bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factors Associated With a Delay in Achieving Full Knee Extension Before Anterior Cruciate Ligament Reconstruction
Authors: Gage Andrew , Kluczynski Melissa A. , Bisson Leslie J. , Marzo John M. 
Published: March 2019

Background: Arthrofibrosis commonly occurs after an acute anterior cruciate ligament (ACL) injury and following ACL reconstruction and can lead to poor outcomes. Preoperative stiffness has been shown to be associated with postoperative stiffness; however, few studies have examined predictors of preoperative delay in obtaining full knee extension. Purpose: To examine demographic and injury factors as predictors of time required to achieve full knee extension preoperatively in patients with an acute ACL injury. Study Design: Case-control study; Level of evidence, 3. Methods: A total of 172 patients with an acute ACL tear at presentation (defined as ≤3 weeks from injury) who underwent magnetic resonance imaging (MRI) within 6 weeks of the injury were included in this analysis. Preoperative data included date of injury, age at injury, sex, body mass index, mechanism of injury (noncontact/contact), time from injury to surgery (days), time to achieve full extension prior to surgery (weeks), and bone bruising on MRI. Time to achieve full extension was categorized as <3 or ≥3 weeks. Unadjusted and adjusted logistic regression was used to examine predictors of delayed time to achieve full extension (≥3 vs <3 weeks). Odds ratios and 95% CIs were reported. Results: Time to achieve full extension was early (<3 weeks) in 98 patients and delayed (≥3 weeks) in 74 patients. The average time to achieve full extension was 7 days in the early group and 32.5 days in the delayed group. Delayed time to achieve full extension was associated with increased lateral femoral condyle (LFC) bruising compared with early time to achieve extension (82.8% vs 66.7%, respectively; P = .03). No other statistically significant predictors were found after adjustment for age, sex, body mass index, and mechanism of injury. Conclusion: Acute ACL injuries associated with LFC bone bruising seen on MRI are more likely to result in reduced extension prior to ACL reconstruction. These injuries should be identified and addressed by an appropriate preoperative rehabilitation program, and surgery should be delayed to avoid risking arthrofibrosis postoperatively by reconstructing a knee with less than full extension.
Patient-reported distress can aid clinical decision-making in idiopathic pulmonary fibrosis: analysis of the PROFILE cohort
Authors: Stewart Iain , McKeever Tricia , Braybrooke Rebecca , Oballa Eunice , Simpson Juliet K. , Maher Toby M. , Marshall Richard P. , Lukey Pauline T. , Fahy William A. , Jenkins Gisli , Saini Gauri 
Published: March 2019

Idiopathic pulmonary fibrosis is a progressive and fatal interstitial lung disease. We aimed to determine if patient response to a palliative assessment survey could predict disease progression or death.We undertook a cross-sectional study in a UK clinical cohort of incident cases. Rasch-based methodology provided a disease distress value from an abridged 11-item model of the original 45-item survey. Distress values were compared with measures of lung function. Disease progression or mortality alone was predicted at 12 months from survey completion, with risk of death assessed at 3, 6 and 12 months.Disease distress values were negatively correlated with lung function (r=−0.275 for the percentage predicted diffusing capacity of the lung for carbon monoxide). Expected survey scores computed from distress values could distinguish disease progression (n=8.8, p=0.004) and death (n=10.2, p=0.002) from no disease progression (n=6.9). Actual survey scores predicted disease progression and death with an area under the curve of 0.60 and 0.64, respectively. Each point increment in actual score increased risk of 12-month mortality by 10%; almost 43% of people scoring above 18 did not survive beyond 105 days.We define a short questionnaire that can score disease distress and predict prognosis, thus assisting clinical decision-making in progressive fibrosis.
The management of post-traumatic stress disorder and associated pain and sleep disturbance in refugees
Authors: Lies July , Jones Lester , Ho Roger 
Published: March 2019

