tbuckley/cabot-search huggingface dataset:
Outcomes of patients with metastatic clear cell renal cell carcinoma treated with second-line VEGFR-TKI after first-line immune checkpoint inhibitors.
Authors: Amishi Yogesh Shah, Ritesh Kotecha, Emily Lemke, Anuradha Chandramohan, Joshua Chaim, Pavlos Msaouel, Lianchun Xiao, Jianjun Gao, Matthew T Campbell, Amado J. Zurita, Jennifer Wang, Paul Gettys Corn, Eric Jonasch, Robert J. Motzer, Padmanee Sharma, Martin Henner Voss, Nizar M. Tannir
Journal: Journal of Clinical Oncology (2019)

575 Background: Immune checkpoint inhibitors (ICI) are being increasingly utilized in front-line (1L) setting of metastatic clear-cell renal cell carcinoma (mccRCC). Limited data exist on responses and survival on second-line (2L) VEGFR-TKI therapy after 1L ICI therapy. Methods: This is a retrospective study of mccRCC patients treated with 2L VEGFR-TKI after progressive disease (PD) with 1L ICI. Patients were treated at MD Anderson Cancer Center or Memorial Sloan Kettering Cancer Center between December 2015 and February 2018. Objective response was assessed by blinded radiologists’ review using RECIST v1.1. Descriptive statistics and Kaplan-Meier method were utilized. Results: 70 patients were included in the analysis. Median age at mccRCC diagnosis was 59 years old; 8 patients (11%) had IMDC favorable-risk score, 48 (69%) had intermediate-risk score, and 14 (20%) had poor-risk score. As 1L therapy, 12 patients (17%) received anti-PD-(L)1 monotherapy with nivolumab or atezolizumab, 33 (47%) received nivolumab plus ipilimumab, and 25 (36%) received combination anti-PD-(L)1 plus bevacizumab. 2L TKI therapies included pazopanib, sunitinib, axitinib, and cabozantinib. On 2L TKI therapy, one patient (1.5%) achieved a complete remission (CR), 27 patients (39.7%) a partial response (PR), and 36 patients (52.9%) stable disease (SD), adding to a 94% disease control rate (DCR). Median progression-free survival (mPFS) was 13.2 months (95% CI: 10.1, NA). Estimated 1-yr overall survival (OS) probability was 79.6% (95% CI: 70.2 – 90.3). Median duration of 2L TKI therapy was 10.1 months. In total, 45.7% of subjects required a dose reduction, and 27% of patients discontinued treatment due to toxicity. Conclusions: In this retrospective study of patients with mccRCC receiving 2L TKI monotherapy following 1L ICI, we observed 2L antitumor activity and tolerance comparable to historical data for first-line TKI. Further studies are needed to evaluate optimal strategies and sequencing of therapies in mccRCC.
Post-ACA Racial Disparity of Eye Examinations Among the U.S. Noninstitutionalized Population With Diabetes: 2014–2015
Authors: Alisha M. Monnette, M. Kristina Wharton, Yingnan Zhao, Vivian A. Fonseca, Lizheng Shi
Journal: Diabetes Care (2019)

Diabetic retinopathy (DR), a microvascular complication of diabetes, is the leading cause of blindness among adults aged 20 to 74 years (1). Between 2010 and 2014, ∼4.2 million adults aged >40 years were diagnosed with DR (2,3). Of these, 655,000 suffered from advanced DR, which can cause blindness if left untreated (2). The American Diabetes Association recommends eye examinations for people with diabetes based on the evidence of DR present (i.e., if any level of DR is present, then exams should be repeated at least annually; if there is no evidence, then exams every 2 years may suffice) (3). Regardless of stipulations, it is evidenced that racial and ethnic minorities have been previously shown to have fewer exams than recommended (4). This study assesses the racial and ethnic disparities of eye examination rates among U.S. adults with diabetes after the increased access initiatives of the Affordable Care Act (ACA).

