tbuckley/cabot-search huggingface dataset:
Statin use and risk of pancreatic cancer: Results from a large clinic-based case-control study.
Authors: Evan J. Walker, Andrew H. Ko, Elizabeth A. Holly, Paige M. Bracci
Journal: Journal of Clinical Oncology (2014)

4117 Background: Statins are cholesterol-lowering medications whose pleiotropic effects include alterations in growth signaling as well as immunomodulatory and anti-inflammatory effects that may alter cancer risk. Evidence from epidemiologic studies to date is conflicting as to whether statin use is associated with a reduced risk of pancreatic cancer (PC). The current case-control study investigates the association between statins and PC risk overall and by sex. Methods: Patients with a confirmed diagnosis of PC (cases) were recruited from medical and surgical oncology clinics at the University of California, San Francisco, with controls (frequency-matched by sex and age) recruited from general medicine clinics, from 2006-2011. Direct interviews were conducted using an epidemiological risk factor questionnaire covering topics such as lifestyle factors, diet, and medication usage. Adjusted multivariable logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (CI) as estimates of the relative risk of PC. Results: Data were obtained from 536 cases and 869 controls. Ever use of statins was associated with 34% reduced PC risk (OR=0.66, 95%CI 0.47-0.92). In sex-stratified analyses, risk was statistically significantly reduced in men only (men: OR=0.51, 95%CI 0.32-0.80; women: OR=0.86, 95%CI 0.52-1.43). Duration of use was inversely associated with PC risk in men (long-term use: OR= 0.41, 95%CI 0.21-0.79; ptrend=0.005). Exploratory analyses of statins classified according to pharmacologic characteristics showed reduced PC risk in participants using statins with high compared to low bioavailability (p=0.01), whereas no significant differences were observed according to statin potency, solubility, or pattern of metabolism. Conclusions: This is the largest case-control study to demonstrate an inverse association between statin use and PC risk. Risk reduction from statins appears to be sex-specific and is more pronounced in long-term users. Further research is warranted to better characterize this association and clarify the role of underlying biologic mechanisms. If validated, statins could prove useful as preventive drug therapy for this disease. Supported by NIH R01 CA 109767.
Phase Ib/II Study of the Safety and Efficacy of Combination Therapy with Multikinase VEGF Inhibitor Pazopanib and MEK Inhibitor Trametinib In Advanced Soft Tissue Sarcoma
Authors: Vivek Subbiah, Christian Meyer, Ralph Zinner, Funda Meric-Bernstam, Marianna L. Zahurak, Ashley O'Connor, Jason Roszik, Kenna Shaw, Joseph A. Ludwig, Razelle Kurzrock, Nilofer A. Azad
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Pazopanib, a multireceptor tyrosine kinase inhibitor targeting primarily VEGFRs1–3, is approved for advanced soft tissue sarcoma (STS) and renal cell cancer. Downstream of VEGFR, trametinib is an FDA-approved MEK inhibitor used for melanoma. We hypothesized that vertical pathway inhibition using trametinib would synergize with pazopanib in advanced STS. Experimental Design: In an open-label, multicenter, investigator-initiated National Comprehensive Cancer Network (NCCN)-sponsored trial, patients with metastatic or advanced STS received pazopanib 800 mg and 2 mg of trametinib continuously for 28-day cycles. The primary endpoint was 4-month progression-free survival (PFS). Secondary endpoints were overall survival, response rate, and disease control rate. Results: Twenty-five patients were enrolled. The median age was 49 years (range, 22–77 years) and 52% were male. Median PFS was 2.27 months [95% confidence interval (CI), 1.9–3.9], and the 4-month PFS rate was 21.1% (95% CI, 9.7–45.9), which was not an improvement over the hypothesized null 4-month PFS rate of 28.3% (P = 0.79). Median overall survival was 9.0 months (95% CI, 5.7–17.7). A partial response occurred in 2 (8%) of the evaluable patients (95% CI, 1.0–26.0), one with PIK3CA E542K-mutant embryonal rhabdomyosarcoma and another with spindle cell sarcoma. The disease control rate was 14/25 (56%; 95% CI, 34.9–75.6). The most common adverse events were diarrhea (84%), nausea (64%), and fatigue (56%). Conclusions: The combination of pazopanib and trametinib was tolerable without indication of added activity of the combination in STS. Further study may be warranted in RAS/RAF aberrant sarcomas. Clin Cancer Res; 23(15); 4027–34. ©2017 AACR.
A phase 2 trial of high-dose Allovectin-7 in patients with advanced metastatic melanoma
Authors: J. Richards, A. Y. Bedikian, R. Gonzalez, M. B. Atkins, E. D. Whitman, J. Lutzky, M. A. Morse, T. Amatruda, E. Galanis
Journal: Journal of Clinical Oncology (2004)