SUMMARYMore than 68 million people worldwide have been forcibly displaced and one-third of these are refugees. This article offers an overview of the current literature and reviews the epidemiology and evidence-based psychological and pharmacological management of post-traumatic stress disorder (PTSD), sleep disturbance and pain in refugees and asylum seekers. It also considers the relationship between sleep disturbance and PTSD and explores concepts of pain in relation to physical and psychological trauma and distress. During diagnosis, clinicians must be aware of ethnic variation in the somatic expression of distress. Treatments for PTSD, pain and sleep disturbance among refugees and asylum seekers are essentially the same as those used in the general population, but treatment strategies must allow for cultural and contextual factors, including language barriers, loss of freedom and threat of repatriation.LEARNING OBJECTIVESAfter reading this article you will be able to:•recognise the challenges faced by the large number of refugees worldwide•understand the relationship between PTSD, sleep disturbance and pain in refugees•broadly understand the evidence for psychological and pharmacological therapy for treating PTSD, sleep disturbance and pain in refugees.DECLARATION OF INTERESTNone.
ARAMIS: Efficacy and safety of darolutamide in nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Fizazi Karim , Shore Neal D. , Tammela Teuvo , Ulys Albertas , Vjaters Egils , Polyakov Sergey , Jievaltas Mindaugas , Luz Murilo , Alekseev Boris Y. , Kuss Iris , Kappeler Christian , Snapir Amir , Sarapohja Toni , Smith Matthew Raymond 
Published: March 2019

140 Background: Delaying metastases for nmCRPC patients, while minimizing the risk of adverse events, is an important treatment goal. Darolutamide, a structurally unique androgen receptor (AR) antagonist, is being evaluated for the treatment of advanced prostate cancer. The ARAMIS trial studied the efficacy and safety of darolutamide in nmCRPC patients. Methods: This double-blind, placebo-controlled phase III trial randomized nmCRPC patients in a 2:1 ratio to receive darolutamide 600 mg (two 300 mg tablets) twice-daily or placebo, while continuing androgen deprivation therapy. Patients were stratified by prostate-specific antigen doubling time (≤6 months or >6 months) and use of osteoclast-targeted therapy. The primary endpoint was metastasis-free survival (MFS), with independent central review of radiographic imaging every 16 weeks. Secondary endpoints include overall survival (OS), times to pain progression (assessed by Brief Pain Inventory), first cytotoxic chemotherapy and first symptomatic skeletal event, as well as safety profile. Results: In total, 1,509 patients were randomized (955 to darolutamide, 554 to placebo). Median MFS was 40.4 months with darolutamide vs 18.4 months with placebo (hazard ratio [HR] 0.41; 95% confidence interval [CI] 0.34–0.50; 2-sided p<0.0001). OS showed a trend in favor of darolutamide (HR 0.71, 95% CI 0.50–0.99, 2-sided p=0.045), as did time to pain progression (HR 0.65; 95% CI 0.53–0.79; 2-sided p<0.0001). Other secondary and exploratory efficacy endpoints also favored darolutamide. Incidences of treatment-emergent adverse events (AEs) with ≥5% frequency or grade 3–5 were comparable between darolutamide and placebo arms; none except fatigue occurred in >10%. Discontinuation rates due to AEs were 8.9% with darolutamide and 8.7% with placebo. Grouped terms for AEs noted with other AR inhibitors (including fracture, falls, seizures, weight decrease, hypertension, and cognitive disorder) showed minimal or no difference in incidence between study arms. Conclusion: Among men with nmCRPC, MFS was significantly longer with darolutamide than with placebo with a low incidence of treatment-related AEs in this asymptomatic patient population. Clinical trial information: NCT02200614.
Cost-effectiveness of metastasis-directed therapy in the setting of oligometastatic hormone-sensitive prostate cancer.
Authors: Parikh Neil Rohit , Nickols Nicholas George , Rettig Matthew , King Christopher R. , Raldow Ann C. , Steinberg Michael L. , Tran Phuoc T. , Kishan Amar Upadhyaya 
Published: March 2019

