tbuckley/cabot-search huggingface dataset:
A phase 1 study of NOX66 in combination with carboplatin in patients with end stage solid tumours.
Authors: Paul L. de Souza, Marinella Messina, Ian Minns, Mikheil Shavdia, Nana Chikhladze, Graham Kelly
Journal: Journal of Clinical Oncology (2018)

2585 Background: NOX66 is under development as an enhancer of chemotherapy and radiotherapy across multiple tumour types. The primary mechanism of action of idronoxil (the active ingredient of NOX66) stems from its selective binding to ENOX2 - a tumour-specific NADH oxidase - inhibiting Sphingosine kinase activity within tumour cells and leading to inhibition of the PI3K/Akt pathway and induction of apoptosis. Here we report the results of the first-in-human study of NOX66 as monotherapy and in combination with carboplatin (carbo). Methods: 19 patients with metastatic end stage solid tumours were recruited to one of two dose cohorts, NOX66 400mg, and 800mg respectively. Following a monotherapy run in period (NOX66 administered PR, Day 1-14 followed by a 7 day break) patients received 6 cycles of combination therapy - NOX66 administered on Day 1-7 and intravenous carbo on Day 2 of a 28-day schedule. Carbo was administered at AUC4 for 3 cycles, followed by AUC6 for 3 cycles. Recruitment is complete, with last patient last visit scheduled for May 2018. Results: 16 patients have completed study treatment. Radiologic assessment of disease state is shown in the table below (Progressive Disease – PD; Stable Disease – SD; Partial Response – PR). 4 SAEs (including 3 deaths) were reported, none were considered related to NOX66. One Adverse Event (Grade 2 anaemia, NOX66 800mg + carbo AUC4) considered possibly related to NOX66 has been reported. Conclusions: NOX66 is well tolerated as a monotherapy and in combination with carboplatin at AUC = 4 or AUC = 6. Efficacy signals from this study warrant further investigation of NOX66 as a chemo-sensitizing agent. Clinical trial information: NCT02941523.NOX66 Dose 400mg 800mg Enrolled 8 11 Completed 3 cycles carbo (AUC4) 8 10 Evaluable 4 (All SD) 9 (1PR; 7SD; 1PD) Completed 6 cycles carbo (AUC4; AUC6) 6 5 Evaluable 2 (1SD; 1PD) 3 (2SD; 1PD) Ongoing 0 3
Prognostic role of BRAF mutation in malignant cutaneous melanoma.
Authors: Amikar Sehdev, Ross Hayden, Mathew Joseph Kuhar, Liang Cheng, Simon John Warren, Lawrence Aaron Mark, William Arthur Wooden, Douglas Jay Schwartzentruber, Theodore F. Logan
Journal: Journal of Clinical Oncology (2018)

e21599 Background: Prognostic role of BRAF mutation is not well-studied in malignant cutaneous melanoma. We conducted a large retrospective study using a state-wide database to assess the clinical characteristics and prognostic role of BRAF mutations. Methods: The Indiana Network for Patient Care (INPC) was used to identify patients diagnosed with malignant melanoma and who underwent BRAF testing between 1995-2016. The INPC represents the largest and longest tenured clinical data warehouse of the Indiana Health Information Exchange in the USA. Using natural language processing, we extracted the date of diagnosis, age, gender, race, Breslow thickness, ulceration, mitotic rate, stage, primary site, smoking, body mass index (BMI), LDH, BRAF status, date and cause of death. Chi-square or t-test was used for univariate analyses. Overall survival (OS) was estimated by Kaplan-Meier method. Logistic and Cox regression was used for multivariate analyses (adjusted for all variables except LDH and BMI). Results: Of 1971 study patients, 920 (46.7%) had BRAF mutation. On univariate analyses, male gender, non-Caucasian race, higher Breslow thickness ( > 1 mm), higher mitotic rate ( > 1/mm2), primary site, smoking and advanced stage (III and IV) were associated with BRAF mutation (p < 0.05). Multivariate logistic regression showed that the BRAF mutation is significantly (p < 0.05) associated with advanced stage (AOR 1.22, 95% CI [1.10-1.34]), male gender (1.15 [1.06-1.26]), presence of ulceration (1.22 [1.07-1.39]), higher Breslow thickness (1.03 [1.01-1.04]), higher mitotic rate (1.11 [1.01-1.22]), primary melanoma of trunk (0.85 [0.76-0.96]) and smoking (1.27 [1.17-1.39]). Kaplan-Meier analysis revealed that the BRAF mutant patients have significantly better OS as compared to BRAF wild-type patients (144 vs. 85 months; HR 0.72 [0.59-0.88], p = 0.001). However, BRAF mutation was not predictive of OS in multivariate Cox model (HR 1.28 [0.68-2.41], p = 0.43) unlike advanced stage, male gender and higher Breslow thickness. Conclusions: BRAF mutation in malignant cutaneous melanoma is associated with more aggressive clinical features however BRAF mutation is not an independent prognostic factor when adjusted for other prognostic variables.
Safety of limited dose modifications for palbociclib associated neutropenia in ER+ metastatic breast cancer.
Authors: Anthony Dominick, Anne O'Dea, Qamar J. Khan, Bruce F. Kimler
Journal: Journal of Clinical Oncology (2018)

