tbuckley/cabot-search huggingface dataset:
Radiotherapy (RT) for brain metastases (BM) near end of life (EOL): Does referral setting matter?
Authors: Joan Joonsun Ryoo, Michael Batech, Chengyi Zheng, Raymond W Kim, Michael K Gould, A. Robert Kagan, Winston Wei Lien
Journal: Journal of Clinical Oncology (2015)

e17723 Background: Incidence of BM in non-small cell lung cancer (NSCLC), treatment referral patterns, and receipt of brain RT are not well-described. We assessed frequency of BM development, brain RT, and RT receipt near EOL. Methods: Incident NSCLC cases from 2007-2011 were identified by an integrated health care system tumor registry. BM were determined by imaging review. Patient (pt) and treatment characteristics were obtained by chart abstraction. Brain RT near EOL was examined by multivariate analysis. Results: Of 5187 pts, 52% were male, 63% white; 23% had stage I/II, 21% III disease. BM were on presentation in 10%; 7% developed BM thereafter. Among 900 with BM: 15% were not referred for RT, that decision made during admission for 72% [mean time BM to death 43 d (SD 67)]; 9% were seen post-surgery; RT was not advised in 5%. RT was received by 639: 116 had >1 episode of RT; 50 did not finish RT as planned [mean time RT to death 19 d (SD 35)]; 100 (16%) received RT within 14 d of death. Mean time from RT to death was shorter when 5 vs 10 fractions were planned (78 vs 179 d, p<0.01), suggesting providers’ sense of prognosis. Inpt consultation and fractions were higher at outside facilities, and RT more likely not to be completed (p<0.01). Independent predictors of death ≤14 d of RT were inpt consultation and increasing metastatic sites. Conclusions: BM incidence in this NSCLC cohort was 17%. While 15% of pts were not referred for RT, largely on inpt evaluation and aptly given lifespan, 16% receiving brain RT died ≤14 d of therapy, predicted by inpt assessment. Careful consideration of RT recommendation and fractionation, especially in acute care settings, should aim to minimize the projected proportion of remaining days in treatment, if any, and maximize quality of life. No RT N=261 RT >14 d of death N=539 RT ≤14 d of death N=100 Age, mean yrs (SD) 69 (11) 64 (11)* 68 (11)* Performance Status — Good/Fair 33 (13) 275 (41)* 44 (44)* — Poor 91 (35) 34 (6)* 25 (25)* — Unknown 137 (52) 230 (43)* 31 (31)* Extracranial Disease Control 16 (6) 106 (20)* 9 (9)* Extracranial Metastatic Sites — 1-2 148 (57) 351 (66)* 43 (43)* — 3+ 112 (43) 188 (34)* 57 (57)* Code Status DNR 109 (42) 59 (11)* 26 (26)* Inpt RT Consultation 42 (16) 118 (22)* 46 (46)* Values N(%) unless stated; *p<0.05, t-test or chi2.
Eltanexor (KPT-8602), a second-generation selective inhibitor of nuclear export (SINE) compound, in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Jingsong Zhang, David D. Chism, Scott T. Tagawa, Paul Monk, Robert S. Alter, William Reichman, William Senapedis, Erkan Baloglu, Sharon Shacham, Michael G. Kauffman
Journal: Journal of Clinical Oncology (2019)