Annual data from the 2014–2015 Medical Expenditure Panel Survey (MEPS) Household Component data files were analyzed. The study population included adults aged 18 years and older with a self-reported diagnosis of diabetes from a health care professional. The primary outcome was the annual eye examination rate, defined as …
Are prostate cancer patients with BRCA1 and BRCA2 mutations safe for active surveillance?
Authors: Marc Dall'era, Christopher P. Evans, Chong-Xian Pan, Mamta Parikh, Primo Lara, John McPherson
Journal: Journal of Clinical Oncology (2019)

19 Background: Active surveillance (AS) is recommended as a treatment option for men presenting with low risk (Gleason 3+3) and some intermediate risk (Gleason 3+4) prostate cancer. BRCA1 or 2 germline mutations have been implicated in prostate cancer pathogenesis. It is unknown if germline BRCA1/2 mutations in AS candidacy are associated with more aggressive histologic grade, higher stage or other worse genetic alterations, such as RB1 and p53 deletions. Methods: We analyzed sequencing data from 498 men who underwent radical prostatectomy from The Cancer Genome Atlas (TCGA) data set. The primary outcome was the difference in the proportions of AS candidates among subjects with and without BRCA homodeletions. Tests for differences in the proportions were conducted using Fisher’s Exact Test. Equivalence tests for proportions of AS candidates were conducted using the two-one sided tests (TOST) method. As a secondary outcome we studied the associated coincident mutations in the men with BRCA1 and BRCA2 homodeletions. Results: Forty-one men (8%) of the cohort had homodeletion of BRCA1 or BRCA2. Ten men (2%) had complete loss of BRCA1 while 31 (6%) had loss of BRCA2. Rates of candidacy for AS based on histology and stage (defined as stage T2, Gleason 6) are not different between subjects with and without BRCA 1 or 2 homodeletions, within an equivalence margin of 10 percentage points. These findings are similar when the AS criteria are modified to add Gleason 3+4 subjects. Fifty percent of men with organ confined (pT2), 3+3 and 3+4 prostate cancer with BRCA1 or BRCA2 homodeletions had concomitant RB1 deletions compared with 16.5% of the entire cohort (p = 0.002). This was primarily driven by BRCA2 deletions co-occurrent with RB1 deletions (log OR: 2.4, p &lt; 0.001). Twenty-nine percent of men from this group had concomitant p53 deletions compared to 7.5% of the entire cohort (p = 0.004). Conclusions: Men with prostate cancer and BRCA1 or BRCA2 homodeletions present with similar stage and grade tumors than men without these deletions. Despite having low or low intermediate grade histology, BRCA1 and BRCA2 deleted tumors are enriched with deletions in RB1 and TP53, both of which are associated with more aggressive phenotypes and treatment resistance.
Abstract MP11: Role of Modifiable and Non-Modifiable Risk Factors in the Association of Kidney Function With Dementia Incidence in Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Sanaz Sedaghat, Michael Bancks, Ian H. de Boer, Holly Kramer, Orlando Gutierrez, WT Longstreth, Kiarri N. Kershaw, Mercedes Carnethon
Journal: Circulation (2019)