e13033 Background: The cyclin-dependent kinase (CDK) 4/6 inhibitor palbociclib (P) improves outcomes in metastatic breast cancer (MBC). P has a consistent side effect profile with a high incidence of neutropenia, although with low rates of febrile neutropenia (FN) or serious neutropenia-related infections. In MBC trials of CDK4/6 inhibitors, it is recommended that dose reduction occur with an absolute neutrophil count (ANC) < 1000 (Grade 3 neutropenia). Dose interruptions or reductions occur in > 50% of patients due to neutropenia, with potential negative impact on patient outcomes. Methods: Pharmacy data was utilized to identify patients with MBC treated with P. Patient demographics, disease characteristics, and safety data was collected. Only patients who underwent limited dose modification defined as a dose reduction/interruption for ANC < 500 (Grade 4 neutropenia) were included in this analysis. Primary endpoints were incidence of FN, infection, and percent who underwent dose reduction due to neutropenia. Results: 50 patients with MBC who received P were included. 34(68%) received P plus an aromatase inhibitor and 16(32%) received P plus fulvestrant. 31(62%) received P as first treatment for MBC. 14% had received 1 prior therapy and 8% had received 2 prior lines of therapy for metastatic disease. 16% had received ≥3 lines of prior therapy. 15(30%) had received chemotherapy for treatment of MBC. Mean duration of P treatment was 321 days. One incidence of FN was observed in a patient who received > 24 months of P and a source of fever was not identified. 7(14%) patients experienced grade 4 neutropenia requiring cycle delay/dose reduction. 14(28%) experienced infection of any grade; 10 patients received outpatient treatment for respiratory infections and 3 were treated for UTI. One patient experienced Grade 3 colitis of undetermined cause. Conclusions: Limited dose reduction for Grade 4 neutropenia of P does not result in increased infections or higher rates of FN. Patients receiving treatment with limited dose modification experienced fewer dose reductions/interruptions. More trials are warranted to determine if limited dose modification of P in MBC will translate into improved patient outcomes.
Effects of patient navigation on satisfaction with cancer care: A systematic review.
Authors: Pascal Jean-Pierre
Journal: Journal of Clinical Oncology (2017)

e18088 Background: Patient navigation (PN) is a model of health care coordination designed to ameliorate health disparities by reducing barriers to achieving optimal health outcomes. Systematic reviews that evaluate whether PN is associated with higher patient satisfaction with cancer care are lacking. Methods: We conducted a systematic review to synthesize evidence of comparative studies evaluating the effectiveness of PN programs to improve satisfaction with cancer-related care. We included studies reported in English that: 1) evaluated a PN intervention designed to increase satisfaction with cancer care; and 2) involved a randomized controlled trial (RCT) or observational design. We abstracted data from studies using standardized forms, and evaluated these studies for methodological quality. Data were summarized qualitatively and synthesized under a random effects model. Results: The initial search yielded 831 citations, of which 3 RCTs and 6 observational studies met inclusion criteria. These nine studies involving 4,200 surveyed patients revealed either a neutral or positive effect in patient satisfaction in the majority of studies of PN and cancer-related care. However, only 5 studies (1 RCT and 4 observational) had adequate datato include in the meta-analysis. Methodological quality of eight of the included studies ranged from weak to moderate to strong, with half rated as weak. Findings of the RCT showed a statistically significant increase in satisfaction with cancer care involving PN [standardized mean difference (SMD) = 2.30; 95% Confidence Interval (CI): 1.79, 2.80, p &lt; .001]. Pooled results from non-RCTs showed no significant association between PN and satisfaction with cancer-related care (SMD = 0.39; 95% CI: -0.02, 0.80, p = .06). Conclusions: More systematic reviews are needed to characterize the relationship between PN and satisfaction with cancer-related care across the cancer care continuum and across different types of cancer.
Biomarker-driven access to vemurafenib in BRAF-positive cancers: Second study of the French National AcSé Program.
Authors: Jean-Yves Blay, Natalie Hoog Labouret, Claire Cropet, Julien Mazieres, Frederique Nowak, Ivan Bieche, Xavier Troussard, Etienne Lonchamp, Julie Charles, Stéphane Dalle, Eve Maubec, Sophie Leboulleux, David Malka, Bertrand Arnulf, Aude Flechon, Isabelle Ray Coquard, David Pérol, Veronica Pezzella, Marta Jimenez, Agnes Buzyn
Journal: Journal of Clinical Oncology (2016)

