tbuckley/cabot-search huggingface dataset:
Racial disparities in the initial treatment of hepatocellular carcinoma in the population 65+ years in the United States.
Authors: Stephanie Costa, David J. Delgado, Michael Ross Kaufman, Brandon George, Edith P. Mitchell
Journal: Journal of Clinical Oncology (2018)

431 Background: Insufficient evidence exists regarding the initial management of elderly patients with hepatocellular carcinoma (HCC). The purpose of this study was to describe racial differences in initial treatment of 65+ year old patients with HCC diagnosed in the United States (2004-2014). Methods: A retrospective cohort study was conducted using the 1973-2014 Surveillance, Epidemiology and End Results Program (SEER) database of the National Cancer Institute. Patients with primary hepatocellular carcinoma, diagnosed between 2004 and 2014, and with complete information on race, gender, year of diagnosis, age, marital status, region, tumor status at diagnosis and initial treatment were included. Descriptive statistics were used to compare race with sociodemographic and clinical variables. Univariate and multivariate logistic regressions were performed to describe the association of race with receiving any treatment for HCC (local hepatic therapy and surgical treatment versus no treatment). Results: The sample consisted of 25,499 HCC patients: 70.0% White, 9.1% Black, 19.8% API, 1.0% AI; 68.6% male; 46.8% diagnosed in 2004-2009; 54.8% age 65-74, 45.2% 75 and older; 54.7% married, 7.3% Midwest, 13.8% Northeast, 15.7% Southeast; 81.3% first malignant primary indicator, 13.8% metastasis, 49.3% localized site, and 20.9% receiving initial treatment. After controlling for confounding variables, as compared to White patients, African American patients (OR:0.739 95% CI:0.652, 0.839) had decreased odds of receiving initial treatment; and Asian/Pacific Islander patients (OR:1.490 95% CI:1.371,1.618) had increased odds of receiving initial treatment. Conclusions: Racial disparities exist at the presentation of HCC in the 65+ population. African American patients are less likely to receive treatment and Asian/Pacific Islander patients are more likely to receive treatment. Further research is needed to understand these relationships in subpopulations.
Diagnostic capability of a next-generation, ultra-miniaturized ultrasound system in patients with cardiopulmonary compromise assessed using basic critical care echocardiography
Authors: Marine Goudelin, Bruno Evrard, François Dalmay, Ana Hernandez Padilla, Céline Gonzalez, Thomas Lafon, Thomas Daix, Anne-Laure Fedou, Bruno François, Philippe Vignon
Journal: Intensive Care Medicine (2018)
The immune milieu of anal squamous cell carcinoma and implications of IDO expression on outcome.
Authors: Devarati Mitra, Diane Brackett, Nora Horrick, Theodore Sunki Hong, Aparna Parikh, Jeffrey W. Clark, David P. Ryan, Vikram Deshpande, Jennifer Y Wo
Journal: Journal of Clinical Oncology (2018)

659 Background: Recent studies have examined the immune microenvironment in anal squamous cell carcinoma (ASCC) with focus on T-cell infiltrate and PD-1/-L1 expression. This study examines a variety of immune markers in our institution’s pre-treatment localized ASCC cohort including indoleamine-2,3-dioxygenase 1 (IDO1) and class I HLA (hc10) which have not been previously studied in ASCC. Methods: Retrospective review identified 48 patients with localized ASCC treated at our institution with definitive chemoradiation between 2006-2016 with ≥6 months of follow-up in survivors and tissue locally available. Immunohistochemistry (IHC) for the immune markers CD8, PD1, PDL1, HLA class I (hc10) and IDO1 was performed and scored by two pathologists. Univariate and multivariate analyses were performed using a Cox proportional hazards model. Results: Of the 48 patients studied, distribution by stage was: I-14.5%, II-33%, IIIA-14.5%, IIIB-35%, unknown-2% with 27% having HIV or being on immunosuppressive medication. The distribution of immune marker staining was: median (med) CD8 72/hpf (0-319/hpf), med PD1 16/hpf (0-178/hpf), med PDL1 1% (0-40%), and med IDO1 3% (0-100%). Hc10 staining showed &gt; 50% loss of HLA class I in 12.5% of patients. Spearman correlation calculations suggested that patients with high CD8 tended to have higher PD1 (R = 0.47, p = 0.0006) and tumor PDL1 (R = 0.36, p = 0.04) though hc10 and IDO1 expression were not correlated. Median follow-up for surviving patients was 35 months (6-102 months). CD8, PD1, PDL1 and hc10 expression did not correlate with clinical outcomes. However, IDO1 staining in &gt; 50% of tumor cells was associated with worse outcomes, even when adjusted in a multivariable model for higher T-stage and nodal positivity: HR for progression 5.7 (95% CI 1.5-20.7, p = 0.008) and HR for death 5.6 (95% CI 1.5-21.5, p = 0.01). No other clinical variables were associated with outcome. Conclusions: ASCC has a diverse immune milieu. While patients generally do well with standard therapy, IDO1 may serve as a prognostic indicator of poor outcome and suggest a patient population in which IDO-directed therapies may prove particularly valuable.
Scrap the cap on overseas doctors
Authors: Tom Moberly
Journal: BMJ (2018)

