gastric acid suppressant exposure and recurrent CDI. Search terms included Clostridium difficile, pseudomembranous colitis, proton pump inhibitor, and histamine H2 blocker.Case-control studies, cohort studies, and clinical trials that included patients with CDI who did or did not receive gastric acid suppressant therapy and who were evaluated for recurrent CDI were included, with no restriction on study setting (inpatient or outpatient).The Newcastle-Ottawa scale was used to assess the methodologic quality of included studies. In this scale, case-control and cohort studies were scored on selection, comparability, and ascertainment of the outcome of interest. Data were independently abstracted to a predetermined collection form by 2 investigators. Summary odds ratio estimates with 95% CIs were calculated using the random-effects model and software to calculate the pooled effect size of studies reporting multivariate analyses.Risk of recurrent infection in patients with CDI and its association with use of gastric acid suppressant medication.Sixteen observational studies were included, together reporting 7703 patients with CDI; among these, 1525 patients (19.8%) developed recurrent CDI. The rate of recurrent CDI in patients with gastric acid suppression was 22.1% (892 of 4038 patients) compared with 17.3% (633 of 3665) in patients without gastric acid suppression, which indicated an increased risk by meta-analysis (odds ratio [OR], 1.52; 95% CI, 1.20-1.94; P < .001). There was significant heterogeneity among the studies, with an I2 value of 64%. Subgroup analyses of studies adjusting for age and potential confounders confirmed an increased risk of recurrent CDI with use of gastric acid suppressants (OR, 1.38; 95% CI, 1.08-1.76; P = .02).Meta-analyses of observational studies suggest that patients who receive gastric acid suppressants may be at increased risk for recurrent CDI. These data should be interpreted with caution because they may be confounded owing to the observational design of the individual studies. It may be reasonable to re-evaluate the need for these medications in patients with CDI.
Molecular Genetics Analysis of Von Williebrand Disease: Studies in Cohort Pakistani Patients
Authors: Shariq Ahmed, Arshi Naz, Hamideh Yadegari, Julia Driesen, Tahir Shamsi, Nisar Ahmed, Shahla Tariq, Samina Tufail Amanat, fazal-E- Razik, Mohammad Nadeem, Johannes Oldenburg
Journal: Blood (2015)
Coordination of the Hippo and TOR pathways by Rheb via RASSF1A.
Authors: Nicholas C Nelson, Geoffrey J Clark
Journal: Journal of Clinical Oncology (2015)

e22197 Background: Tuberous sclerosis disease is caused by inherited mutations in the TSC1 or TSC2 proteins, which function as a complex. Somatic mutations in TSC proteins also occur in spontaneous tumors. The TSC complex acts as a negative regulator (GAP) for the small GTPase Rheb. Inactivation of TSC leads to the inappropriate activation of Rheb, which binds and activates the mTOR kinase complex. Constitutive activation of the TOR pathway drives Tuberous sclerosis, cancer development, and is commonly observed in human tumors. The TOR pathway can coordinate with a second growth controlling pathway, the Hippo pathway. Exactly how these pathways are connected remains unclear. Here, we investigate the effect of a novel interaction between Rheb and the RASSF1A tumor suppressor—a key upstream regulator of the Hippo pathway—on the coordinate regulation of TOR and Hippo pathways. Methods: NCI-H1299 and NCI-H1792 lung tumor cells stably expressing Rheb were generated in our lab, in the presence or absence of RASSF1A. Cells were seeded at confluence and serum starved overnight. mTOR and Hippo activity was scored by Western blot analysis of phospho-S6 and phospho-Yap, respectively. Endogenous immunoprecipitation was performed in MCF10A human breast epithelial cells using anti-RASSF1A antibody and the lysates Western blotted with anti-Rheb antibody. Results: We have discovered that Rheb can form an endogenous complex with the tumor suppressor and Hippo pathway activator RASSF1A. In human lung tumor cells, Rheb synergizes with RASSF1A to activate the Hippo pathway while RASSF1A suppresses the ability of Rheb to stimulate the TOR pathway. The suppression is specific, as the TOR independent effects of Rheb on mitophagy are not affected by RASSF1A. Conclusions: The interaction of Rheb with RASSF1A as well as the TOR complex may allow the co-ordinate regulation of the TOR pathway and the Hippo pathway by Rheb. The frequent loss of RASSF1A expression in tumors may alter the balance of Rheb activity away from pro-apoptotic Hippo signaling and towards pro-tumorigenic mTOR signaling.
A first-in-human study of the oral selective androgen receptor down-regulating drug (SARD) AZD3514 in patients with castration-resistant prostate cancer (CRPC).
Authors: Aurelius Gabriel Omlin, Robert J. Jones, Ruud van der Noll, Janet Graham, Michael Ong, Richard D. Finkelman, Jan HM Schellens, Andrea Zivi, Mateus Crespo, Glen Clack, Joshi J. Alumkal, Angela Dymond, Andrew Dickinson, Malcolm Ranson, Michael D Malone, Johann Sebastian De Bono, Tony Elliott
Journal: Journal of Clinical Oncology (2013)

4511 Background: AZD3514 is a first in class, orally bio-available drug that inhibits androgen-dependent and –independent androgen receptor (AR) signaling through two distinct mechanisms; inhibition of ligand-driven nuclear AR translocation and down-regulation of AR levels. Methods: A rolling six design was employed initially using a once a day (QD) schedule (A). PK assessments led to a change to twice daily (BD) dosing (B) to increase exposure. PK profiles were studied over 96 hours after a single dose and over 24 hours at start of/following 21 days continuous dosing. PD analyses included PSA and CTC quantification. Results: 49 CRPC patients (pts) have been treated with escalating doses of AZD3514 (A 35 pts, B 14 pts). Starting doses were 100 mg (A) and 1000 mg (B). The AZD3514 formulation was switched from capsules to tablets at 1000mg (QD). 2000mg BD was considered non-tolerable due to multiple grade 2 toxicities (nausea [N], vomiting [V], fatigue). No adverse events (AEs) met the DLT definition. The most frequent drug-related AE’s were N; G1/2 36/49 (73%), G3 2/49 (4%) and V; G1/2 24/49 (49%) &amp; G3 3/49 (6%). N/V were managed with oral anti-emetics. Dose proportional increases in plasma concentrations were observed following a single dose. Geometric mean (%CV) Cmax and AUC at MTD were 9,608 (38.5) ng/mL and 61,734 (40.6) ng.hr/mL, respectively. Compared with single dose continuous dosing led to a mean decrease of 26% in exposure. Maximum PSA and CTC declines are summarized below. Objective soft tissue responses per RECIST1.1 were observed in 2/26 (8%) pts. One pt with abiraterone resistant disease remained on study for 19 months. At 6 and 12 months 21 (43%) and 8 (16%) pts remained on study without evidence of bone or soft tissue progression, respectively. Conclusions: AZD3514 has antitumor activity in patients with advanced CRPC. Clinical trial information: NCT01162395. [Table: see text]