TPS11620 Background: Vemurafenib (V) is registered in monotherapy for the treatment of adult patients (pts) with BRAF V600 mutation (mut) unresectable or metastatic melanoma but responses were observed in other tumor types. To avoid off-label use and allow for a nationwide safe access to V for pts with BRAF mut, the French National Cancer Institute (INCa) launched the AcSé V program, funding both access to molecular diagnosis in the 28 INCa molecular genetic centers and an exploratory phase II trial testing V in pts with BRAF mut tumors. AcSé V was launched following the AcSé crizotinib study. Methods: BRAF mut identification is proposed to pts with advanced cancers including lung, ovarian, bladder, thyroid, prostatic cancers; cholangiocarcinoma, sarcoma/GIST, multiple myeloma, Chronic Lymphocytic Leukemia (CLL) and Hairy Cell Leukemia (HCL), all known from literature to harbor this mut. If not eligible to another academic or industry trial targeting the same mut, a pt with BRAF V600 mut may be included in the appropriate pathology cohort to receive V 960 mg BID. Pts with BRAF non-V600 mut (on exon 11 or 15) or other BRAF alteration identified through a pangenomic tumor profile are also eligible in a miscellaneous cohort. Emerging new data are examined by a steering committee who may propose to open additional cohorts. Objective Response (OR) is evaluated every 8 weeks using RECIST V1.1 for solid tumors and appropriate criteria for myeloma, CLL and HCL. A Bayesian approach allows continuous monitoring of the OR. Sequential analyses are performed in each cohort to allow early stopping using an inefficacy bound for OR of 10% until a maximum sample size of 30 to 50 pts (efficacy bound at the end of the study: 30%). From Oct. 2014 to Jan. 2016, 70 pts out of > 1200 screened were included. A dermatological monitoring has been established with regular consultations carried out by dermatologists belonging to the network of the Skin Cancer Group from the French Society of Dermatology. Moreover 3 specialists have been appointed by the Group to provide expertise and advice on the management of BRAF inhibitors specific skin toxicities. Around 3,000 molecular tests and up to 500 pts treated in 150 centers are planned over 3 years. Clinical trial information: NCT02304809.
Assessment of health related quality of life (QOL) in phase III trials in advanced colorectal cancer (CRC): Frequency, time trends, and QOL improvement.
Authors: Krzysztof Adamowicz, Everardo D. Saad, Jacek Jassem
Journal: Journal of Clinical Oncology (2016)

e18209 Background: QOL is often one of the endpoints in cancer clinical trials. We assessed the frequency and correlates of QOL usage as an endpoint in phase III trials in advanced CRC. Methods: We used the medical subject headings “colorectal neoplasms” and “drug therapy” to search PubMed for phase III trials on systemic antineoplastic therapies published between 1/1998 and 12/2014 in 10 leading journals (Ann Oncol, Br J Cancer, Cancer, Clin Cancer Res, Eur J Cancer, JCO, JNCI, Lancet, Lancet Oncol,and NEJM). We also searched for companion papers reporting on QOL separately. We excluded papers reporting on correlative biology or prognostic factors in isolation from the main trial results, as well as trials on supportive care and on local forms of therapy. Results: We retrieved 94 trials that enrolled a total of 56,559 patients in 206 trial arms. QOL was reportedly used as endpoint in 37 (39%) trials, in all but one case as a secondary endpoint. There was a trend for higher frequency of QOL usage between 1998 and 2006 (49%) than between 2007 and 2014 (31%; P = 0.09). Formal statistical comparisons involving QOL parameters were reported in 30/37 trials (81%), with a significant difference between arms found in only 9/30 (30%) trials, in 5 cases favoring the experimental arm. Trials with a significant QOL difference included more patients than those without (medians of 750 vs 471), but the difference was not significant. Conclusions: QOL has been assessed formally in nearly 40% of contemporary phase III trials in advanced CRC and about one-third of them have shown a significant gain in QOL. It is questionable, therefore, whether QOL results may help select between treatments with no differential impact on OS or other efficacy endpoints. This assumption may be the reason for decreasing usage of QOL as endpoint in phase III trials in advanced CRC.
Regional variation in high-resource utilization among lung cancer-related emergency department visits in the United States.
Authors: Cynthiya Ruban, Marc Kowalkowski, Christopher Michael Blanchette
Journal: Journal of Clinical Oncology (2017)