7509 Background: A bicistronic plasmid encoding HLA-B7 and β-2 microglobulin genes formulated in cationic lipids, Allovectin-7® (A-7), is an immunotherapeutic designed to induce a pro-inflammatory response and express MHC-class I after tumor injections. Expression of HLA-B7 in tumors may result in increased immunorecognition of tumors that in turn elicits an antitumor response. Methods: We are conducting a phase 2 trial to evaluate the activity of A-7 in patients (pts) with metastatic melanoma (MM). Eligible pts have stage III or IV MM recurrent or unresponsive to prior therapy; injectable (1 to 25 cm2 cutaneous, subcutaneous, or nodal) lesion(s); ECOG PS 0–1 and adequate organ function. Pts with brain or non-lung visceral metastases or any lesion ≥ 100 cm2 are excluded. Pts with 2 or more injectable lesions are randomized to receive injections into 1 or up to 5 lesions. Pts receive weekly intratumoral injections of a total of 2 mg for 6 wks followed by 3 wks of observation and evaluation. Response is assessed using RECIST guidelines two wks following the last injection of each cycle. Pts with stable or responding disease receive additional cycles. Results: Interim unaudited data will be presented for all 133 pts enrolled. All pts were evaluated for safety (6 pts in the dose escalation stage plus 127 pts in the high-dose stage), and 127 pts are evaluated for efficacy. In an interim data analysis 12 of 91 pts (13.2%) achieved an objective response lasting a median duration of 6.4 months. Median overall survival has not yet been reached and durability of response is still accruing. One Grade 3 and no Grade 4 adverse event associated with A-7 have been reported. Conclusions: Interim results indicate that high-dose A-7 is an active, well-tolerated treatment for Stage III/IV MM pts with injectable cutaneous, subcutaneous, or nodal lesions. No significant financial relationships to disclose.
Impact of epidermal growth factor receptor mutations on intracranial treatment response and survival after brain metastases in lung adenocarcinoma patients.
Authors: Shih-Hsin Hsiao, Horng-Chyuan Lin, Ming-Chih Yu, Chi-Li Chung
Journal: Journal of Clinical Oncology (2013)

e19030 Background: Brain metastases (BM) commonly occur in patients with lung adenocarcinoma and usually lead to a poor prognosis. Epidermal growth factor receptor (EGFR) mutation is a predictive and prognostic factor for EGFR tyrosine kinase inhibitor (TKI) treatment for lung adenocarcinoma. The present study aimed to elucidate the predictive role of EGFR mutations in BM treatment response and survival after BM in patients with lung adenocarcinoma patients. Methods: From January 2006 through February 2012, 180 of 505 lung adenocarcinoma patients developed BM during their disease course were reviewed for eligibility, and 139 patients, including 89 EGFR mutant and 50 EGFR wild-type patients, were identified for analysis. BM treatment response was assessed radiologically 1 month after start of treatment and survival data was collected. Results: EGFR mutant patients, compared with EGFR wild-type patients, had significantly greater treatment response of BM (85% vs. 53%, P = 0.001) and longer median survival after BM diagnosis (13.2 vs. 6.8 months, P &lt; 0.001). EGFR mutation (P = 0.001) and use of EGFR TKI during treatment (P = 0.037) were independently associated with BM treatment response. Furthermore, EGFR mutation (P = 0.005), good performance status (P &lt; 0.001) and absence of extracranial metastases (P = 0.033) correlated with better survival. Conclusions: EGFR mutation is an independent predictive factor for both BM treatment response and survival after BM in patients with lung adenocarcinoma. Further studies on incorporation of EGFR mutation status into therapeutic strategy and survival prediction system for lung adenocarcinoma with BM are warranted.
Treatment patterns and outcome following initial relapse or refractory disease in patients with systemic light chain amyloidosis
Authors: Nidhi Tandon, Surbhi Sidana, Morie A. Gertz, Angela Dispenzieri, Martha Q. Lacy, Francis K. Buadi, David Dingli, Amie L. Fonder, Miriam A. Hobbs, Suzanne R. Hayman, Wilson I. Gonsalves, Yi Lisa Hwa, Prashant Kapoor, Robert A. Kyle, Nelson Leung, Ronald S. Go, John A. Lust, Stephen J. Russell, Steven R. Zeldenrust, S. Vincent Rajkumar, Shaji K. Kumar
Journal: American Journal of Hematology (2017)