Since its inception 70 years ago the NHS has relied on doctors who trained in other countries. Today, one in three doctors working in the UK trained abroad, and one in four trained outside Europe. Crucially, these doctors have often worked in areas that home grown doctors haven’t wanted to, as Julian Simpson reflects in an essay this week (doi:10.1136/bmj.k2336).

But the number of overseas trained doctors working in the UK is falling—by …
Is it all for naught? What does mathematical coupling mean for acute:chronic workload ratios?
Authors: Johann Windt, Tim J Gabbett
Journal: British Journal of Sports Medicine (2018)

Traditional calculations of the acute:chronic workload ratio (ACWR) are ‘mathematically coupled’, as the most recent week is included in estimates of both the acute and chronic workloads. As Lolli and colleagues rightly point out, this induces a spurious correlation between the acute and chronic loads of ~0.50 (r=0.52 in their simulated data of 1000 athletes).1 They suggest that the simplest solution is to use uncoupled ACWRs (where the acute load is not part of the chronic load) instead (figure 1).



Figure 1 
The distinction between traditional ‘coupled’ and ‘uncoupled’ estimates of the acute:chronic workload ratio. The inclusion or exclusion of the most recent week in ‘chronic load’ calculations is the key distinction.



Notably, at least two studies have already used uncoupled ACWR calculations, both demonstrating that rapid workload increases are associated with higher injury risks.2 3 To this end, Lolli and colleagues’ suggestion warrants consideration—should we use ‘uncoupled’ ACWRs instead of ‘coupled’? We have two aims in this editorial: (1) to further comment on how mathematical coupling affects ACWR estimates and (2) to encourage researchers and practitioners to use a critical approach to load management, wherein ACWRs may play a part.

### Defining coupled and uncoupled ACWRs

We define mathematical coupling in the same manner as Lolli et al , where a number is represented in both the numerator and denominator of a ratio, contributing to a spurious correlation. In the case of the ACWR, both …
Energy-Based Tissue Fusion for Sutureless Closure: Applications, Mechanisms, and Potential for Functional Recovery
Authors: Eric A. Kramer, Mark E. Rentschler
Journal: Annual Review of Biomedical Engineering (2018)

As minimally invasive surgical techniques progress, the demand for efficient, reliable methods for vascular ligation and tissue closure becomes pronounced. The surgical advantages of energy-based vessel sealing exceed those of traditional, compression-based ligatures in procedures sensitive to duration, foreign bodies, and recovery time alike. Although the use of energy-based devices to seal or transect vasculature and connective tissue bundles is widespread, the breadth of heating strategies and energy dosimetry used across devices underscores an uncertainty as to the molecular nature of the sealing mechanism and induced tissue effect. Furthermore, energy-based techniques exhibit promise for the closure and functional repair of soft and connective tissues in the nervous, enteral, and dermal tissue domains. A constitutive theory of molecular bonding forces that arise in response to supraphysiological temperatures is required in order to optimize and progress the use of energy-based tissue fusion. While rapid tissue bonding has been suggested to arise from dehydration, dipole interactions, molecular cross-links, or the coagulation of cellular proteins, long-term functional tissue repair across fusion boundaries requires that the reaction to thermal damage be tailored to catalyze the onset of biological healing and remodeling. In this review, we compile and contrast findings from published thermal fusion research in an effort to encourage a molecular approach to characterization of the prevalent and promising energy-based tissue bond.
Abstract 13236: Coronary Vasospasm Induced in Transgenic Mouse With Overexpression of p122RhoGAP/DLC1
Authors: Takahiko Kinjo, Makoto Tanaka, Tomohiro Osanai, Ikuyo Narita, Tomohiro Tannno, Kimitaka Nishizaki, Shuji Shibutani, Yuji Ishida, Hirofumi Tomita, Yoshimi Homma, Ken Okumura
Journal: Circulation (2015)