e20038 Background: Regional variation is common in oncology care but is not defined for emergency department (ED) care for cancer patients, particularly patients with lung cancer (LC) who regularly utilize EDs for management of acute cancer or treatment related illness. This study analyzed regional variation and other factors associated with high total episodic charge (≥75 th percentile; HTC) among LC patients evaluated in the ED in relation to discharge or admission. Methods: A retrospective study of LC-related ED visits in the US was conducted using the 2013 Nationwide ED Sample. LC-related ED visits among adults were identified by LC-specific Clinical Classification Software codes (CCS = 19; mapping to ICD-9 = 162.x, 209.21, 231.2, V10.11). Multivariable logistic regression analyzed the association between patient and hospital factors and HTC, weighted to represent ED visits nationwide. Results: Among 373,761 LC-related ED visits, 134,838 (36%) were treated and discharged and 238,923 (64%) were admitted (ranging from 51% (West [W]) to 76% (South [S]). HTC was ≥$5,655 (median = $2,993) for ED discharges and ≥$54,760 (median = $29,590) for admissions. The proportion of visits with HTC differed by region and admission status (discharged: 7% [W] to 27% [S]; admitted: 20% [Midwest] to 39% [W]). After adjusting for clinical and hospital factors associated with increased HTC odds (metastases, common acute comorbid disorder [chest and abdominal pain, pneumonia, sepsis, respiratory failure], diagnostic radiology use, thoracic/other surgery, chemo/radiotherapy, length of stay, primary payer, and hospital ownership, location and teaching status), significant HTC variation remained by hospital region with opposing relative HTC odds among discharged and admitted patients (discharged: W v S OR = 0.3 95%CI = 0.2-0.6, Northeast v S OR = 0.5 95%CI = 0.3-0.7; admitted: W v S OR = 3.8 95%CI = 2.5-5.7). Conclusions: Regional variation in HTC suggest differences in ED use and management patterns for LC and may reflect quality of care concerns. Clinical outcome linkage (including ED revisit tracking) is needed to better define the impact of variation and develop strategies to improve care for patients with LC.
Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults — United States, 2016
Authors: James Dahlhamer, Jacqueline Lucas, Carla Zelaya,, Richard Nahin, Sean Mackey, Lynn DeBar, Robert Kerns, Michael Von Korff, Linda Porter, Charles Helmick
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Chronic pain, one of the most common reasons adults seek medical care (1), has been linked to restrictions in mobility and daily activities (2,3), dependence on opioids (4), anxiety and depression (2), and poor perceived health or reduced quality of life (2,3). Population-based estimates of chronic pain among U.S. adults range from 11% to 40% (5), with considerable population subgroup variation. As a result, the 2016 National Pain Strategy called for more precise prevalence estimates of chronic pain and high-impact chronic pain (i.e., chronic pain that frequently limits life or work activities) to reliably establish the prevalence of chronic pain and aid in the development and implementation of population-wide pain interventions (5). National estimates of high-impact chronic pain can help differentiate persons with limitations in major life domains, including work, social, recreational, and self-care activities from those who maintain normal life activities despite chronic pain, providing a better understanding of the population in need of pain services. To estimate the prevalence of chronic pain and high-impact chronic pain in the United States, CDC analyzed 2016 National Health Interview Survey (NHIS) data. An estimated 20.4% (50.0 million) of U.S. adults had chronic pain and 8.0% of U.S. adults (19.6 million) had high-impact chronic pain, with higher prevalences of both chronic pain and high-impact chronic pain reported among women, older adults, previously but not currently employed adults, adults living in poverty, adults with public health insurance, and rural residents. These findings could be used to target pain management interventions.
A first-in-class, first-in-human phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) study of Hu5F9-G4, an anti-CD47 monoclonal antibody (mAb), in patients with advanced solid tumors.
Authors: Branimir I. Sikic, Nehal J. Lakhani, Amita Patnaik, Sumit Shah, Sreenivasa R Chandana, Drew W. Rasco, A. Dimitrios Colevas, Timothy J. O'Rourke, Kyriakos P. Papadopoulos, George A. Fisher, Mark Chao, Balaji Agoram, James Y Chen, Jenny Huang, Matthew Axt, Ravindra Majeti, Irving L. Weissman, Chris H.M. Takimoto, Mark D. Pegram, Sukhmani Kaur Padda
Journal: Journal of Clinical Oncology (2018)

