tbuckley/cabot-search huggingface dataset:
Hypofractionated radiation therapy in low-risk prostate cancer: Outcome, toxicity, and sexual function.
Authors: Luca Marinelli, Chiara Reverberi, Mattia Falchetto Osti, Vitaliana De Sanctis, Manuela Giuliani, Lidia Tronnolone, Maurizio Valeriani
Journal: Journal of Clinical Oncology (2017)

e16575 Background: To evaluate efficacy, toxicity of image-guided hypofractionated radiotherapy (HFRT) in patients with low-risk prostate cancer. Methods: Eighty-five low-risk prostate cancer patients (Gleason score ≤6, clinical stage T1/T2a-b N0 M0, and PSA ≤10 ng/mL) were treated with HFRT from March 2007 to November 2015. All patients were staged with multi-parametric contrast-enhanced MRI. Clinical target volume (CTV) encompassed prostate with proximal seminal vescicles. Margin from CTV to PTV was 5 mm in all directions. Patients received a total dose of 60 Gy in 20 fractions with 3D-CRT. Daily cone beam CT (IGRT) was executed. RTOG/EORTC morbidity Scoring Scale was used for evaluate toxicities. Results: Median follow-up was 54 months (range 11-116 months). The actuarial 8-years Overall Survival was 97.1%. Eight-years Cancer Specific Survival was 100%, 8-years Biochemical Relapse Free Survival was 98.8%, no patients presented clinical local recurrence. Median of PSA at diagnosis was 3.27 ng/mL (range 1.69-9.98 ng/mL) and at the last follow-up was 0.39 ng/mL (range 0.01-2.26 ng/mL). Acute grade 1-2 gastrointestinal (GI) toxicity occurred in 13 patients (15.3%), grade 1-2 genitourinary (GU) toxicity in 33 cases (38.8%). Grade 3 GU toxicity occurred in 2 patients (2.4%). Grade 1-2 GI and GU late toxicities were observed in 4 (4.7 %) and 25 (29.4 %) patients, respectively. Sexual functionality was qualitatively evaluated, scoring 0 for absence, 1 for presence of erection but insufficient for intercourse, 2 for a sufficient one. Before RT, 4.7 % had score 0, 47.1% had score 1 and 48.2% had score 2. After RT, 34.1% of patients presented score 0, 51.8% score 1 and 14.1% score 2 (Chi-square p = 0,004). After treatment, patients with &lt; 70 years presented score 0 in 4.7% of patients, score 1 in 20% and score 2 in 8.2%. Those with &gt; 70 years, 29.4% presented score 0, 31.8% score 1 and 5.9% score 2 (Chi square p = 0.011). Conclusions: Long-term results of our study demonstrated that HFRT in low-risk prostate cancer is efficacy and well tolerated. HFRT significantly worsened sexual function, even if patients with age &lt; 70 years had a higher probability to maintain any form of sexual function after therapy.
Phase 1-2 study of progesterone receptor (PR) inhibition with extended-release (ER) onapristone (ONA) alone or in combination with abiraterone (AA) in patients (pts) with castration-resistant prostate cancer (CRPC) incorporating plasma DNA analysis to define androgen receptor (AR) status.
Authors: Anuradha Jayaram, Karolina Nowakowska, Joaquin Mateo, Sanjeev Kumar, Tatiana Hernandez, Ben Fulton, Daniel Nava Rodrigues, Ruth Riisnaes, Alexander Zukiwski, Alice Susannah Bexon, Stefan Proniuk, Charles Barranco, Diletta Bianchini, Zafeiris Zafeirou, Raquel Perez Lopez, Nina Tunariu, Simon Pacey, Robert J. Jones, Johann S. De Bono, Gerhardt Attard
Journal: Journal of Clinical Oncology (2017)