147 Background: Androgen deprivation therapy (ADT) has historically been used as the backbone of treatment in patients with newly-diagnosed hormone-sensitive metastatic prostate cancer. However, recent literature has suggested the potential utility of metastasis-directed therapy (MDT) in a subset of patients with oligometastatic prostate cancer (OPC), potentially allowing for ADT-free survival. Methods: A cost-effectiveness analysis was performed comparing (1) ADT upfront versus (2) MDT followed by salvage ADT in patients with asymptomatic hormone-sensitive OPC. MDT was delivered via stereotactic body radiation therapy (SBRT) over 3 fractions. ADT consisted of Lupron injections every 3 months. Costs were calculated from a payor’s perspective based on Medicare CPT codes, CLAB fee schedule, and ASP drug prices. ADT-free survival was modeled based on results from STOMP trial; costs of retreatment were not considered in the MDT arm. Based on prior literature, health utility was assumed to be 0.9 without ADT, and 0.82 with ADT. Given paucity of long-term data on survival effect of MDT with delayed ADT, both arms were assumed to have identical long-term disease transition state probabilities. Results: Total cost of ADT upfront vs. MDT + salvage ADT was $3,430 vs. $9,434 at 1 year, and $10,289 vs. $13,806 at 3 years. Compared to ADT alone, MDT + salvage ADT showed improvements in quality-adjusted life years (QALYs) of 0.07 and 0.15 at 1 and 3 years respectively, translating to incremental cost-effectiveness ratio (ICER) of $85,385/QALY at 1 year and $24,118/QALY at 3 years. Conclusions: Using a willingness-to-pay ICER threshold of $100,000/QALY, MDT with SBRT is shown to be a cost-effective option compared to ADT alone in patients with OPC, particularly when utilizing a longer follow-up time period.
Outcomes of the miltuximab first in human trial and proposed study design for a phase I trial 89Zr/177Lu theranostic trial.
Authors: Campbell Douglas , Sabanathan Dhanusha , Gurney Howard , Gillatt David , Trifunovic Marko , Poursoultan Pirooz , Ho Shon Kevin , Mackay Tiffany , Bailey Dale L , Roach Paul , Walsh Brad 
Published: March 2019

261 Background: Miltuximab is a chimeric antibody targeting Glypican-1 which is overexpressed in prostate cancer. Miltuximab has shown promising safety and efficacy in radioimmunotherapy models of prostate cancer. Methods: Metastatic patients (prostate, pancreatic and bladder) were dosed with unlabelled Miltuximabfollowed by the infusion of 1 mg/250MBq 67Ga-Miltuximab. Patients underwent whole body gamma and SPECT/CT scans up to 144 hours post-infusion. Standard of care imaging was performed at least 14 days before and after participation. Safety was evaluated by an external monitoring committee. Total organ exposure was determined by dosimetry of whole-body gamma scans. Antibody pharmacokinetics were also determined. Results: 12 patients were enrolled into the trial. Miltuximabwas well tolerated and did not elicit any drug-related adverse reactions. Liver and spleen uptake of 67Ga-Miltuximabwas observed from 30 min to 72 hours post dose. Pre-infusion of unlabelled Miltuximab resulted in reduced liver accumulation and increased distribution in the rest of the body. Miltuximab targeting to sites of active progressive disease was observed in certain prostate cancer patients who had failed enzalutamide treatment. Dosimetry analysis combined with antibody pharmacokinetic data was used to establish safe dose limits for a Phase 1 study. Conclusions: This study is the first in human for Miltuximaband demonstrates its potential for further clinical evaluation as a theranostic in prostate cancers and formed the basis for a Phase I imaging and therapy study planned for 2019. This study will use 89Zr-labelled Miltuximab to screen eligible patients and confirm tumour localisation, followed by treatment with 177Lu-labelled Miltuximab. Clinical trial information: ACTRN12616000787482.
PEAX: Men with metastatic castrate-resistant prostate cancer (mCRPC) treated with either sipuleucel-T (SIP-T), enzalutamide (ENZA) or abiraterone acetate (ABI) undergoing cardiopulmonary exercise testing (CPET).
Authors: Harrison Michael Roger , Khouri Michel , Armstrong Andrew J. , Zhang Tian , McNamara Megan Ann , Anand Monika , Bratt Ellen , Hood Hillary , Coyne Brian , Wu Yuan , Healy Patrick , George Daniel J. 
Published: March 2019