3002 Background: Hu5F9-G4 (5F9) is a humanized mAb that inhibits CD47, a “don’t eat me” signal for macrophages, and can enhance tumor cell phagocytosis and T-cell priming. Preclinically, 5F9 is active against a wide range of tumors. Methods: Patients (pts) were enrolled in 3 dose escalation groups using a 3+3 design (NCT02216409). Part A (11 pts) defined 1 mg/kg of 5F9 as the optimal week (wk) 1 priming dose that was used subsequently in Parts B & C. Part B (14 pts) evaluated higher weekly (wkly) maintenance doses starting wk 2 and Part C (18 pts) evaluated an additional loading dose in wk 2. Safety, PK, PD and efficacy data are presented here. Results: In 58 pts (median age 60 y; median prior treatments 5) the common tumor types were colorectal (CRC), ovarian, adenoid cystic, breast, pancreatic, and squamous cell head & neck cancers. Using a priming + load/maintenance dose, no maximum tolerated dose (MTD) was reached in Part B where 14 pts received ≥20 mg/kg of 5F9 wkly, nor in Part C where doses of 20 (7 pts), 30 (8 pts) and 45 mg/kg (3 pts) were well tolerated. Common Part C drug-related adverse events were fatigue 50%, chills 50%, pyrexia 45%, anemia 39%, headache 34%, lymphopenia 28%, hemagglutination 17%, transient hyperbilirubinemia 17%, and myalgias 11%. Most AEs were Grade (Gr) 1 or 2 occurring in cycle 1 (28 days) with Gr 3+ being uncommon and no cumulative effects. Transient Grade 1/2 acute anemia due to CD47 blockade on older RBCs was common but was mitigated by the priming dose strategy. Saturation of nonlinear PK occurred at ≥10 mg/kg resulting in a prolonged t½ ~14 days, 5F9 levels exceeding preclinical antitumor activity thresholds (200 ug/mL) and resulting in > 99% WBC CD47 receptor occupancy. The recommended Phase 2 dose is 1 mg/kg priming dose wk 1 followed by 30 mg/kg wkly x 3 and then 30 mg/kg Q2 wks thereafter. Two pts (ovarian and fallopian tube cancers) had confirmed partial responses and were treated for 23 and 41+ weeks, respectively. In 13 CRC pts treated at doses ≥20 mg/kg, 6 had stable disease with a median treatment duration of 18 wks. Conclusions: 5F9 prime + maintenance doses are well tolerated and demonstrate monotherapy antitumor activity. Clinical trial information: NCT02216409.
Abstract 16899: Exome Sequencing for Genetic Etiology in Families With Sudden Cardiac Death or Arrest
Authors: Victoria L Vetter, Noreen P Dugan, Sawona Biswas, Mindy Li, Matthew C Dulik, Vijayakumar Jayaraman, Laura K Conlin, Basal Devkota, Edward J Romasko, Jenica Abrudan, Nancy B Spinner, Ian D Krantz
Journal: Circulation (2016)

Introduction: Sudden cardiac arrest/death (SCA/D) is an uncommon, but tragic occurrence in youth. Causes include inherited structural, functional, and electrical cardiac abnormalities, with more th...
TCT-786 Clinical Features of Subacute Myocardial Infarction - Multicenter Registry from Tokyo CCU Network Database
Authors: Ryosuke Ito, Jun Yamashita, Takaaki Mase, Kaito Abe, Satoshi Higuchi, Masatomo Yoshikawa, Hiroyuki Tanaka, Masao Yamasaki, Katsumi Miyauchi, Taishiro Chikamori, Ken Nagao, Takeshi Yamamoto, Morimasa Takayama
Journal: Journal of the American College of Cardiology (2018)