Introduction: As many as 20-50% of persons with chronic kidney disease have mild-to-moderate cognitive impairment or overt dementia. Shared risk factors, such as aging, sex, hypertension, and diabetes have been suggested to play a role in this association. Our objective was to examine the contribution of non-modifiable and modifiable risk factors to this association. Hypothesis: We hypothesize that non-modifiable and modifiable risk factors could explain part, but not all, of the association between worse kidney function with incidence of dementia. Methods: We included 6025 CVD free participants (mean age 62 yrs, 51% women, 38% white). Kidney function was assessed by estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR). Participants were followed for an average of 12±4 yrs for dementia ICD code hospitalization. Multiple Cox regression models, adjusted for baseline non-modifiable (age, sex, race, and APOE4 carriership) and modifiable risk factors (BMI, smoking, SBP, diabetes, cholesterol, alcohol intake, education, physical activity, and healthy diet score) were used to estimate the association of worse kidney function with incidence of dementia hospitalization. Results: During follow-up, 268 (4.4%) participants were hospitalized for dementia. Non-modifiable risk factors vs. modifiable risk factors were associated with greater reduction in HRs from a crude model for association between each SD lower eGFR and risk of dementia (70% vs. 8%). Non-modifiable risk factors explained a higher percentage of the association of doubling ACR with risk of dementia than modifiable risk factors (14% vs. 7%) (Figure). Adjusting for all factors, worse kidney function remained associated with incident dementia. Conclusions: Findings suggest that conventional modifiable and non-modifiable risk factors cannot fully explain higher risk of dementia in relation to worse kidney function. This finding warrants exploring other potential novel vascular and nonvascular mechanisms of this association.
Pharmacokinetic profile and receptor occupancy of avelumab (MSB0010718C), an anti-PD-L1 monoclonal antibody, in a phase I, open-label, dose escalation trial in patients with advanced solid tumors.
Authors: Christopher Ryan Heery, Geraldine Helen O'Sullivan Coyne, Jennifer L. Marte, Harpreet Singh, Lisa M Cordes, Ravi Amrit Madan, Renee Nicole Donahue, Italia Grenga, Lauren Lepone, Berend Neuteboom, Isabell Speit, Kevin M. Chin, Jeffrey Schlom, James L. Gulley
Journal: Journal of Clinical Oncology (2015)

3055 Background: The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against multiple cancers. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody currently being investigated in clinical trials. Reported here is the pharmacokinetic (PK) profile of avelumab and receptor occupancy (RO) from a phase I dose escalation trial (NCT01772004). Previous in vitro experiments spiking anti-PD-L1 into human whole blood samples from healthy donors confirmed that 1 mcg/mL was sufficient for > 95% RO. Methods: In this study, dose escalation (3+3 design) was performed for 4 dose levels (DL 1, 3, 10, and 20 mg/kg). The dose limiting toxicity (DLT) evaluation period was 3 weeks. After DL safety was determined, accrual of additional patients (pts) was allowed for the purpose of generating additional safety, PK, and RO data. Results: 50 pts with advanced solid tumors were enrolled and treated with avelumab, Q2W. 4, 13, 13, and 20 pts were accrued to DL 1-4, respectively. Median pt age was 59 yrs (range 29-77); 19 had an ECOG PS of 0 and 29 had an ECOG PS of 1 (2 unknown).The median number of prior lines of therapy was 3 (range 1- ≥ 4). Data from 45 pts were evaluable for PK analysis. Cmaxand AUC increased linearly with dose. Half-lives were 66, 86, 92, and 115 h for DL 1, 2, 3 and 4, respectively, with no statistically significant differences between the 3 higher DLs. Trough levels at 10 mg/kg, but not at 1 and 3 mg/kg, were sufficient for > 95% RO at all dosing occasions. Population PK analysis showed that a 2-compartment model with linear elimination best described the data. Covariate analysis did not demonstrate significant correlation between body-size metrics and clearance. There was no significant change in absolute lymphocyte count or in additional multiple immune cell subsets evaluated. Conclusions: The PK and RO data indicate the 10 mg/kg dose of avelumab achieves excellent RO with a predictable PK profile. Based on these data and the safety profile reported separately, the 10 mg/kg dose is being tested in ongoing phase II trials. *Proposed INN. Clinical trial information: NCT01772004.
Abstract P253: The Association of Goal-Striving Stress With Measures of Adiposity in the Jackson Heart Study
Authors: Loretta R Cain, LáShauntá Glover, Joshua Joseph, Alain Bertoni, Mario Sims
Journal: Circulation (2019)

