tbuckley/cabot-search huggingface dataset:
FOXO Transcription Factors Both Suppress and Support Breast Cancer Progression
Authors: Marten Hornsveld, Lydia M.M. Smits, Maaike Meerlo, Miranda van Amersfoort, Marian J.A. Groot Koerkamp, Dik van Leenen, David E.A. Kloet, Frank C.P. Holstege, Patrick W.B. Derksen, Boudewijn M.T. Burgering, Tobias B. Dansen
Journal: Cancer Research (2018)

Abstract FOXO transcription factors are regulators of cellular homeostasis and putative tumor suppressors, yet the role of FOXO in cancer progression remains to be determined. The data on FOXO function, particularly for epithelial cancers, are fragmentary and come from studies that focused on isolated aspects of cancer. To clarify the role of FOXO in epithelial cancer progression, we characterized the effects of inducible FOXO activation and loss in a mouse model of metastatic invasive lobular carcinoma. Strikingly, either activation or loss of FOXO function suppressed tumor growth and metastasis. We show that the multitude of cellular processes critically affected by FOXO function include proliferation, survival, redox homeostasis, and PI3K signaling, all of which must be carefully balanced for tumor cells to thrive. Significance: FOXO proteins are not solely tumor suppressors, but also support tumor growth and metastasis by regulating a multitude of cellular processes essential for tumorigenesis. Cancer Res; 78(9); 2356–69. ©2018 AACR.
P134 The lymphatic system plays an important role in the migration of pathogenic: T-cells towards synovial joints and entheses in psoriasis
Authors: D Verhaegh, E Prens, A Mus, P Asmawidjaja, N Davelaar, A Hofman, J-B Jaquet, M Kok, S Tas, H Yagita, J Hazes, E Lubberts, R Bisoendial
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Psoriasis (PsO) is a common inflammatory skin disease that is characterised by acanthosis, oedema formation, immune cell infiltration, abnormal vascular proliferation, and remodelling of the lymphatic system. Up to ~30% of PsO patients are affected by psoriatic arthritis, a devastating form of arthritis, which leads to disability and deterioration of quality of life. Thusfar, the transition from PsO to PsA, particularly the factors that determine the propensity of pathogenic T-cells in psoriasis to colonise synovial membrane in joints and entheses are poorly understood. Lymphatic endothelial cells (LECs), core components of the lymphatic vascular system and lymph nodes, may control the transmission of pathogenic T-cells in PsO to other sites including synovial joints and entheseal regions by programming these T-cells in terms of their homing properties. <h3>Objectives</h3> The focus of our proposal is to investigate whether LECs are capable of modulating the differentiation and homing receptor profile on CD4 memory T-cells. <h3>Methods</h3> Human dermal lymphatic endothelial cells (LEC; 0.5×10<sup>4</sup>), and fibroblast-like synoviocytes of a patient with PsA (FLS; 1.0×10<sup>4</sup>) were pre-incubated for 3 days with PsA synovial fluid (PsA-SF; 0/10/20% v/v). Then, LEC or FLS were co-cultured with 2.5×10<sup>4</sup> allogeneic CD4<sup>+</sup>CD45RO<sup>+</sup>CD25<sup>-</sup> T-cells that were sorted from peripheral blood mononuclear cells (PBMC) of 3 healthy donors with or without stimulation with αCD3 (0.3 µg/ml) and αCD28 (0.4 µg/ml). <h3>Results</h3> By means of flow-cytometry based phenotypical analysis, dermal LECs appear to suppress the generation of Th17 cells from stimulated CD4 memory T-cells of healthy donors, as compared to co-culture experiments involving synovial fibroblasts. Initial studies to the underlying mechanisms suggest that blocking the non-canonical NF-κB pathway downstream of the lymphotoxin beta receptor (LTβR) impairs the capacity of the LECs to suppress Th17 generation. In addition, Delta-like ligand 4 (DLL4) is differentially expressed in LECs and synovial fibroblasts after 3 days of co-culture. Earlier studies have shown that DLL4 may induce RORyt expression. Blocking DLL4 using a monoclonal antibody also impairs the capacity of the LECs to suppress Th17 generation. <h3>Conclusions</h3> In our co-culture setup, LECs suppress Th17 generation from stimulated CD4 memory T-cells, and are thus directly involved in T-cell differentiation. The LTβR/non-canonical NF-κB pathway and downstream DLL4-Notch1/4 may be involved in LEC mediated modulation of T-cell homing and deserves further exploration. <h3>Disclosure of interest</h3> None declared
Abstract P2-02-13: Utilization of cell-free circulating tumor DNA for management of breast cancer: Practices in academic and community oncology
Authors: RA Thomas, N Klar, L Kiedrowski, RJ Nagy, AV Lee, A Brufsky
Journal: Cancer Research (2018)