197 Background: Overexpression of exportin 1 (XPO1) in malignant cells increases the nuclear export/inactivation of tumor suppressor proteins (eg. p53), and promotes the translation of eIF4E-bound oncoprotein mRNAs (eg. c-MYC). XPO1 inhibition reduces total androgen receptor levels, including ARv7, and may re-sensitize prostate cancer (PC) cells to androgen deprivation therapy. Selinexor, the first-in-human SINE compound, showed anticancer activity in patients (pts) with mCRPC. Eltanexor (ELTA), a second-generation SINE compound, showed promising anticancer activity in preclinical models of PC, including in abiraterone (ABI) resistant cell lines. Therefore, ELTA ± ABI was evaluated in mCRPC. Methods: This was part of a phase 1/2 study to determine the safety, preliminary efficacy, and recommended phase 2 doseof ELTA in pts with advanced cancers. Pts with mCRPC received oral ELTA once daily for 5 days per week over a 28-day cycle in 4 cohorts: single-agent (20 mg; n=7 or 30 mg; n=6) or in combination with ABI (20 mg; n=13 or 30 mg; n=4). Pts may have prior exposure to chemotherapy. Pts receiving ELTA + ABI had prior response to ABI then progressed. Response was evaluated by PCWG3 / RECIST v1.1. Results: As of 17 Sept 2018, 30 pts were treated with ELTA ± ABI with a median age of 71 and a median of 4 prior regimens; (87% ABI, 60% enzalutamide, and 57% chemotherapy). Twenty-one pts with mCRPC were evaluable for efficacy: 2 partial response (10%), 15 stable disease (71%), and 4 progressive disease (19%). The median treatment duration is 75.5 days; 4 pts still on treatment. Treatment-related adverse events (TRAEs) occurring in ≥30% of the pts: fatigue (67%; 13% Gr≥3), nausea (63.3%; 0% Gr≥3), decreased appetite (57%; 0% Gr≥3), diarrhea (47%; 3% Gr≥3), weight decreased (43%; 3% Gr≥3), vomiting (37%; 7% Gr≥3), anemia (33%; 7% Gr≥3), and dysgeusia (33%; 0% Gr≥3). The 2 Gr4 TRAEs were neutropenia and elevated AST. Conclusions: ELTA± ABI is well-tolerated with AEs mostly limited to Gr 1/2 and demonstrates preliminary anti-tumor activity in patients with mCRPC. With enrollment complete, these results warrant further investigation of ELTA ± ABIin mCPRC. Clinical trial information: NCT02649790.
Seminomatous germ cell tumors are heterogenic and metastasis can be predicted based on a gene signature of the tumor invasive front.
Authors: Tim Nestler, Friederike Haidl, Maike Wittersheim, Priya Dalvi, Pia Paffenholz, Svenja Wagener-Ryczek, David J. K. P. Pfister, Martin Hellmich, Reinhard Büttner, Margarete Odenthal, Axel Heidenreich
Journal: Journal of Clinical Oncology (2019)

528 Background: Up to 40% of pure seminomatous germ cell tumors (GCTs) are clinically metastasized at initial diagnosis. Additionally, up to 20% of patients have occult metastasis but are not diagnosed due to missing markers. We hypothesize that pure seminomatous GCTs differ from metastasized to non-metastasized patients, possibly owing to differences in tumor heterogeneity. Since in few other tumor types genes linked to metastasis are shown to be more often upregulated at the tumor front, we investigated different regions of seminomas in non-metastasized and metastasized patients. Methods: Seminoma patient samples without metastasis, with no adjuvant therapy, and with recurrence-free follow-up of at least two years (n = 21), and patients showing metastasis (n = 14) were selected for the study. Based on formalin-fixed paraffin embedded tissues, the tumor front (TF) and tumor center (TC) regions of each patient were determined and separately collected using laser capture microdissection. RNA was extracted and a multiplex gene expression analysis was performed on all TF and TC samples using nCounter technology of Nanostring. A panel of 770 transcripts was analyzed using the PanCancer Progression panel. Different bioinformatics tools were employed for analyzing the expression data. Results: Hierarchical cluster analysis showed no differential gene clustering between metastasized and non-metastasized patients. Comparing TF and TC in the metastasized group more genes (29 genes) were significantly differentially expressed (log2 fold change &gt; 1.5, FDR &lt; 0.05) compared to cSI patients (12 genes). Pairwise comparison of TF and TC for each individual patient showed differential expression of genes in these two regions. Lasso regression analysis of TC could not reveal any signature to predict metastasis. However, with respect to the TF a signature of only six genes was sufficient to predict metastasis with a specificity of 100%, and a sensitivity of 92.9%. Conclusions: This study describes tumor heterogeneity in seminomas and identifies a gene signature that could predict metastasis and has to be validated on occult metastasized seminomatous patients.
Common mental disorders within chronic inflammatory disorders: a primary care database prospective investigation
Authors: Alexandru Dregan, Faith Matcham, Lisa Harber-Aschan, Lauren Rayner, Anamaria Brailean, Katrina Davis, Stephani Hatch, Carmine Pariante, David Armstrong, Robert Stewart, Matthew Hotopf
Journal: Annals of the Rheumatic Diseases (2019)