Backgrounds: We reported that the activity of phospholipase C (PLC)-δ1, a key enzyme for Ca2+ signaling in the artery, was 3-fold enhanced in patients with coronary spastic angina (CSA), and was positively correlated with coronary vasomotility. We recently showed that p122RhoGAP/DLC1 (DLC1) protein, which was discovered as a stimulator of PLCδ-1, was upregulated in CSA patients. We tested the hypothesis that overexpression of DLC1 cause coronary spasm in mice. Methods and Results: We generated transgenic (TG) C57BL/6J mice with vascular smooth muscle-specific overexpression of DLC1. The gene and protein expression of DLC1 was enhanced by 11-fold and 4.4-fold, respectively, in the homozygous TG aorta compared with wild type (WT) mice. Systolic blood pressure and heart rate measured by tail-cuff method were similar between TG and WT mice, and no early mortality was found until the age of 30 weeks. PLC enzymatic activities in the plasma membrane and the whole cell were enhanced by 1.4 and 2.0 times, respectively, in cultured aortic vascular smooth muscle cells from homozygous TG compared with those from WT. To induce coronary spasm, ergometrine at 50 mg/kg was injected into the jugular vein of the anesthetized mice, and the ECG in lead II was recorded continuously. Heart rate, PR interval, QRS duration, and QRS morphology at baseline were all similar between TG and WT mice. Immediately after ergometrine injection, ST segment elevation was observed in one of 7 WT (14%), 6 of 7 heterozygous TG (84%), and 7 of 7 homozygous TG mice (100%) (both p&lt;0.05, WT vs TGs). This ST segment elevation in TG was followed by atrioventricular conduction disturbance and wide QRS rhythm, which are suggestive of myocardial ischemia. In the isolated Langendorff hearts, coronary perfusion pressure was increased after ergometrine in homozygous TG mice but not in WT mice despite the fact that the response to prostaglandin F2α was similar between TG and WT mice (n=5). In the group treated with ergometrine, focal narrowing of the coronary artery was documented only in TG mice (2 lesions in 2 hearts). Conclusion: Upregulated DLC1 caused enhanced coronary vasomotility after ergometrine injection in mice. Upregulation of DLC1 in the coronary artery can be a cause of coronary spasm in humans.
Associations of TP53- and/or PIK3CA mutated HR-positive, invasive ductal breast cancers (IDBC) of the METABRIC collection with distant recurrence risk (DRR) and time-to-recurrence (TTR).
Authors: Wolfgang Hackl
Journal: Journal of Clinical Oncology (2018)

e12542 Background: PIK3CA and TP53 count amongst the most frequently mutated genes in LumBCa. In the study presented here we worked with ER and/or PR positive, HER2 negative IDBCs from METABRIC collection (N=1.104) to assess the associations between PIK3CA- or TP53 mutation status and DRR or TTR. Methods: Clinical-pathologic and genomic variables (oncogenic mutations/CNVs, gene expression) were used to develop a parsimonious prognostic model for disease free survival using a robust, innovative statistics approach combined with cross-validation methodology. The predictive accuracy of the different sets of information was assessed using time-dependent ROC curves. Results: With the exception of a higher frequency of PIK3CA mutations (H1047R, E542K, E545K) in late recurring (58%) compared to early recurring tumors (40%), no other specific distribution patterns or associations with specific subpopulations were observed. Consistent with data from the literature [1, 5, 6 ] the relapse-free survival rate amongst patients with PIK3CA mutated tumors was higher than in patients with wild-type tumors. No significant difference was observed between IDBCs with low compared to high distant recurrence risk. The relapse-free survival rate in patients with PIK3CA mutated, early recurring IDBCs (= or < 5 years post diagnosis) was 47% (95% CI 40-54), whereas in late recurring IDBCs (> 5 years post diagnosis) it was 19% (95% CI 15-24). TP53 LoF mutations were enriched in three clusters, late recurring IDBCs (IDBC1b) and early recurring IDBCs (IDBC2b, IDBC3b). Common hallmarks were positive lymph nodes (= or > N4), tumor size (= or > 5cm) and histologic grade (G3) [3]. Conclusions: Our data show that TP53-mutated IDBC is a heterogeneous disease associated with high DDR. TTR predictions based on TP53 mutation status, however, remain highly ambiguous. Our data provide also an intuitive explanation why TP53 LoF mutation is a co-variate predictive of high distant recurrence risk of ER and/or PR positive, HER2 negative IDBCs, whereas PIK3CA GoF mutation or other reported mutations (e.g. 11q amplification, 8p amplification) are not.
Molecular alterations and late recurrence in postmenopausal women with hormone receptor-positive node-positive breast cancer (BC): Results from the “SOLE” trial.
Authors: Elena Guerini Rocco, Kathryn P. Gray, Elisabetta Munzone, Caterina Fumagalli, Marta Rita Reforgiato, Isabella Leone, Rosita Kammler, Giuseppe Viale, Patrick Neven, Erika Hitre, Guy Heinrich Maria Jerusalem, Edda Simoncini, Andrea Gombos, Ines Deleu, Angelo Di Leo, Aron Goldhirsch, Massimo Barberis, Meredith M. Regan, Marco Colleoni
Journal: Journal of Clinical Oncology (2018)