281 Background: Both ENZA and ABI are associated with significant toxicity to the cardiovascular-musculoskeletal system and physical side effects. However whether they cause a decline in cardiorespiratory fitness (CRF), as conventional ADT does, has not been studied. We hypothesized that men treated with ENZA or ABI would have a significant decline in CRF, whereas those treated with SIP-T would not. Methods: Men starting standard of care (SOC) ENZA or ABI for asymptomatic or minimally symptomatic mCRPC were treated per institutional standards. SIP-T (SOC) is the control arm. Primary endpoint is change in VO2peak from baseline to week 21 by CPET. Secondary endpoints include measurement of functional status by patient reported outcomes (FACT-P, FACIT-Fatigue) and physician reported outcomes (ECOG PS, AEs). Results: In this single-site, prospective, parallel group, observational study, 28 pts completed the baseline and week 21 CPET and secondary assessments. Median age was 68 years; 86% were white. Two-thirds of pts had ECOG PS 0; the rest had PS 1. 93% were nonsmokers. Intention to treat analyses for mean 21-week change from baseline with a 95% confidence interval (CI) for each assessment by arm are presented in the Table. Conclusions: Unexpectedly, there was great heterogeneity in 21-week ΔVO2peak within each therapy group. Reasons for heterogeneity will be explored and correlated with baseline variables, clinical status, and questionnaire data. A low percentage of patients exercised regularly. Larger trials of exercise training interventions in this setting are warranted. Clinical trial information: NCT02353715. [Table: see text]
ATM mutation is associated with shorter overall survival in relapsed/advanced urothelial cancer.
Authors: Yin Ming , Grivas Petros , Mortazavi Amir , Monk Paul , Emamekhoo Hamid , Holder Sheldon L. , Drabick Joseph J. , Pal Sumanta K. , Woo Michele Sue-Ann , Dexter Jin , Vasekar Monali K. , Joshi Monika 
Published: March 2019

370 Background: Somatic mutations of ATM are frequently found in UC and have been associated with a better response to cisplatin-based neoadjuvant chemotherapy. However, we previously showed ATM mutations were associated with a short survival in UC (PMID: 29682192 ). In this study, we focused on prognostic values of mutations in ATM in tumors of patients with relapsed or advanced (TxN2-3M0-1) UC through three independent datasets. Methods: 81 UC pts who underwent FoundationOne genomic sequencing (315 cancer-related genes) were used as a discovery dataset. Results were then validated in additional 91 pts with UC who received FoundationOne test (collected separately) and 129 relapsed/advanced UC patients selected from 412 TCGA bladder cohort. Fisher Exact test was used to determine difference of ATM mutation rates. Logistic regression analysis was performed to calculate odds ratio (OR) and 95% confidence interval (CI). Overall survival (OS) was measured from time of initial diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% CI. Results: The median ages of the 3 cohorts were 65 (44–84), 65 (21–91) and 67 (45–-90). The majority of pts were Caucasians (86.4%, 75.8% and 81.4%) and ever smokers (77.8%, 67% and 76.7%). ATM mutations were present in 14.8% (12/81), 11% (10/91) and 6.2% (8/129) of the three cohorts (Fisher Exact, p = 0.118). In all three groups of pts, ATM mutations consistently correlated with a significantly shorter OS (Discovery: HR = 2.25, 95% CI, 1.03–4.89, p = 0.041; Validation 1: HR = 3.15, 95% CI, 1.17–8.44, p = 0.023; and Validation 2: HR = 2.17, 95% CI, 0.99–4.75, p = 0.051). In 144 pts treated with cisplatin or carboplatin pooled from the three cohorts, ATM mutations correlated with a non-significantly higher objective response rate (OR = 1.54, 95% CI 0.44–5.35, p = 0.5), but were still associated with a poorer survival (HR = 1.95, 95% CI 1.00–3.83, p = 0.05). Conclusions: These results suggest that ATM mutations may be considered as a negative prognostic biomarker in relapsed/advanced UC pts. Further studies are required to determine the underlying mechanisms.
Patient-reported symptoms and impacts of locally advanced or metastatic urothelial cancer (la/mUC) after chemotherapy followed by a PD-1/PD-L1 checkpoint inhibitor (CPI).
Authors: Shah Manasee , Devine Jacob , Wang Sam , Hepp Zsolt , Shah Sonali 
Published: March 2019