There is inconsistent evidence about the association between inflammatory disorders and depression and anxiety onset in a primary care context. The study aimed to evaluate the risk of depression and anxiety within multisystem and organ-specific inflammatory disorders.This is a prospective cohort study with primary care patients from the UK Clinical Practice Research Datalink diagnosed with an inflammatory disorder between 1 January 2001 and 31 December 2016. These patients were matched on age, gender, practice and index date with patients without an inflammatory disorder. The study exposures were seven chronic inflammatory disorders. Clinical diagnosis of depression and anxiety represented the outcome measures of interest.Among 538 707 participants, the incidence of depression ranged from 14 per 1000 person-years (severe psoriasis) to 9 per 1000 person-years (systemic vasculitis), substantively higher compared with their comparison group (5-7 per 1000 person-years). HRs of multiple depression and anxiety events were 16% higher within inflammatory disorders (HR, 1.16, 95% CI 1.12 to 1.21, p<0.001) compared with the matched comparison group. The incidence of depression and anxiety was strongly associated with the age at inflammatory disorder onset. The overall HR estimate for depression was 1.90 (95% CI 1.66 to 2.17, p<0.001) within early-onset disorder (<40 years of age) and 0.93 (95% CI 0.90 to 1.09, p=0.80) within late-onset disorder (≥60 years of age).Primary care patients with inflammatory disorders have elevated rates of depression and anxiety incidence, particularly those patients with early-onset inflammatory disorders. This finding may reflect the impact of the underlying disease on patients' quality of life, although the precise mechanisms require further investigation.
Integration of radium-223 dichloride (Xofigo) into clinical practice for the treatment of castration-resistant prostate cancer.
Authors: Catherine Mary Doyle, Matthew Mills, Sultan Damgaci, Johnna Smith, Jingsong Zhang, Mayer N. Fishman, Ghassan El-Haddad
Journal: Journal of Clinical Oncology (2019)

312 Background: Radium-223 dichloride (Xofigo) is an FDA-approved radionuclide used to treat symptomatic bone metastases in patients with castration-resistant prostate cancer (CRPC) with no known visceral metastases. Outside of clinical trial, the benefits of Radium-223 dichloride (Ra-223) in the treatment of CRPC have not yet been fully delineated in real life setting. Therefore, the purpose of this study was to evaluate the outcome of patients with CRPC who were treated with Ra-223, especially studying the variables associated with completion of 6 cycles of therapy. Methods: A total of 114 patients with CRPC and bone metastases referred for treatment with Ra-223 between March 2010 and February 2018 were identified for retrospective analysis. A chart review was conducted to analyze clinical characteristics, treatments, and outcomes including radiologic bone scans. Categorical variables were compared using Chi-square and independent student t test, and survival rates were generated using Kaplan-Meier analysis. Multivariate analysis (MVA) Cox proportional hazard ratios (HR) model was used in the assessment of OS and PFS. Results: Of the 114 patients referred for treatment, the overall median OS was 12.6 months. In MVA, improved OS was most strongly associated with completion of all six doses (p &lt; 0.001). Median OS for the 56 patients who received full treatment was 24 months, while median OS for the 107 patients who did not complete treatment was 5.9 months. In univariate analysis, treatment completion was significantly associated with prior Sipuleucel-T (p = 0.002), concurrent Denosumab (p = 0.027), and baseline PSA &lt; 30 ng/mL (p = 0.004). Conclusions: Completion of treatment with Ra-223 is a significant factor associated with improved OS. Therefore it is clinically important to delineate which patients are to the most appropriate candidates to complete treatment. Factors notable for treatment completion suggest patients might benefit from initiating Ra-223 treatment after receiving Sipuleucel-T and while their PSA remains low. Further consideration should be given to the sequence of Ra-223 in clinical practice, including use of concurrent Abiraterone and Enzalutamide.
Oxygen compared to air during exercise training in COPD with exercise-induced desaturation
Authors: Jennifer A. Alison, Zoe J. McKeough, Regina W.M. Leung, Anne E. Holland, Kylie Hill, Norman R. Morris, Sue Jenkins, Lissa M. Spencer, Catherine J. Hill, Annemarie L. Lee, Helen Seale, Nola Cecins, Christine F. McDonald
Journal: European Respiratory Journal (2019)