Abstract Background: Next-generation sequencing (NGS) of cell-free DNA (cfDNA) is increasingly being utilized to assess somatic genomic alterations in patients with breast cancer. We investigated the clinical use of such testing in breast cancer care in a major healthcare system with both academic and community-based practices. We also explored the observed genomic landscape in the analyzed patient cohort and whether treatment plans were modified based on the results. Methods: A retrospective review of cfDNA NGS results (Guardant360) ordered at the University of Pittsburgh Medical Center for patients with breast cancer from 7/2015-3/2017 was performed. Test ordering patterns, the landscape of genomic alterations identified, and clinical use of select results were assessed. Results: During this period 95 samples were submitted, 73 (77%) ordered by academic center providers and 22 (25%) from community providers. Alterations were detected in 88 samples (93%) with a median of 3 alterations per test. Five patients had serial samples ordered assessing dynamic cfDNA across clinical treatment and progressions, leaving 84 unique patients in the dataset. The average patient age was 57, and 95% of patients were female. Patients were most often observed to have alterations in TP53 (51%), PIK3CA (44%), and ESR1 (26%). Additional clinical data were collected for 48 patients with mutations or amplifications in PIK3CA, ESR1, and/or ERBB2 (HER2) to assess for clinical use of genomic information. Results were used to change clinical care in 13 (27%) of these cases. Community providers were more likely to use genomic results to guide clinical management in these cases (9/16, 56%) than academic providers (4/32, 12.5%), p=0.001. Of this patient subset, those with tests ordered by an academic provider had more lines of prior therapy at the time of testing vs. those in the community (average 5.9 vs 3.4 respectively, p=0.019). Conclusions: CfDNA NGS analysis for somatic genomic alterations in breast cancer is being ordered clinically by both academic and community practices within this healthcare system. Results for a subset of clinically annotated patients were acted on more frequently by community-based ordering providers, which may be related to patients tested at academic sites having had more lines of prior treatment. Citation Format: Thomas RA, Klar N, Kiedrowski L, Nagy RJ, Lee AV, Brufsky A. Utilization of cell-free circulating tumor DNA for management of breast cancer: Practices in academic and community oncology [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-02-13.
Operative skills in ear, nose, and throat surgery
Authors: Anjali Manuel
Journal: BMJ (2009)

This two day course, run by the Royal College of Surgeons in London, is designed to teach core operating skills in ear, nose, and throat (ENT) surgery by the use of cadaveric specimens, models, and operating equipment.

The course is intended for surgical trainees interested in ENT surgery. Participants were primarily core surgical trainees but also included foundation year 2 and other senior surgical trainees.

I took this course during year 1 of my core training, after 4 months’ experience in ENT during my foundation year 2 training.

Aspects of ENT training often seem to be a “one man show,” with the trainee watching from behind a microscope or attempting to peer down a rigid scope. The course promised to equip trainees with …
Identifying the barriers to cancer care at safety-net hospitals: A novel comparison of a safety-net hospital to a neighboring quaternary referral academic institution in the same health care system.
Authors: Mohammad Zaidi, Jesse Rappaport, Cecilia Grace Ethun, Theresa Wicklin Gillespie, Natalyn Nicole Hawk, Saurabh Chawla, Kenneth Cardona, Shishir Maithel, Maria C. Russell
Journal: Journal of Clinical Oncology (2018)