5071 Background: An urgent need exists for new therapies after progression (PD) onAA and enzalutamide (ENZ). Increased PR expression or progesterone-activating AR mutations have been associated with resistance to AR targeting. We aimed to test ONA, a type I PR antagonist with clinical activity in PR pos cancers, in AA/enz-resistant CRPC. In a prospectively defined exploratory analysis, we aimed to report outcome by plasma AR status ( pAR). Methods: This was a multi-institution, open label phase I/II clinical trial in pts progressing after ENZ/AA. Pts were first treated with single agent (SA) ONA using a randomised dose escalation design. ONA at 2 doses was then combined with AA (1000mg od with pred 5mg bid) in pts progressing on AA. The primary end-points were safety, pharmacokinetics (PK) and anti-tumor activity split by p AR. Archival and metastatic biopsies were collected when possible and tested for PR status. p AR was studied using previous methods (Romanel STM 2015). Results: 21 pts received SA ONA (5 = 10mg/ 5 = 20mg/ 4 = 30mg/ 4 = 40mg /3 = 50mg BID) and 15 pts received ONA-AA combination (5 = 30mg ONA BID, 10 = 50mg ONA BID). There were not DLTs or significant LFT abnormalities and no G3/4 adverse events (AE), no treatment discontinuations due to AEs and no SAEs considered related to ONA. PK in SA ONA observed active plasma concentrations and no interaction with AA. Of 32 evaluated pts 15 had a 2105T &gt; A (p.L702H) or 2632A &gt; G (p.T878A) AR mutation detected in plasma pre-treatment and 1 had AR copy number gain. PSA declines were not observed with SA ONA but in 2 pts with combination (-30%, -7%) who were AR normal. The rPFS on SA ONA was 2.8 months for AR normal and 2.6 for AR aberrant (Hazard ratio (HR) 1.41; 95% CI, 0.62-3.72; P 0.48) and on combination was 4.4 months for AR normal (8/15) and 2.2 for AR aberrant (7/15) (HR 6.08; 95%CI, 6.32-221.9; P &lt; 0.001). Conclusions: ONA is safe in CRPC as SA and in combination with AA. There was no difference in rPFS by p AR status for SA ONA but on the combination with AA, pts who were plasma AR normal had a significantly longer rPFS. Clinical trial information: NCT02049190.
To Cycle or Fight—CDK4/6 Inhibitors at the Crossroads of Anticancer Immunity
Authors: Malaka Ameratunga, Emma Kipps, Alicia F.C. Okines, Juanita S. Lopez
Journal: Clinical Cancer Research (2018)

Abstract Dysregulation of cell division resulting in aberrant cell proliferation is a key hallmark of cancer, making it a rational and important target for innovative anticancer drug development. Three selective cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are FDA and European Medicines Agency (EMA) approved for hormone receptor–positive/HER2-negative advanced breast cancer. A major emerging appreciation is that these inhibitors not only are cytostatic, but also play critical roles in the interaction between tumor cells and the host immune response. However, to trigger an effective immune response, lymphocytes must also proliferate. This review aims to assimilate our emerging understanding on the role of CDK4/6 inhibitors in cell-cycle control, as well as their biological effect on T cells and other key immune cells, and the confluence of preclinical evidence of augmentation of anticancer immunity by these drugs. We aim to provide a framework for understanding the role of the cell cycle in anticancer immunity, discussing ongoing clinical trials evaluating this concept and challenges for developing rational combinations with immunotherapy.
Contrast enhancement as a prognostic factor in IDH1/2 mutant glioma.
Authors: Bogdana Suchorska, Ulrich Schüller, Annamaria Biczok, Friedrich Wilhelm Kreth, Markus Lenski, Nathalie Lisa Albert, Armin Giese, Birgit Ertl-Wagner, Michael Ingrisch, Joerg Tonn
Journal: Journal of Clinical Oncology (2018)

2029 Background: Mutational status of the IDH1/2 gene and co-deletion of on chromosome 1p/19q (co-del 1p/19q) is gaining further relevance for the evaluation of clinical outcome in lower grade glioma. Out of the established clinical and imaging parameters known to influence survival in these tumors, contrast enhancement (CE) has been reported to indicate poor outcome in the past. The present study aimed at re-assessing the value of clinical and imaging parameters in lower grade glioma within the framework of molecular markers using a machine learning approach (random survival forests, RSF) as well as conventional Cox regression modeling. Methods: 301 patients with grade II (n = 181) or grade III diffuse glioma (n = 120) were stratified according to their molecular profile (presence of IDH1/2 mutation and/or co-deletion 1p/19q.) Preoperative magnetic resonance (MR) imaging was reviewed and volumetrical analyses of CE and T2 volumes were performed. Multivariate cox models and RSF were trained on this data set using five-fold cross validation to assess the predictive value of pre-therapeutic molecular and imaging factors as well as age, Karnofsky performance status, surgical procedure and adjuvant therapy to predict the individual risk for each patient. As a measure of prediction accuracy, the concordance indices for Cox and RSF models were determined. Results: RSF modeling revealed presence of IDH1/2 mutation, co-deletion 1p/19q and WHO II to be the most relevant factors for favorable outcome in lower grade glioma. In IDH1/2 mutant tumors, both conventional Cox regression modeling and RSF analyses show that CE on initial MR imaging is a prognostic factor for survival independently of its magnitude in both co-deleted and non-co-deleted tumors (p < 0.05). In contrast, presence of CE on initial MRI is not associated with outcome in IDH1/2 wildtype tumors. Likewise, the RSF model identified predictive influence of CE in the IDH1/2 mutant tumors only. Conclusions: In patients with diffuse IDH1/2 wildtype gliomas WHO grade II/III, CE is not associated with survival. In tumors with an IDH1/2 mutation, presence of CE on initial MRI is linked to inferior survival.
Fear of recurrence as a triage strategy to identify testicular cancer survivors in need of psychological interventions.
Authors: Hector De La Mora, Claudia López, Brenda Jimenez, Patricia Sánchez, Christianne Bourlon, Jose Dionisio Castillo, Maria Teresa Bourlon
Journal: Journal of Clinical Oncology (2018)