We analyzed the outcomes following initial relapse or refractory disease in systemic light chain amyloidosis (AL) and the impact of type of therapy employed.A total of 1327 patients with AL seen at Mayo Clinic within 90 days of diagnosis, between 2006 and 2015, were reviewed. The study included 366 patients experiencing a documented hematological or organ relapse or refractory disease requiring start of second line therapy. Overall survival (OS) and time to next treatment (TTNT) were calculated from start of second line treatment.The median time to require second line treatment was 16.2 months (1-93) from the start of first line therapy. At relapse, patients received proteasome inhibitors (PI; 45.1%), immunomodulators (IMiD; 22.7%), alkylators (9%), PI and IMiD combination (4.1%), autologous transplant (3.8%), steroids and other therapies (4.9%). Among these, 124 (33.9%) required change or reinstitution of therapy. The median time to require third line treatment was 31 months (95% CI; 24, 40.5) and the median overall survival (OS) was 38.8 months (95% CI; 29.6, 52.6) from the start of second line treatment. Retreatment with same therapy at relapse significantly reduced TTNT (22 m vs 32.3 m; P = .01) as compared to different therapy; but did not have any impact OS (30.8 m vs 51.1 m; P = .5). In conclusion, this study provides important information about outcomes of patients with AL who require second line treatment for relapsed/refractory disease . Treatment with a different therapy at relapse improves time to next therapy but does not impact OS.
Dermatologic Features of Classic Movie Villains
Authors: Julie Amthor Croley, Vail Reese, Richard F. Wagner
Journal: JAMA Dermatology (2017)

Dichotomous dermatologic depictions of heroes and villains in movies have been used since the silent film age.To evaluate the hero-villain skin dichotomy in film by (1) identifying dermatologic findings of the all-time top 10 American film villains, (2) comparing these dermatologic findings to the all-time top 10 American film heroes quantitatively and qualitatively, and (3) analyzing dermatologic portrayals of film villains in depth.In this cross-sectional study, dermatologic findings for film heroes and villains in mainstream media were identified and compared quantitatively using a χ2 test with α < .05, as well as qualitatively. The all-time top 10 American film villains and heroes were obtained from the American Film Institute 100 Greatest Heroes and Villains List.Primary outcomes include identification and frequencies of dermatologic findings of the top 10 film villains and of the top 10 film heroes.Six (60%) of the all-time top 10 American film villains have dermatologic findings, including cosmetically significant alopecia (30%), periorbital hyperpigmentation (30%), deep rhytides on the face (20%), multiple facial scars (20%), verruca vulgaris on the face (20%), and rhinophyma (10%). The top 10 villains have a higher incidence of significant dermatologic findings than the top 10 heroes (60% vs 0%; P = .03).Dermatologic findings of the all-time top 10 American villains are used in film to highlight the dichotomy of good and evil, which may foster a tendency toward prejudice in our society directed at those with skin disease.
Abstract 37: Nrip Deficiency Leads to Dilated Cardiomyopathy
Authors: Show-Li Chen
Journal: Circulation Research (2015)