59 Background: The three-delays model for vulnerable and minority populations to receive care include delays in seeking, reaching, and receiving care. The dominant delay for vulnerable patients with gastric adenocarcinoma (GAC) is not known. Our aim was to define those patients with GAC who reached care at our regional safety-net hospital compared to academic centers from the National Cancer Database (NCDB). We also aimed to compare survival outcomes of patients who received curative-intent resection at our safety-net hospital to those in a nearby quaternary referral hospital. Methods: Grady-Memorial-Hospital (GMH), a safety-net hospital and Emory-University-Hospital (EUH), a quaternary referral hospital, are within the same healthcare-system. Clinicopathologic data of patients at presentation from NCDB-participating academic centers were compared with GMH from 2004-2014. Patients undergoing curative-intent resection of GAC at GMH were compared to those at EUH during a similar time period. Primary outcome for the latter was overall survival (OS). Results: At presentation, compared to NCDB-participating academic centers (n = 69,662), GMH patients (n = 154) were more likely to be black (85.1 vs 17.2%; p &lt; 0.001), uninsured (30.5 vs 4.7%; p &lt; 0.001), have stage IV disease (43.5 vs 30.1%; p = 0.017), and receive no treatment (40.3 vs 18.4%; p &lt; 0.001). When only comparing those who underwent curative-intent resection at GMH (n = 23) to EUH (n = 137), median OS was similar between both groups (GMH: median not reached; EUH: 59.8mos; p = 0.785). Conclusions: Patients with gastric cancer who reached care at our safety-net hospital are more likely to be uninsured, have stage IV disease, and receive no treatment compared to academic centers. When they receive curative-intent resection, however, overall survival is similar. Efforts must be made to identify and overcome the barriers in seeking and reaching care for this vulnerable patient population, as it appears that outcomes are acceptable in those who receive care.
Is surveillance without immediate treatment an option for newly diagnosed testicular germ-cell cancer patients with borderline size retroperitoneal lymph nodes on computed tomography scan?
Authors: Nadav Milk, Ilan Leibovitch, Daniel Keizman, Hadas Dresler, Itay Sternberg
Journal: Journal of Clinical Oncology (2018)

560 Background: The AJCC TNM Staging System for Testicular Cancer (TC) does not set a minimal diameter to define positive lymph nodes (LN) on computed tomography scan. It is common to refer to LN ≥ 1 cm in diameter as positive, even though benign LN in the borderline size of 1-1.5cm are common. Our goal is to describe the outcome of TC patients with borderline size retroperitoneal LN of undetermined significance managed initially with surveillance. Methods: We retrospectively reviewed the medical records of all TC patients treated at our institution during 2006-2016. Demographic, clinical, laboratory, imaging, pathological, treatment and surveillance data were obtained. Results: Of a total of 109 TC patients, 25 patients (22.7%) with borderline size LN were assigned to an active surveillance protocol by our tumor board. Median age at the time of orchiectomy was 37.2 years (IQR, 23.9-40.3). With a median follow-up of 3.9 years (IQR 1.7-6.5), overall survival rate in the group was 100%. Nine of 25 patients (36%) relapsed and were treated within a median of 4.9 months (IQR 2.2-5.5). Median follow-up for 16 patients who did not relapse was 3.4 years (IQR 1.5-5.4). Relapse-free survival was 71% (95% CI 48-85), and 61% (95% CI 38-77) at one and two years, respectively. Orchiectomy pathology included pure seminoma in 18/25 (72%), and a nonseminomatous tumor in 7/25 (28%). Tumor type was not associated with likelihood of relapse (p = 0.66). The median LN diameter at the time of diagnosis was 11 mm (IQR 9-12, mean 10.4). LN diameter was not associated with likelihood of relapse (p = 0.34). Patients who relapsed during follow-up were significantly younger at the time of TC diagnosis than patients who did not relapse (Median age 23.9 years [IQR 19.6-35.2] and 39.2 years [IQR 34.3-47.9] respectively, p = 0.0056). Conclusions: Surveillance alone for TC patients with borderline size LN of undetermined significance at diagnosis is a possible option and may help avoid overtreatment in 60% of these patients.
Association of low PTEN expression by fluorescence immunohistochemistry (F-IHC) and lethal disease in men with surgically-treated prostate cancer (PrCa).
Authors: Anis Hamid, Kathryn P. Gray, Ying Huang, Michaela Bowden, Massimo Loda, Mark Pomerantz, Christopher Sweeney
Journal: Journal of Clinical Oncology (2018)