Almost half the patients referred to pulmonary rehabilitation with chronic obstructive pulmonary disease (COPD) desaturate during exercise. Although oxygen supplementation may ameliorate oxygen desaturation, the effects on outcomes of exercise training have not been rigorously evaluated. This study aimed to determine whether supplemental oxygen during exercise training was more effective than medical air in improving exercise capacity and health-related quality of life (HRQoL) in people with COPD. People with COPD who demonstrated oxygen desaturation &lt;90% during the 6-min walk test were recruited to this multicentre trial with randomisation (independent, concealed allocation) to either an Oxygen group or Air group, blinding (participants, exercise trainers and European Respiratory Journal assessors) and intention-to-treat analysis. Both groups received the respective gas from concentrators via nasal prongs at 5 L·min −1 during exercise training consisting of treadmill and cycle exercise, three times per week for 8 weeks. Primary outcomes were the endurance shuttle walk test (ESWT) time and Chronic Respiratory Disease Questionnaire (CRQ)-Total score. 111 participants (60 males), mean± sd age 69±7 years, with moderate to severe COPD were recruited and 97 completed (Oxygen group n=52; Air group n=45). At the end of the 8-week training programme there were no between-group differences in change in ESWT (mean difference 15 s (95% CI −106–136 s) or change in CRQ-Total (0.0 points (95% CI −0.3–0.3 points)). Within-group changes at end-training were significant for ESWT and CRQ-Total (all p&lt;0.01). Exercise capacity and HRQoL improved in both groups, with no greater benefit from training with supplemental oxygen than medical air.
A phase I/II trial of pazopanib alternating with bevacizumab in treatment-naïve metastatic clear cell renal cell carcinoma (CCRCC) patients: Phase I results.
Authors: Saby George, Laurie Herbst, Marcus Sikorski, Ann Marie Diraddo, Gissou Azabdaftari, Charles Roche, Eric Kauffman, Qiang Li, Thomas Schwaab, Ellis Glenn Levine, Roberto Pili, Gurkamal S. Chatta, Leonard Joseph Appleman, Adrienne Groman, Rahul Atul Parikh, Alan Hutson
Journal: Journal of Clinical Oncology (2019)

561 Background: Pazopanib as single agent and bevacizumab plus interferon were approved for use in metastatic RCC (MRCC) based on their ability to modulate the vasculature and prolong progression free survival. VEGF levels rose unopposed while using VEGF tyrosine kinase inhibitors (TKI) without break. We hypothesized that adding a break as well as bevacizumab which removes VEGF could prolong PFS in MRCC pts. Methods: This phase I trial was conducted in VEGF treatment naïve MRCC pts. This trial utilized a unique regimen of alternating Pazopanib (day 1-28) with bevacizumab (on days 36 and 50) in a 10-week cycle. The study employed a classic 3+3 design for dose escalation (dose levels in table 1). Safety utilized CTCAE version 4.0 and response evaluation was done using RECIST 1.1 criteria. The primary endpoint of this phase I trial was to find the recommended phase 2 dose (RP2D) of this novel regimen. Key secondary endpoints included objective response rate (ORR), safety/ toxicity and pharmacokinetics. Phase I safety committee acknowledged the completion and approved reporting of Phase I portion of this study. Results: This phase I study was conducted at two academic centers. Twenty-five pts were enrolled in the phase I portion. Median age was 64 years and 68% were male patients. The Commonest adverse events (AE) included fatigue (64%), diarrhea (52%), hypertension (48%), nausea (36%), dysgeusia (36%), vomiting (24%) and proteinuria (28%). The commonest grade 3/4 AE of more than 5% frequency included hypertension (20%) and proteinuria (12%). The dose levels 1 and 4 were expanded due to one DLT each and RP2D was established at dose level 4. The ORR was 25% among evaluable pts who completed at least one cycle of therapy (n=20). The median PFS of the ITT cohort (n=25) was 20.9 months. Conclusions: These data demonstrate that this novel regimen could be safely tested in a phase II trial. The safety and efficacy data suggest that this novel regimen could be optimal for MRCC patients with favorable/intermediate risk. Clinical trial information: NCT01684397. [Table: see text]
The impact of Charlson Comorbidity Index on survival outcomes in men with prostate cancer who underwent definitive prostate radiotherapy.
Authors: Ahmed I. Ghanem, Remonda M Khalil, Gehan Abd Elatti Khedr, Amy Tang, Amr A. Elsaid, Indrin Chetty, Benjamin Movsas, Mohamed A. Elshaikh
Journal: Journal of Clinical Oncology (2019)