Introduction: Obesity is a public health epidemic, with a US prevalence of 39.8%. African Americans (AAs) have an even greater prevalence of obesity (46.8%), when compared to non-Hispanic whites at (37.9%). Behavioral risk factors, such as poor diet and sedentary lifestyle, are important antecedents to obesity, but psychosocial risk factors such as stress and perceived discrimination are also determinants of obesity. Goal-striving stress, (GSS), the difference between aspiration and achievement, weighted by the level of disappointment if goals are not reached, may be an important stressor among AAs that may influence measures of adiposity; however, this has yet to be explored. The objective of this study was to examine the relationship between GSS and measures of adiposity in AAs. Hypothesis: GSS is positively associated with measures of adiposity, including BMI, waist circumference, waist-to-height ratio (WHR), and neck circumference. Methods: We analyzed data from the baseline exam of the Jackson Heart Study (JHS; n=5306), an AA sample of women and men, 35-84 years old. GSS was derived assessing the difference between aspiration for the following year and current achievement (both using a 10-point scale), weighted by a disappointment is achievement is not reached, using 4-point scale. GSS was then divided by the standard deviation (SD) (5.05) to create GSS-SD units. BMI was measured in kg/m 2 and waist and neck circumference was measured in cm. WHR was derived from waist circumference and height measured in cm. We excluded participants with missing data on GSS, measures of adiposity, and covariates. Spline regression analyses were used to obtain the coefficient. Models were adjusted for sex, age, socioeconomic status, alcohol, smoking, physical activity, nutrition, hypertension, diabetes, history of cardiovascular disease, and discrimination. Results: There were 4360 participants included in this analysis; 64.29% female with a mean (± SD) age of 55.47 (± 12.57) years and mean BMI of 31.85 (±7.20) kg/m 2 , mean waist circumference of 100.75 (±16.14) cm, mean WHR of 59.80% (± 9.78), and mean neck circumference of 38.53 (±3.76) cm. After full adjustment, significant results show a positive association of GSS with waist circumference (b=1.30; p=0.0418) and WHR (b=0.80; p=0.0299). GSS was not associated with BMI or neck circumference. Conclusion: GSS was positively associated with measures of adiposity, specifically waist circumference and WHR. Potential interventions should consider the extent to which GSS may contribute to increases in adiposity. Also, future research should explore the longitudinal associations of GSS with measures of adiposity.
Epidemiology of Lyme borreliosis through two surveillance systems: the national Sentinelles GP network and the national hospital discharge database, France, 2005 to 2016
Authors: A Septfons, T Goronflot, B Jaulhac, V Roussel, S De Martino, S Guerreiro, T Launay, L Fournier, H De Valk, J Figoni, T Blanchon, E Couturier
Journal: Eurosurveillance (2019)

Lyme borreliosis (LB) is the most frequent vector-borne disease in France. Since 2009, surveillance of LB is conducted by a sentinel network of general practitioners (GPs). This system, in conjunction with the national hospitalisation database was used to estimate the incidence and describe the characteristics of LB in France.To describe the estimated incidence and trends in GP consultations and hospital admissions for LB in France and identify risk groups and high-incidence regions.From 2011 to 2016, the mean yearly incidence rate of LB cases was 53 per 100,000 inhabitants (95% CI: 41-65) ranging from 41 in 2011 to 84 per 100 000 in 2016. A mean of 799 cases per year were hospitalised with LB associated diagnoses 2005-16. The hospitalisation incidence rate (HIR) ranged from 1.1 cases per 100,000 inhabitants in 2005 to 1.5 in 2011 with no statistically significant trend. We observed seasonality with a peak during the summer, important inter-regional variations and a bimodal age distribution in LB incidence and HIR with higher incidence between 5 and 9 year olds and those aged 60 years. Erythema migrans affected 633/667 (95%) of the patients at primary care level. Among hospitalised cases, the most common manifestation was neuroborreliosis 4,906/9,594 (51%).Public health strategies should focus on high-incidence age groups and regions during the months with the highest incidences and should emphasise prevention measures such as regular tick checks after exposure and prompt removal to avoid infection.
Reduction in primary pancreatic and metastatic tumor burden in the phase III MPACT trial of <i>nab</i>-paclitaxel (<i>nab</i>-P) plus gemcitabine (Gem) versus Gem alone.
Authors: Volker Kunzmann, Ramesh K. Ramanathan, David Goldstein, Darryl Neil Penenberg, Stefano Ferrara, Brian D. Lu, Daniel D. Von Hoff
Journal: Journal of Clinical Oncology (2015)