15 Background: Loss of PTEN expression correlates with poorer clinical outcomes after definitive therapy for non-metastatic (M0) PrCa. While most studies have used biochemical-based end points, there is limited data regarding PTEN loss by IHC and risk of lethal disease after surgery. Methods: A retrospective cohort of patients who underwent radical prostatectomy (RP) was identified from the Dana-Farber Prostate Clinical Research Information Systems (CRIS) database. Formalin-fixed, paraffin-embedded RP specimens were used to construct tissue microarrays and F-IHC for PTEN was performed. Using multispectral imaging analysis, tumor-only PTEN expression was quantified. PTEN expression was analyzed continuously and dichotomously (low [ &lt; lower quartile] vs other [≥lower quartile]). Kaplan-Meier method estimated the distribution of time from RP to metastatic disease and overall survival (OS). Cox model assessed association of PTEN status and the disease outcomes, with adjustment of age, Gleason score and pathological stage in multivariate analyses (MVA). Prognostic ability of PTEN was also explored using a logistic regression model. Results: The analysis cohort comprised 91 patients with either non-lethal (no metastatic or biochemical relapse) or lethal disease (metastasis post-RP). The median follow-up was 12.4 years. PTEN low was significantly associated with lethal disease as both a continuous (HR 1.82, 95% CI 1.35-2.44) and dichotomous (HR 2.94, 95% CI 1.52-5.56) variable. Significant association of PTEN-low expression and poorer OS was observed (cont: HR 2.22, 95% CI 1.54-3.23; low vs other: HR 4.00, 95% CI 1.89-8.33). MVA models yielded consistent results. A prognostic model assessing 10-year disease outcomes showed incremental prognostic improvement with PTEN status added to age/Gleason/stage (lethal disease: area under curve (AUC) 0.79 vs 0.84 [+PTEN status]; death: AUC 0.71 vs 0.76 [+PTEN status]). Conclusions: Low PTEN expression by F-IHC in primary prostate cancer is an independent prognostic biomarker of lethal disease and death after surgery. Quantitative F-IHC for PTEN is a viable diagnostic assay in this context.
Difference of genomic signatures and opportunities for targeted and immunotherapies in castrate resistant TMPRSS2:ERG fusion positive and TMPRSS2:ERG wild type refractory acinar (CRPC) and neuroendocrine prostate cancer (CRNEPC).
Authors: Gennady Bratslavsky, Hugh A.G. Fisher, Timothy Byler, Joseph M Jacob, Jon Chung, Julia Andrea Elvin, Jo-Anne Vergilio, Shakti Ramkissoon, James Suh, Eric Allan Severson, Sugganth Daniel, Siraj Mahamed Ali, Alexa Betzig Schrock, Vincent A. Miller, Philip J. Stephens, Laurie M. Gay, Leszek Kotula, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2018)

348 Background: We performed comprehensive genomic profiling (CGP) to learn whether sub-categorization of TMPRSS2 fusion status would impact therapy opportunities in patients with refractory CRPC and CRNEPC. Methods: DNA was extracted from 40 µm of FFPE sections of 2,424CRPC and 143 CRNEPC. CGP was performed on hybridization-captured, adaptor ligation-based libraries for up to 315 cancer-related genes. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: The median ages for all 4 groups was similar (Table). TMPRSS2+( TMP+) CRPC features significantly greater TP53 and PTEN GA and TMPRSS2-( TMP-) CRPC featured higher MYC and ATM GA. Differences in BRCA2 and RB1 GA were not significant in the CRPC group. RB1 GA were more frequent in CRNEPC than CRPC. TP53 GA were higher in TMP+ CRNEPC than in TMP+ CRPC whereas GA in PTEN and MYC were similar in comparative groups. GA in AR and ATM were more frequent in CRPC than CRNEPC. The median TMB was higher in CRNEPC than CRPC and higher in TMP- than TMP+ tumors. TMP- CRPC and TMP- CRNEPC had higher TMB levelsthan TMP+ tumors in both groups. MSI-High status was more frequent in the TMP- CRPC and TMP- CRNEPC groups. Conclusions: For CRPC but not CRNEPC, the frequency of TMP+CRPC cases appears lower in advanced vsearly stage disease (TCGA data). CGP reveals significant differences in both targetable GA and markers of immunotherapy response between TMP+ and TMP- CRPC and CRNEC. Thus, when CRPC and CRNEPC areevaluated as to their TMPRSS2:ERG fusion status, significant genomic differences emerge which may impact therapy selection.[Table: see text]
Influence of public health is under threat as senior posts remain unfilled
Authors: Caroline White
Journal: BMJ (2012)

Unfilled senior staff vacancies in public health in local authorities have led to fears that the strategic grip and influence of the specialty will be undermined when local government assumes responsibility for public health from next April.1

Shortages were particularly acute in London, a stocktake by the Local Government Association of staff transfers out of the NHS has shown.