517 Background: Women with hormone receptor-positive BC have an ongoing risk of relapse. We performed molecular analyses of primary BC from postmenopausal patients (pts) enrolled in the extended adjuvant intermittent letrozole vs. continuous letrozole (SOLE) trial to identify prognostic factors and potential targets. Methods: From 4884 pts enrolled, 3162 had FFPE tumor samples and were eligible. A case-cohort design selected 599 pts, and 499 DNA samples underwent next-generation sequencing of 35 and 19 actionable genes for mutation (SNV) and copy number gain (CNG) analyses. Correlations of SNV/CNG with clinicopathologic factors were analyzed. Associations with breast cancer free-interval (BCFI) and distant recurrence free-interval (DRFI) were assessed using weighted proportional hazards models to obtain unbiased and consistent estimates representing the overall trial population. With 403 pts there was 90% power to detect a hazard ratio (HR) = 2.0 (SNV/CNG+ vs. -; assuming a 40% mutation prevalence), with 0.05 two-sided significance level and adjusted standard error estimate from the weighed Cox model. Results: SNV and CNG data were available for 403 (81%) and 350 (70%) of 499 samples, respectively. 294 samples had ≥1 SNV or CNG; 132 had concurrent alterations. PIK3CA was the most frequently mutated gene (42%). Other genes showed < 5% SNV rate. Recurrent CNGs were seen in CCND1 (15%), ERBB2 (10%), FGFR1 (8%) and MYC (8%). PIK3CA SNVs and MYC CNG were associated with low (p = 0.032) and high (p = 0.004) tumor grade. Ki-67 index was high in tumors with CNG of CCND1, ERBB2 and MYC (each p < 0.01). No association was seen between PIK3CA SNV and recurrence. FGFR1 CNG was associated with worse outcomes (BCFI: HR = 3.2; 95% CI, 1.5-6.9, p = 0.003; and DRFI: HR = 3.5; 95% CI, 1.6-7.7, p = 0.002). The results were consistent in multivariable models adjusting for clinicopathologic factors. Conclusions: We showed that pts with hormone receptor-positive node-positive BC with FGFR1 CNG had an increased risk of late recurrence despite extended therapy. FGFR1 analysis may improve the risk stratification in this population and represent a potential therapeutic target. Clinical trial information: NCT00553410.
Electronic cigarette use in youths: a position statement of the Forum of International Respiratory Societies
Authors: Thomas W. Ferkol, Harold J. Farber, Stefania La Grutta, Frank T. Leone, Henry M. Marshall, Enid Neptune, Charlotta Pisinger, Aneesa Vanker, Myra Wisotzky, Gustavo E. Zabert, Dean E. Schraufnagel
Journal: European Respiratory Journal (2018)