e15299 Background: nab-P + Gem was superior to Gem alone for treating metastatic pancreatic cancer (MPC) in the phase III MPACT trial for all endpoints examined, including overall response rate (ORR; 23% vs 7%; P < 0.001) and overall survival (updated analysis; median, 8.7 vs 6.6 months; HR 0.72; P < 0.001). This prespecified analysis examined the activity of nab-P + Gem vs Gem alone in pancreatic and nonpancreatic lesions. Methods: Previously untreated patients (pts) with MPC (N = 861) were randomized 1:1 to receive nab-P 125 mg/m2 + Gem 1000 mg/m2 days 1, 8, and 15 every 4 weeks or Gem alone 1000 mg/m2weekly for 7 weeks followed by 1 week of rest (cycle 1) and then days 1, 8, and 15 every 4 weeks (cycles ≥ 2). Most pts (99%) underwent spiral CT imaging, allowing precise tumor measurement. Changes in the sums of target lesion diameters from baseline to postbaseline nadir were evaluated separately for pancreatic and nonpancreatic lesions by independent review. Results: Baseline sizes of pancreatic and nonpancreatic tumors were comparable between treatment arms (Table). nab-P + Gem elicited an approximately 3-fold greater median percentage decrease than Gem alone in pancreatic (−22.15% vs. −7.02%) and nonpancreatic (−24.27% vs −8.74%) tumor burden, in agreement with the 3-fold higher ORR of target lesions by RECIST. Change in tumor burden also favored nab-P + Gem over Gem in pts with a ≥ 20% decrease in metabolic activity by positron emission tomography, ≥ 20% decrease in carbohydrate antigen 19-9 (CA19-9), or ≥ 3 cycles of therapy received (Table). Conclusions: nab-P + Gem was associated with a greater reduction in pancreatic and nonpancreatic tumor burden than Gem alone. ClinicalTrials.gov NCT00844649 Clinical trial information: NCT00844649.Change in tumor burden. Sum of Target Lesions Pancreatic Lesions Nonpancreatic Lesions nab-P + Gem n = 334 Gem n = 318 nab-P + Gem n = 328 Gem n = 326 Baseline, median, mm 50.75 49.50 85.00 86.25 Change at nadir, median, % −22.15 −7.02 -24.27 −8.74 With an FDG uptake decrease ≥ 20% n Median change, % 78 −26.53 60 −7.78 79 −30.97 65 −17.54 With a CA19-9 decrease ≥ 20% n Median change, % 212 −29.68 150 −15.93 208 −34.59 151 −27.27 With ≥ 3 cycles received n Median change, % 235 −29.63 177 −16.07 232 −35.50 183 −25.36
Long term survival with modified-increased FEP followed by chemo-radiation for locally advanced nasopharyngeal carcinoma.
Authors: Abdelhak Ouhajjou
Journal: Journal of Clinical Oncology (2015)