The stocktake indicates that, although 95% of local authorities expected to fulfil public health functions effectively from next April, key leadership posts remained a concern “through the transition and beyond.”

As of October 2012, 19 of the expected 133 posts of director of public health in England’s 152 councils remained unfilled. The Midlands and East of England, the North, and the South clusters of strategic health authorities each have …
Racial/Ethnic Minority Youth With Recent-Onset Type 1 Diabetes Have Poor Prognostic Factors
Authors: Maria Jose Redondo, Ingrid Libman, Peiyao Cheng, Craig Kollman, Mustafa Tosur, Robin L. Gal, Fida Bacha, Georgeanna J. Klingensmith, Mark Clements, Maria Jose Redondo, Mustafa Tosur, William Tamborlane, Georgeanna Klingensmith, Mark A. Clements, Tamara S. Hannon, Rubina Heptulla, Joane Less, Ashley Shoemaker, Morey Haymond, Fida Bacha, Elizabeth Johnson, David Gomez, Alix Halter, Andrene McDonald, Lynda Fisher, Jamie Wood, Brian Ichihara, Megan Lipton, Sejal Shah, Avni Shah, Bruce Buckingham, Liana Hsu, Heidi Haro, Katherine Manseau, Janet Silverstein, Desmond Schatz, Michael J. Haller, Teresa Lyles, Jamie Thomas, Michelle Van Name, Eda Cengiz, Amy Steffen, Elvira Duran, Jennifer Finnegan, Joyce M. Lee, Surair Bashir, Ashley Eason, Roy W. Beck, Lindsey C. Beaulieu, Peiyao Cheng, Robin L. Gal, Craig Kollman, TJ Mouse, Samantha Reese, Katrina J. Ruedy
Journal: Diabetes Care (2018)

OBJECTIVE To compare races/ethnicities for characteristics, at type 1 diabetes diagnosis and during the first 3 years postdiagnosis, known to influence long-term health outcomes. RESEARCH DESIGN AND METHODS We analyzed 927 Pediatric Diabetes Consortium (PDC) participants &amp;lt;19 years old (631 non-Hispanic white [NHW], 216 Hispanic, and 80 African American [AA]) diagnosed with type 1 diabetes and followed for a median of 3.0 years (interquartile range 2.2–3.6). Demographic and clinical data were collected from medical records and patient/parent interviews. Partial remission period or “honeymoon” was defined as insulin dose–adjusted hemoglobin A1c (IDAA1c) ≤9.0%. We used logistic, linear, and multinomial regression models, as well as repeated-measures logistic and linear regression models. Models were adjusted for known confounders. RESULTS AA subjects, compared with NHW, at diagnosis, were in a higher age- and sex-adjusted BMI percentile (BMI%), had more advanced pubertal development, and had higher frequency of presentation in diabetic ketoacidosis, largely explained by socioeconomic factors. During the first 3 years, AA subjects were more likely to have hypertension and severe hypoglycemia events; had trajectories with higher hemoglobin A1c, BMI%, insulin doses, and IDAA1c; and were less likely to enter the partial remission period. Hispanics, compared with NHWs, had higher BMI% at diagnosis and over the three subsequent years. During the 3 years postdiagnosis, Hispanics had higher prevalence of dyslipidemia and maintained trajectories of higher insulin doses and IDAA1c. CONCLUSIONS Youth of minority race/ethnicity have increased markers of poor prognosis of type 1 diabetes at diagnosis and 3 years postdiagnosis, possibly contributing to higher risk of long-term diabetes complications compared with NHWs.
NHS must help overseas doctors fit into its culture, says RCGP
Authors: Abi Rimmer
Journal: BMJ (2015)

The NHS should help doctors who graduated from medical schools outside the UK fit in with the working culture of the NHS, the Royal College of General Practitioners’ lead on education has said.

Speaking at the Royal College of General Practitioners’ conference in Glasgow on Thursday 1 October, Jonathan Foulkes, the college’s medical director for quality management and training standards, said that the NHS needed international medical graduates and should help them to fit in.

“We are short of doctors. Not just GPs: we are short of paediatricians as well. All specialties are wanting more doctors,” Foulkes said. “If we want these doctors, as …