114 Background: Life expectancy is very essential in deciding treatment options in men with prostate cancer (PCa); however, the impact of comorbidities on outcomes is not well-established. We investigated the influence of Charlson Comorbidity Index (CCI) on survival endpoints in men with localized PCa who were treated with prostate radiotherapy (RT). Methods: Men with intermediate and high risk PCa who were treated with definitive RT between 1/2007 and 12/2012 were included. Groups were created according to their baseline CCI score at diagnosis into no, mild and severe comorbidity (CCI 0, 1 or 2+). The groups were then compared based on patients’ characteristics and prognostic factors. Kaplan-Meier curves and Uni/multivariate analyses (MVA) were used to examine the impact of CCI groups on overall (OS), disease specific (DSS), and biochemical relapse free (BRFS) survival. Results: 257 patients were identified after excluding low risk, metastatic cases and those with inadequate follow up. Median follow-up was 92 months (range: 2-135) and median age was 73 years (range: 48-85). 53% of the cases were black and 67% were of intermediate risk. Median RT dose was 76 Gy and 47% received androgen deprivation therapy. CCI groups 0, 1 and 2+ encompassed 76 (30%), 54 (21%) and 127 (49%) patients, respectively. Groups were generally well-balanced. 10 and 15 years OS was significantly different across CCI groups (76% &amp; 53%, 46% &amp; 31% and 55% &amp; 14%, for CCI-0, 1 and 2+ respectively; p &lt; 0.001). CCI-0 had better DSS than CCI-2+ ( p = 0.03) with no difference for CCI-0 vs 1 ( p = 0.1). BRFS was non-different among CCI groups ( p = 0.99). On MVA, increased CCI was deterministic for OS ( p &lt; 0.001) after adjusting for age, Gleason’s score and T-stage. For DSS, only age and T3 vs T1/2 were independently prognostic ( p &lt; 0.001); whereas CCI-1 vs 0 was only marginal ( p = 0.05). Conclusions: Higher CCI was a significant predictor of shorter OS in intermediate and high-risk PCa. Baseline comorbidities should be taken into consideration during patient counselling for treatment options and in designing prospective trials for men with localized prostate cancer.
Creation of a global emergency-department research network: a feasibility study
Authors: Prashant Mahajan, Sanjeev Bhoi, Vijaya Arun Kumar, Qingbian Ma, Vidya Menon, Chip Jin Ng, Rockfeller Oteng, Beatriz Perondi, Apoorva Belle, Robert Neumar
Journal: The Lancet Global Health (2019)

BackgroundThe epidemiology of emergency care globally is largely unknown, especially in developing countries, because of a lack of common taxonomy, an absence of robust reporting mechanisms, and because emergency medicine is not always recognised as a subspecialty in its own right. Other disease-specific and specialty-specific research networks have addressed these barriers and brought about improved health of populations as a result. The University of Michigan's Department of Emergency Medicine is developing an international emergency-department research network to study the epidemiology of emergency visits in developed and developing countries. Our objectives are: to describe the first steps taken in creation of an international emergency-department research network; to discuss lessons learned; and propose a feasibility pilot study to determine epidemiology of emergency department visits across ten emergency departments in eight countries.MethodsWe contacted emergency departments that have a training programme for emergency medicine and have an existing collaboration with the University of Michigan's Global Reach programme in China, India, Ghana, Brazil, Taiwan, Austria, Finland, and the USA. We conducted a survey of research-related resources and electronic data access to determine whether sites were suitable for inclusion in the network. Finally, we proposed a feasibility study to measure interest in the project at sites as well as their ability to participate.FindingsWe noticed substantial variation between sites with respect to: the emergency department triage process; access to consultants; definitions of levels of severity of illness; management of resuscitation; and discharge disposition, even for the same condition. We developed a manual of operations, standard taxonomies, and are working on Institutional Review Board approval and data transfer agreements. We will be enrolling patients in prospective and retrospective studies with a sparse simultaneous-sampling design over a period of 6 months. The data collected will have ongoing quality checks to confirm validity and reliability.InterpretationDespite some substantial barriers, development of an infrastructure to study emergency care at a global level is feasible. The sustainability plan is to create a robust network that nurtures future investigators, identifies funding sources, and works on collaborative research. We anticipate challenges in collecting baseline data on emergency department presentations, so have designed two pathways to collect data: a retrospective Electronic Health Record query; and prospective data collection in real-time. We are planning an in-person meeting to establish standard processes for research priorities and resource allocation.FundingNone.