e17070 Background: To evaluate the experience of induction chemotherapy using modified increased doses FEP regimen (mid FEP) (Epirubicin, Cisplatin, 5-FU, and Leucovorin) followed by concurrent chemoradiation for nasopharyngeal carcinoma (NPC). Methods: Between August 1994 and December 2009, 72 patients with pathological proven nonmetastatic NPC were enrolled. Ninty five percent of patients were locally advanced (IIB – IVB). Patients were first treated with 3 cycles of induction chemotherapy with increased doses FEP regimen (mid FEP) .After induction chemotherapy, weekly cisplatin was administered concurrent with radiation. Radiation consisted of 65-70 Gy to the planning target volumes of the primary tumor and 45 -60 Gy to any positive nodal disease using 1,8 Gy per fraction Results: With a median follow-up of 96 months (Range, 5-190 months). After completion of induction chemotherapy, 46 evaluable patients (35%) achieved complete clinical response in regional nodes and nasopharynx. After completion of the whole treatment, small residual tumors were noted either at the primary site and / or neck with 26 % of patients, The complete response rate of the nodal area and primary location was 72 %. These residual tumors all showed complete regression upon follow-up after 3 months. The estimated 5-year PFS was 78% , The 5-year OS was 80 % and the estimated 8-year PFS was 67% , The 8-year OS was 73 % . The main grade 3 to 4 (G3/G4) adverse events during neoadjuvant chemotherapy were hematological Conclusions: Induction chemotherapy using modified increased doses FEP regimen (mid FEP) (Epirubicin, Cisplatin, 5-FU, and Leucovorin) followed by concurrent chemoradiation for locoregionally advanced NPC is feasible and effective in regard to locoregional control and distant metastasis with high compliance. A long-term follow-up study is needed to confirm these preliminary findings.
Nucleoporin Seh1 Interacts with Olig2/Brd7 to Promote Oligodendrocyte Differentiation and Myelination
Authors: Zhixiong Liu, Minbiao Yan, Yaoji Liang, Min Liu, Kun Zhang, Dandan Shao, Rencai Jiang, Li Li, Chaomeng Wang, Daniel R. Nussenzveig, Kunkun Zhang, Shaoxuan Chen, Chuanqi Zhong, Wei Mo, Beatriz M.A. Fontoura, Liang Zhang
Journal: Neuron (2019)
Impact of anemia in oropharyngeal cancer patients treated with concurrent chemoradiation.
Authors: Nicole Nolan, John C. Grecula, Dukagjin Blakaj, Virginia Maria Diavolitsis, Aashish D. Bhatt
Journal: Journal of Clinical Oncology (2015)

e17087 Background: Anemia prior to the start or during chemoradiation for squamous cell cancer of the head and neck has noted inferior outcomes. With the de-escalation of treatment in this group of patients due to favorable outcomes, we set out to look at anemia in oropharyngeal squamous cell cancer patients (OPSCC) treated with concurrent chemotherapy and intensity modulated radiation therapy(IMRT). Methods: We conducted a retrospective review of patients treated at Ohio State University with a diagnosis of OPSCC between 2010 and 2013. Both postoperative (range 6000-6600cGy, n = 27) and definitively (6996-7020cGy, n = 169) treated patients were included. All patients received chemotherapy, Cetuximab(n = 47) or Platinum-based (n = 149). Statistics utilizing univariate, multivariate(MVA) and Kaplan-Meier analyses were then preformed. Results: 196 patients were eligible, with a median age of 57 and median follow up of 26.7 months. Majority (85.2%) were male. Tumor site was tonsil (48%), base of tongue (49%), and other (3%). Stage III (8.7%), IVA (84.2%), and IVB (7.1%). p16 was positive in 86.7%. At last follow up, in 48 patients there were 25 loco-regional and 31 distant failures and 27 patients had died (13.8%). Two year OS, LRFS, DMFS and DFS were 89.2%, 88.3%, 84.1% and 76.6% respectively. Pretreatment anemia on univariate analysis found inferior OS (p = 0.023), DFS (p = 0.018) and DMFS (p = 0.021), and on MVA a trend to inferior DFS (p = 0.069). On MVA, the use of Cetuximab (p = 0.002), p16 negativity (p = 0.0001) and smoking (p = 0.035) were independent factors for inferior OS, while T3/T4 disease(p = 0.02) and use of Cetuximab (p = 0.0003) were associated with inferior DFS. Conclusions: In our cohort of patients, anemia does predict for inferior OS, DFS and DMFS. Other factors such as use of Cetuximab, p16 negativity and smoking also predicted for inferior OS. In the era of de-escalation of treatment, the presence of anemia and use of Cetuximab may be associated with inferior outcomes.