Previously, we demonstrate a gene, nuclear receptor interaction protein (NRIP, also named DCAF6 or IQWD1) as a Ca2+- dependent calmodulin binding protein that can activate calcineurin phosphatase activity. Here, we found that α-actinin-2 (ACTN2), is one of NRIP-interacting proteins from the yeast two-hybrid system using NRIP as a prey. We further confirmed the direct bound between NRIP and ACTN2 using in vitro protein-protein interaction and in vivo co-immunoprecipitation assays. To further map the binding domain of each protein, the results showed the IQ domain of NRIP responsible for ACTN2 binding, and EF hand motif of ACTN2 responsible for NRIP bound. Due to ACTN2 is a biomarker of muscular Z-disc complex; we found the co-localization of NRIP and ACTN2 in cardiac tissues by immunofluorescence assays. Taken together, NRIP is a novel ACTN2-interacting protein. To investigate insights into in vivo function of NRIP, we generated conventional NRIP-null mice. The H&amp;E staining results are shown in the hearts of NRIP KO mice are enlarged and dilated and the cell width of NRIP KO cardiomyocyte is increased. The EM of NRIP KO heart muscles reveal the reduction of I-band width and extension length of Z-disc in sarcomere structure; and the echocardiography shows the diminished fractional shortening in heart functions. Additionally, the calcium transient and sarcomere contraction length in cardiomyocytes of NRIP KO is weaker and shorter than wt; respectively. In conclusion, NRIP is a novel Z-disc protein and has function for maintenance of sarcomere integrity structure and function for calcium transient and muscle contraction.
Leveraging technology to facilitate distress screening.
Authors: Susan Franco, Dawn Jourdan
Journal: Journal of Clinical Oncology (2017)

195 Background: Research has shown cancer patients are at increased risk for distress during their cancer treatment. Distress screening is required for cancer programs seeking accreditation from the American College of Surgeons, Commission on Cancer and certification from the American Society of Clinical Oncology Quality Oncology Practice Initiative. Developing a successful distress screening program is essential for cancer programs. Methods: The purpose of this project was to create a comprehensive distress screening program utilizing the electronic health record (EHR) to identify patients requiring screening and document interventions. A multidisciplinary team was established to develop a distress screening process for our cancer program. The team developed a screening tool based on the National Comprehensive Cancer Network Distress Thermometer. The distress screening tool was built into the EHR. An alert was created to notify staff at visit check-in to provide the distress screening tool. Once completed, the score and any areas of distress indicated by the patient are entered into the EHR by the medical assistant. When a score is documented, the nurse case manager (CM) receives a “Distress Score” alert when accessing the patient’s chart, indicating the need for nursing review. The CM reviews the score, assesses patient needs and documents any needed interventions or referrals. A specific score does not require a specific intervention, rather the CM is required to determine the needs of the individual patient and take appropriate action. Results: In 2015, 8069 patients were offered distress screening with 13,527 distress screenings completed. This resulted in 629 referrals to social work. 803 distress screens had a score of seven or greater (6%). Conclusions: The multidisciplinary team continues to evaluate the process and make changes. Auditing reveals compliance with documenting a distress score of 95% or greater across all oncology areas and review by the CM of at least 93% on a consistent basis. In many instances, the physician and/or the CM address distress related to the patient’s disease or symptom management. Use of the EHR has facilitated the workflow and allowed information to be visible to the care team.
Phase I study of humanized IgG1 anti-epidermal growth factor receptor (EGFR) monoclonal antibody EMD 72000 plus gemcitabine (Gem) in advanced pancreatic cancer
Authors: U. Graeven, I. Vogel, B. Killing, S. Hinz, W. Von Bernstorff, J. Baselga, F. Rojo, J. Tillner, P. Gropp, W. Schmiegel
Journal: Journal of Clinical Oncology (2004)