e22110 Background: Testicular cancer survivors (TCS) can experience long-term psychological sequel. Physicians are poorly trained to inquire about psychological problems and there is a limited availability of mental health practitioners. Clinicians need a strategy to help them identify those TCS who will profit the most from a psychological intervention. Fear of recurrence (FOR) does not disappear over time and might be an indicator of functional impairment. Our aim was to evaluate FOR as a strategy to identify TCS in need of a psycho-oncologic intervention. Methods: FOR (defined as score ³13) was evaluated in our TCS cohort with the Spanish version of the Cancer Worry Scale (CWS), Quality of Life (QoL) and anxiety were assessed with: EORTC QoL Questionnaire (QLQ-C-30), testicular specific QoL Questionnaire QLQ-TC26, Trait-State Anxiety Inventory (STAI). The associations of clinical and demographic characteristics, diminished QoL and higher levels of anxiety with FOR were identified via multiple logistic regression analysis. Results: A total of 40 TCS were included. Their median age was 28 (±7.3) yo, median DFS was 19 mo. FOR was found in 37.5% (n = 15). In the univariate analysis, FOR was not significantly associated with any clinical variables such as disease burden, provided treatment, or time on surveillance. FOR was associated with poor QoL; global health status (p= .04), functional scales (p= .004), symptom scales (p= .035), and increased state anxiety (p = 0.001) and trait anxiety (p= 0.008). In the multivariate analysis, state anxiety (p= .01) and low QoL as functional scale (p = .002) were independently associated with a clinically significant level of FOR. Conclusions: FOR identifies those individuals with functional impairment (decreased QoL and increased anxiety) and can help providers select those who may profit the most from a psychological intervention. Additionally, the CWS is an easy to use and not time consuming strategy that could be integrated as routine practice of survivorship clinics to triage TCS for psycho-oncology referral.
Use of Long-term Cumulative Blood Pressure in Cardiovascular Risk Prediction Models
Authors: Lindsay R. Pool, Hongyan Ning, John Wilkins, Donald M. Lloyd-Jones, Norrina B. Allen
Journal: JAMA Cardiology (2018)

Long-term cumulative systolic blood pressure (SBP) is significantly associated with increased rates of atherosclerotic cardiovascular disease (ASCVD) development independent of single SBP levels. However, published ASCVD risk prediction algorithms only include currently measured SBP.To determine whether including long-term (5- and 10-year) cumulative SBP in risk equations improves the predictive ability compared with single SBP measurements.Adults aged 45 to 65 years at the time of risk estimation with at least 20 years of follow-up (5 and 10 years prior to risk estimation and 10 years of event follow-up). The Lifetime Risk Pooling Project included data from the following cohorts: Coronary Artery Risk Development in Young Adults Study, Atherosclerosis Risk in Communities Study, and Framingham Heart Study (both the original and offspring).Ten-year ASCVD risk, calculated using the approach of the 2013 American College of Cardiology/American Heart Association 10-year ASCVD risk equations, first with current SBP and then substituting 5- and 10-year cumulative SBP levels.Incident ASCVD events that occurred over 10 years of follow-up, compared with the predicted risks, using the C statistic, net reclassification index at event rate, and the integrated discrimination index.This study included 11 767 participants with a mean (SD) age of 59.1 (4.7) years at risk estimation. A total of 6873 participants (58%) were women, and 1499 (13%) were African American. In the 10 years of follow-up from risk estimation, 1887 participants (16%) had an ASCVD event. There were no significant improvements in the C statistic when including 5- or 10-year cumulative SBP. However, the addition of cumulative SBP resulted in significant improvements in the net reclassification index at event rate (10-year net reclassification index for men, 0.04 [95% CI, 0.02-0.06]; 10-year net reclassification index for women, 0.03 [95% CI, 0.01-0.06]) and the relative integrated discrimination index (10-year relative integrated discrimination index for men, 0.12; 10-year relative integrated discrimination index for women, 0.10).Using long-term measures of cumulative blood pressure, instead of single measurements, can modestly improve the ability of cardiovascular disease risk prediction models to correctly classify individuals in terms of their risk for cardiovascular disease.
Cancer stem cells in colorectal tumors of various extents.
Authors: Elena Yurievna Zlatnik, Oleg Ivanovich Kit, Inna Arnoldovna Novikova, Elena Petrovna Ulianova, Oksana G. Shulgina, Pavel B. Shulikov, Anton G. Milakin, Sergey Poluektov, Dmitry O. Kaymakchi, Fedor N. Grechkin
Journal: Journal of Clinical Oncology (2018)