380 Background: Published literature on la/mUC patient burden is limited. Patient interviews can help better characterize the symptoms and impacts associated with disease and treatment management. Methods: Patients (pts) aged ≥18 yr with non-resected la/mUC treated with chemotherapy followed by a CPI were recruited. Semi-structured 60 min telephone interviews were conducted; transcripts were analyzed. In a follow-up survey, pts rated the bothersomeness of their symptoms and impacts on quality of life (QoL) on a 0–10 scale (0, not at all bothersome; 10 most bothersome). Results: Twenty-four pts (median age, 55 yrs [range 33–70]) were interviewed; most were female (67%), < 65 yrs (79%) with stage IV mUC (63%). Due to recruitment limitations, this study was conducted in a unique non-resected advanced UC population who were generally younger and included more females than the broader la/mUC population. These pts experienced a range of signs/symptoms and overlap was reported between ongoing disease- and treatment-related symptoms. Fatigue, sexual dysfunction, and sleep disturbances were attributed to both disease and treatment; nausea/vomiting and hair loss were attributed to treatment alone. Common ongoing symptoms were fatigue (92%), hematuria (88%), pain (75%), and urinary symptoms (71%); most salient symptoms (defined as mean bothersome rating ≥5 in ≥50% of pts) were loss of hair, weight, and appetite, as well as fatigue, hematuria, pain, urinary symptoms, and nausea/vomiting. The most salient impacts were those on emotional functioning and family relationships. Most pts did not report significant difficulty with basic activities of daily living (ADLs). Some pts reported challenges with instrumental ADLs (eg, shopping, cooking); most pts reported ncreased reliance on friends and relatives for assistance. Conclusions: Patients with la/mUC treated with chemotherapy and CPI report that symptoms and impacts have profound effects on health-related QoL. The inclusion of instruments within a clinical trial that accurately capture pts’ experiences will enhance understanding of the disease course and the benefits of treatment.
Activity of RX-3117, an oral antimetabolite nucleoside, in subjects with advanced urothelial cancer: Preliminary results of a phase IIa study.
Authors: Salgia Nicholas , Pal Sumanta K. , Chung Vincent , Tagawa Scott T. , Picus Joel , Babiker Hani M. , Gupta Sumati , Wadlow Raymond Couric , Poore Julie , Peterson Christine , Benaim Ely 
Published: March 2019

455 Background: RX-3117 is an oral small molecule antimetabolite that is activated by uridine cytidine kinase 2 (UCK2) which is predominantly expressed in cancer cells. RX-3117 has shown efficacy in xenograft models of gemcitabine resistant pancreatic, bladder and colorectal cancer. Preliminary data from an analysis of a Phase 2a clinical study of RX3117 in advanced urothelial cancer is described. Methods: In the Phase 2a study designed to evaluate safety, tolerability and efficacy, subjects were treated with oral RX-3117 (700 mg) once-daily for 5 consecutive days on and 2 days off for 3 of 4 weeks or all 4 weeks in a 28-day cycle. Eligible subjects (aged ≥ 18 years) had relapsed/refractory metastatic urothelial cancer, ECOG PS of 0 to 1, normal organ function (hepatic, renal and hematology) with no limit on the number of prior therapies. The primary Phase 2a endpoints are progression free survival (PFS) and/or objective clinical response with secondary endpoints of safety, TTP, DOR and ORR. Results: As of October 5, 2018; 33 subjects were treated (23 males and 10 females, median age 67.5 years); 29 subjects were evaluable having completed more than 1 cycle of therapy or discontinued due to a related adverse event. Twenty subjects had received 3 or more prior therapies; 30 received gemcitabine/cisplatin and 25 received a checkpoint inhibitor. The most common related adverse events were anemia (G1-2%, G2-3%, G3-3%), fatigue (G1-6%, G2-3%), neutropenia (G2-2%, G3-5%, G4-2%), diarrhea (G1-4%, G2-2%), and thrombocytopenia (G2-2%, G3-3%, G4-1%). One subject had a complete response after 4 cycles of therapy and continues therapy beyond 10 cycles; 5 subjects had PFS ranging from 133 to 315 days. Conclusions: RX-3117 appears to be safe and well-tolerated in chemotherapy and immunotherapy refractory advanced urothelial cancer with acceptable toxicities. Preliminary results show anti-tumor activity in heavily pre-treated patients. Clinical trial information: NCT02030067.