3061 Background: Monoclonal antibody EMD 72000 blocks ligand binding and inhibits EGFR activation and signal transduction. EGFR is overexpressed in up to 90% of pancreatic cancers. We studied safety and tolerability of EMD 72000 plus Gem in advanced pancreatic cancer. Methods: Open-label, nonrandomized, escalating doses of EMD 72000: 400 mg/wk (I), 800 mg/2 wk (II), or 800 mg/wk (III), followed by a weekly dose of 1000 mg/m2 Gem. After 2 4-wk cycles, pts with stable or responding disease continued treatment until disease progression or unacceptable toxicity. Pharmacodynamic (PD) effects (expression of EGFR and MAPK phosphorylation, proliferation (Ki67) and p27Kip1) were studied in skin biopsies before and after the first treatment cycle. Serum was collected to assess pharmacokinetic (PK) parameters (Cmax, AUC, t1/2) at several timepoints. Results: 17 pts (I/II/III: n = 5/4/8) were enrolled. EGFR expression was confirmed for 16 tumors. Treatment-related toxicities (all grades, in ≥ 3 pts) included skin toxicity (n = 9), fever (4), neutropenia (3), and leukopenia (3). Gr 3 toxicities (all causes, > 1 pt) were neutropenia (3), leukopenia (2), fever (2), cholangitis (2), hypokalemia (2), increased liver enzymes (11), LDH (2). Non-treatment-related Gr 4 toxicities occurred in 3/5 group I (cachexia, increased GGT and bilirubin) and in 1/8 group III quadriplegia) pts. Gr 4 Guillain-Barre syndrome occurring in the patient with quadriplegia was reported by the sponsor as possibly treatment-related. There was 1 death (400 mg) due to non-treatment-related respiratory failure. Stable disease occurred in 3/5 pts in group I, 3/4 in II, and 5/8 in III with continuous treatment for up to 50 wks. Skin biopsies showed EMD 72000 inhibited EGFR activation and affected receptor-dependent signaling and transduction in vivo, effects seen even in the lowest-dose group. PK data were consistent with results of other studies of EMD 72000 monotherapy. Conclusions: EMD 72000 in biologically effective doses plus standard Gem doses appeared well tolerated. PD and PK data corresponded to recent study results of EMD 72000 monotherapy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck KGaA, Darmstadt, Germany Merck KGaA, Darmstadt, Germany Merck KGaA
Effect of corticosteroid (CS) use at baseline (CUB) on overall survival (OS) in patients (pts) receiving abiraterone acetate (AA): Results from a randomized study (COU-AA-301) in metastatic castration-resistant prostate cancer (mCRPC) post-docetaxel (D).
Authors: Robert B. Montgomery, Thian San Kheoh, Arturo Molina, Jinhui Li, Joaquim Bellmunt, Charles J. Ryan, Namphuong Tran, Yohann Loriot, Eleni Efstathiou, Howard I. Scher, Johann Sebastian De Bono
Journal: Journal of Clinical Oncology (2013)

5014 Background: CS have been used to mitigate mineralocorticoid-related effects and restore sensitivity to AA (Attard et al., J Clin Oncol. 2008). Prednisone (P) was also used as an active comparator in the COU-AA-301 (de Bono et al., N Engl J Med. 2011) and COU-AA-302 (Ryan et al., N Engl J Med. 2013) AA pivotal studies. CUB has also been reported to adversely influence OS in the AFFIRM study, which may reflect an influence on disease biology or unrecognized factors that are not a part of clinically based prognostic models (Scher et al., Ann Oncol. 2012). This post hoc exploratory analysis investigated whether CUB is a prognostic factor for OS in mCRPC post-D pts treated with AA + P or P alone. Methods: COU-AA-301 is a randomized double-blind study of AA (1 g) + P (5 mg po BID) vs placebo + P in mCRPC post-D. The primary endpoint was OS. All pts had received CS with D therapy. CUB included P (n = 272), dexamethasone (n = 107), and others (n = 110). 797 pts were not on CUB. Median times were estimated by the product-limit method; Cox model was used to obtain the hazard ratio (HR) and associated confidence interval (CI). Results: Pts with CUB had worse baseline disease characteristics (including adverse ECOG PS, Gleason score, analgesic score, and LDH) (all p &lt; 0.05). Pts receiving CUB had inferior OS; AA + P improved OS independent of CUB. (Table). CUB was an independent prognostic factor in multivariate analysis (p = 0.03; HR 1.22 [95% CI: 1.02-1.45]) that was associated with lower baseline androgen levels (p &lt; 0.0001). In a stepwise selection model, CUB was not an independent prognostic factor. Conclusions: In this study, CUB was not a strong independent prognostic factor in mCRPC post-D pts treated with AA + P or P alone. CUB was associated with worse baseline disease characteristics and inferior OS in this study, in which all pts subsequently received CS. Clinical trial information: NCT00638690. [Table: see text]
Levothyroxine shows no benefit in elderly patients with subclinical hypothyroidism, trial finds
Authors: Susan Mayor
Journal: BMJ (2017)

Treatment with levothyroxine provides no clinical benefit in older people with subclinical hypothyroidism, a UK randomised trial published in the New England Journal of Medicine has shown.1

Subclinical hypothyroidism, defined as an elevated serum thyrotropin level and a serum free thyroxine level within the reference range, is common in older people, affecting 8-18% of over 65s. It is more common in women than men.

Thyroid hormones have a wide …