e15659 Background: The purpose of the study was to assess an association between the tumor invasion and levels of cancer stem cells (CD44+ and CD133+) in colorectal cancer. Methods: The study included colorectal tumor tissues obtained from 60 patients (31 women and 29 men aged 37-78 years). Group 1: 30 patients without distant metastases (T2-4N0M0 n = 21, T3-4N1M0 n = 9), group 2: 30 patients with liver metastases (T3-4aN0M1 n = 8, T3-4аN1-2M1 n = 22). CD44 and CD133 expression on tumor cells was determined by immunohistochemistry. Staining was performed using monoclonal mouse antibodies to CD44 and polyclonal rabbit antibodies to CD133 using the Thermo Scientific autostainer. Membrane staining of ≥10% of tumor cells was evaluated, as well as the staining intensity. Results: We revealed some differences in the expression of the markers. The CD44 expression was found 1.3 times more often in group 1 compared to group 2; significant differences in mean CD44+ values were not found. Comparison of the CD44 expression in the primary tumor and metastases demonstrated lower rates of the positive CD44+ expression in metastatic lymph nodes in group 1 (by 1.7 times) and in liver metastases (by 4.5 times) compared to the primary tumor. The positive CD133+ expression in group 2 exceeded the value in group 1 by 1.4 times; significant differences in mean positive CD133+ values were not found, but the values in group 2 exceeded that in group 1 by 1.6 times. Statistically significant differences in the mean CD133 expression were observed between tumors with minimal (T2-4N0M0) and maximal (T3-4aN1-2M1) invasion, prevailing in the latter (6.3±3.6% vs. 16.7±3.4%, respectively, p≤0.05). An increased CD133 expression was found in liver metastases compared to the primary tumor (by 1.2 times), while in metastatic lymph nodes the level was unchanged. Conclusions: A larger tumor extent in colorectal cancer was associated with decreased CD44 and increased CD133 expression; the latter marker was more often detected in tumors with distant metastases and in metastatic foci.
Abstract P342: Disparities in Awareness of Stroke Symptoms Among Different Socioeconomic, Ethnic/Race, and At-risk-of-stroke Groups
Authors: Phoebe Tran
Journal: Circulation (2017)

Findings from a few small studies suggested that disparities in awareness of stroke symptoms lead to disparities in delays of receiving treatment and outcomes of patients with stroke. Hence it is important to conduct a study with a large sample size to understand the associations between awareness of symptoms of stroke with various socioeconomic factors as well as with modifiable stroke risk factors. We assessed the hypotheses that there are disparities in awareness of different stroke symptoms among different groups with respect to various SES factors (e.g., self-reported race, ethnicity, education, age, and income) in the presence/absence of modifiable stroke risk factors (e.g., smoking status, exercise, body mass index, and blood pressure). We combined four Behavioral Risk Factor Surveillance Surveys (BRFSS) from 2003, 2005, 2007, and 2009 to create a sample of 1,051,834 participants. We ran six logistic regression models, one for each of the measures of awareness of six common stroke symptoms (e.g., sudden confusion, numbness on one side of the body, sudden vision loss, sudden chest pain, sudden dizziness, and severe unexplained headache). The unweighted sample size in each of the six models was greater than 120,000. In addition, we calculated marginal probabilities which give the probability of an outcome (e.g., being aware of a specific stroke symptom) with respect to a specific factor (e.g., in the presence/absence of a stroke risk factor) in the context of averaging over all other factors/covariates. While there was low awareness of stroke symptoms among the US population except for recognition of chest pain or discomfort, we did find an association between the awareness of stroke symptoms with gender, educational levels, and income levels. Additionally, among all the ethnic groups, Native Americans had the lowest awareness of five out of six stroke symptoms. On the other hand, White only-non Hispanic, while being relatively better aware of several stroke symptoms, had the lowest awareness of the most common stroke symptom of sudden chest pain compared with other race/ethnicity groups. In conclusion, the findings from this study can serve as a useful guide to facilitating targeted educational efforts aimed at improving awareness of stroke symptoms that may ultimately reduce disparities in the outcomes of patients at risk for stroke.
Analysis of weight trends over time in female breast cancer survivors.
Authors: Damien Mikael Hansra, Rebecca Rollins, Karen Rados, Anita Johnson, Johnathan Ramey, Rachel Panell, Cynthia Daniels, Cynthia Hogeland, Mary Ninan, John Edward McKnight, Robert Sean Hauser, Ricardo H. Alvarez
Journal: Journal of Clinical Oncology (2018)