Children and adolescents are highly susceptible to nicotine addiction, which affects their brain development, even in those who smoke infrequently. Young people who become addicted to nicotine are at greater risk of becoming lifelong tobacco consumers. The use of nicotine-delivering electronic cigarettes has risen dramatically among youths worldwide. In addition to physical dependence, adolescents are susceptible to social and environmental influences to use electronic cigarettes. The product design, flavours, marketing, and perception of safety and acceptability have increased the appeal of electronic cigarettes to young people, thus leading to new generations addicted to nicotine. Moreover, there is growing evidence that electronic cigarettes in children and adolescents serve as a gateway to cigarette smoking. There can be no argument for harm reduction in children. To protect this vulnerable population from electronic cigarettes and other nicotine delivery devices, we recommend that electronic cigarettes be regulated as tobacco products and included in smoke-free policies. Sale of electronic cigarettes should be barred to youths worldwide. Flavouring should be prohibited in electronic cigarettes, and advertising accessible by youths and young adults be banned. Finally, we recommend greater research on the health effects of electronic cigarettes and surveillance of use across different countries.
Additional one-year follow-up study to evaluate safety and survival in patients who have completed neoadjuvant-adjuvant treatment with SB3 (trastuzumab biosimilar) or reference trastuzumab in HER2-positive early or locally advanced breast cancer.
Authors: Xavier Pivot, Igor Bondarenko, Zbigniew Nowecki, Mikhail Dvorkin, Ekaterina Trishkina, Tomasz Sarosiek, Marek Wojtukiewicz, Yaroslav V. Shparyk, Vladimir Moiseyenko, Younsoo Kim, Jae Yun Lim
Journal: Journal of Clinical Oncology (2018)

e12631 Background: SB3 was approved by the European Commission as a trastuzumab (TRZ) biosimilar. Here, we report safety and survival data with a follow-up of at least 12 treatment-free months after completing 12 months of neoadjuvant-adjuvant therapy. Methods: Patients with HER2 positive early or locally advanced breast cancer were randomly assigned to receive 8 cycles of SB3 or TRZ in neoadjuvant setting concurrently with chemotherapy (4 cycles of docetaxel followed by 4 cycles of 5-fluorouracil/epirubicin/cyclophosphamide). Patients then underwent surgery followed by 10 cycles of adjuvant SB3 or TRZ. After completion of therapy, patients from selected countries were asked for consent to participate in a five-year follow-up study (NCT02771795). Recommended visits were every 6 months for 2 years and annually for the following 3 years. The aim of this study was to observe the incidence of symptomatic congestive heart failure (CHF), asymptomatic significant left ventricular ejection fraction (LVEF) decrease, incidence of other cardiac events, event-free survival (EFS), and overall survival (OS). Results: A total of 367 patients (SB3, n = 186; TRZ, n = 181) were included in the follow-up study. The median follow-up duration from initiation of study treatment was 30.1 months in SB3 and 30.2 months in TRZ. During the additional one-year follow-up, incidence of asymptomatic significant LVEF decrease was low (SB3, n = 1; TRZ, n = 2), with all patients recovering with LVEF ≥ 50%. Symptomatic CHF, cardiac death, or other significant cardiac condition was not reported in either group. A total of 22 patients (SB3, n = 8; TRZ, n = 14) experienced events (disease recurrence or progression or death) and there were 4 deaths (SB3, n = 1; TRZ, n = 3). At 24 months, EFS rates (SB3, 96.7%; TRZ 94.3%) and OS rates (SB3, 100.0%; TRZ, 99.4%) were comparable. Conclusions: Incidence of cardiac safety events was low and survival results were comparable between arms throughout the additional one-year treatment-free follow-up period, further supporting the biosimilarity established between SB3 and TRZ. Clinical trial information: NCT02771795.
Lung Dysbiosis, Inflammation, and Injury in Hematopoietic Cell Transplantation
Authors: David N. O’Dwyer, Xiaofeng Zhou, Carol A. Wilke, Meng Xia, Nicole R. Falkowski, Katy C. Norman, Kelly B. Arnold, Gary B. Huffnagle, Susan Murray, John R. Erb-Downward, Gregory A. Yanik, Bethany B. Moore, Robert P. Dickson
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Hematopoietic cell transplant (HCT) is a common treatment for hematological neoplasms and autoimmune disorders. Among HCT recipients, pulmonary complications are common, morbid, and/or lethal, and they have recently been associated with gut dysbiosis. The role of lung microbiota in post-HCT pulmonary complications is unknown.
Technique and surgical outcomes of mesenterization and intra-operative neural monitoring to reduce recurrent laryngeal nerve paralysis after thoracoscopic esophagectomy: A cohort study
Authors: Hiroyuki Kobayashi, Masato Kondo, Motoko Mizumoto, Hiroki Hashida, Satoshi Kaihara, Ryo Hosotani
Journal: International Journal of Surgery (2018)