e12577 Background: Studies have shown obesity to be risk factor for many breast cancer (BC) subtypes, particularly in ER+ postmenopausal BC. Patients (pts) with BC and overweight/obesity have a worse prognosis. Here we investigate body mass index (BMI) and weight trends among BC survivors. Methods: A retrospective review of a BC research database at Cancer Treatment Centers of America Atlanta from 2012-12/29/17. Definition of a survivor: pts who completed definitive therapy with no evidence of disease. Survivor BMI & weight gain (kg) calculated from chart review. Weight change (Δ) in kg was recorded at baseline +/- post chemotherapy (CH) +/- endocrine therapy (ET), at 3, 6, 9, 12 month (mo) follow up (f/u). Patients who did not receive CH or ET not included in long term f/u analysis. Inclusion: BC pts ≥ 18 yo, all subgroups (ER+/-, PR+/-, HER2+/-), stage 0-IIIC, pts who completed surgery +/- CH +/- ET. Exclusion: Pts who died, had relapsed local or metastatic disease; missing BMI data; pts enrolled in clinical trials; missing continuous BMI data or pathology report; lost to follow up ≥ 12 months. One sample t-test with two tailed p value was used to analyze results using Graphpad software: https://www.graphpad.com. Results: N = 1756 charts of BC pts with stage 0-IIIC reviewed; 1051 pts excluded with 705 pts meeting full study criteria. Average age of survivors = 52 yo (range 25-83). Race: 48.5% black, 48% white, 2.5% other. 59% pts received CH, 65% pts received ET. Average initial BMI for all survivors = 31 kg/m2 (16-53 kg/m2); post CH weight Δ = -0.03 kg (-0.47- 0.41 ) p = 0.9023; at 3 mo f/u = 0.04 kg (-0.32- 0.40) p = 0.8290; at 6 mo f/u = 0.42 kg (0.03-0.81) p = 0.0359; at 9 mo f/u = 1.21 kg (0.77-1.66 ) p < 0.0001; at 12 mo f/u = 1.77 kg (1.25-2.29 ) p < 0.0001. Post ET weight Δ at 3 mo f/u = 0.16 kg (-0.24- 0.56) p = 0.4232; at 6 mo f/u = 0.59 kg (0.15-1.02 ) p = 0.0079; at 9 mo f/u = 1.26 kg (0.75-1.77 ) p < 0.0001; at 12 mo f/u = 1.69 kg (1.08-2.30 ) p < 0.0001. Detailed clinical & demographic information, subset analyses (ER, PR, HER2, race, & menopause status) upon presentation. Conclusions: In our study, female survivors present with obesity. Patients who receive chemotherapy gain significant weight at 6, 9, 12 months. Patients who receive endocrine therapy gain significant weight at 6, 9, 12 months.
Elagolix: First Global Approval
Authors: Yvette N. Lamb
Journal: Drugs (2018)

Elagolix (ORILISSA™), an orally bioavailable, second-generation, non-peptide gonadotropin-releasing hormone (GnRH) receptor antagonist, is being developed AbbVie and Neurocrine Biosciences for the treatment of reproductive hormone-dependent disorders in women. In July 2018, the US FDA approved elagolix tablets for the management of moderate to severe pain associated with endometriosis. This approval was based on positive results in two replicate phase III trials; additional phase III trials in the USA, Canada and Puerto Rico are currently evaluating elagolix as both monotherapy and in combination with low-dose hormone add-back therapy in the same indication. Elagolix with and without low-dose hormone add-back therapy is also undergoing phase III clinical development for heavy menstrual bleeding associated with uterine fibroids in the aforementioned locations. This article summarizes the milestones in the development of elagolix leading to its first approval for the management of moderate to severe pain associated with endometriosis.