tbuckley/cabot-search huggingface dataset:
Abstract ES4-2: Treatment morbidity and quality of life considerations
Authors: T Whelan
Journal: Cancer Research (2019)

Abstract Partial breast irradiation was introduced to reduce treatment times, improve convenience of radiotherapy and reduce radiation exposure to the breast and surrounding normal tissues. A number of techniques have been developed including interstitial brachytherapy, single catheter-based brachytherapy, intraoperative therapy, and 3 dimensional conformal or intensity modulated radiotherapy. The toxicity profile of partial breast irradiation has been dependent on the different techniques used. In general acute toxicity has been less than that observed with whole breast irradiation, particularly for intraoperative approaches where radiotherapy is delivered at the time of breast conserving surgery. Reports of late toxicity have varied. The majority of trials have observed no increase in late toxicity with interstitial brachytherapy and intraoperative treatment when compared to whole breast irradiation. Some studies of 3D conformal radiotherapy have reported an increase in late radiation toxicity such as telangiectasia of the skin and subcutaneous fibrosis of the breast. Limited data are available on cosmetic outcome and quality of life. Again, results to date have varied with some studies reporting similar cosmetic results and others indicating an increase in adverse cosmesis with partial breast irradiation when compared to whole breast irradiation. This presentation will review mature results from completed trials and discuss radiobiological inferences and implications for clinical decision making. Citation Format: Whelan T. Treatment morbidity and quality of life considerations [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES4-2.
Abstract P4-06-15: Role of B lymphocytes and B cell-produced IL-27 in breast cancer progression and drug resistance
Authors: H Yan, S Viswanadhapalli, M Fernandez, C Rivera, G Sareddy, P Casali, R Vadlamudi
Journal: Cancer Research (2019)

Abstract How host immune elements, particularly B cells, are hijacked to promote breast cancer (BCa) tumor progression and acquisition of resistance to current endocrine therapies remain largely unclear. Prompted by our recent findings that B cells are a major source of cytokine IL-27 (the heterodimer of IL-27p28 and EBI3), which regulates many immune functions as both a pro-inflammatory and anti-inflammatory cytokine, as well as the high expression of IL-27 receptor genes in the breast, elevated circulating IL-27 in BCa patients and the association of increased IL-27p28 expression with reduced survival in BCa patients overall and ER+ BCa patients after endocrine therapies, here we hypothesize that B cells promote BCa tumor progression and drug resistance and do so by producing IL-27. In C57 mice transplanted with ERa+ E0771 syngeneic medullary breast adenocarcinoma cells, deficiency in B cells in mMT mice resulted in virtually abolished tumor growth, resulting from significantly high tumor cell death. Remarkably, in residual tumors developed in mMT mice after transplantation with a higher load of E0771 cells, B cells, which were absent in the blood and lymph nodes, were accumulated within tumors – at an even higher frequency than that in wildtype C57 mice – and expressed IL-27. Further, like class-switching B cells that respond to IL-27 produced by neighboring B cells to express an IFNg-induced gene signature in the secondary lymphoid organ during the antibody response, a distinct population of tumor-infiltrating B cells expressed high levels of PD-L1, which could be induced by IL-27 in many immune cell types, including B cells, and several cancer cell types. Finally, IL-27 promoted the growth MCF-7 human BCa cells in the presence of tamoxifen in vitro, consistent with a role of B cell-produced IL-27 in the acquisition of drug resistance by BCa. These, together with the delayed tumor growth in mixed bone marrow chimeric mice with B cell-specific deficiency in IL-27 production, outline a potential role of B cell-produced IL-27 in BCa progression and drug resistance through both BCa cell-intrinsic mechanisms and induction of PD-L1+ B regulatory cells that participate in the immune checkpoint in BCa. Citation Format: Yan H, Viswanadhapalli S, Fernandez M, Rivera C, Sareddy G, Casali P, Vadlamudi R. Role of B lymphocytes and B cell-produced IL-27 in breast cancer progression and drug resistance [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-06-15.
<i>N</i>‐Linked Glycans in the Variable Domain of IgG Anti–Citrullinated Protein Antibodies Predict the Development of Rheumatoid Arthritis
Authors: Lise Hafkenscheid, Emma de Moel, Irene Smolik, Stacey Tanner, Xiaobo Meng, Bas C. Jansen, Albert Bondt, Manfred Wuhrer, Tom W. J. Huizinga, Rene E. M. Toes, Hani El‐Gabalawy, Hans U. Scherer
Journal: Arthritis & Rheumatology (2019)

Objective Anti–citrullinated protein antibodies (ACPAs) are disease‐specific biomarkers in rheumatoid arthritis (RA). More than 90% of IgG ACPAs harbor N ‐linked glycans in the antibody variable (V) domain. The corresponding N ‐glycosylation sites in ACPA V‐region sequences result from somatic hypermutation, a T cell–dependent process. As ample evidence indicates that T cells drive the maturation of the ACPA response prior to arthritis onset, we undertook this study to investigate whether the presence of glycans in IgG ACPA V domains predicts the transition from predisease autoimmunity to overt RA. Methods We analyzed 2 independent sets of serum samples obtained from 126 ACPA‐positive first‐degree relatives (FDRs) of RA patients. Both sets originated from an Indigenous North American population and comprised cross‐sectional and longitudinal samples of individuals who did or did not develop inflammatory arthritis. Serum IgG ACPAs were affinity‐purified and subjected to ultra high‐performance liquid chromatography–based glycan analysis. Results In both data sets, FDR‐derived IgG ACPA displayed markedly lower levels of V domain glycans (&lt;50%) compared to IgG ACPA from RA patients. Notably, FDRs who later developed RA showed extensive V‐domain glycosylation before the onset of arthritis. Moreover, IgG ACPA V‐domain glycosylation was strongly associated with future development of RA (hazard ratio 6.07 [95% confidence interval 1.46–25.2]; P = 0.013). Conclusion Extensive glycosylation of the IgG ACPA V domain is present in a subset of predisposed FDRs of Indigenous North American RA patients. The presence of this feature substantially increases the risk of RA development. Based on these findings, we propose that glycosylation of the IgG ACPA V domain represents a predictive marker for RA development in ACPA‐positive individuals and may serve to better target prevention measures.
T-bet Transcription Factor Promotes Antibody-Secreting Cell Differentiation by Limiting the Inflammatory Effects of IFN-γ on B Cells
Authors: Sara L. Stone, Jessica N. Peel, Christopher D. Scharer, Christopher A. Risley, Danielle A. Chisolm, Michael D. Schultz, Bingfei Yu, André Ballesteros-Tato, Wojciech Wojciechowski, Betty Mousseau, Ravi S. Misra, Adedayo Hanidu, Huiping Jiang, Zhenhao Qi, Jeremy M. Boss, Troy D. Randall, Scott R. Brodeur, Ananda W. Goldrath, Amy S. Weinmann, Alexander F. Rosenberg, Frances E. Lund
Journal: Immunity (2019)
Abstract P6-02-04: Ultrasound assessment of residual disease after neoadjuvant chemotherapy (NACT) in node positive triple negative breast cancer (TNBC)
Authors: BE Adrada, V Valero, SM Reddy, CH Barcenas, R Candelaria, W Wei, GM Rauch
Journal: Cancer Research (2019)

Abstract Purpose: To determine accuracy of preoperative ultrasound after NACT to predict residual disease in triple negative breast cancer (TNBC) patients with confirmed axillary nodal metastasis. Methods: This is an institutional review board approved retrospective study of TNBC patients who received NACT at MD Anderson Cancer Center from January 1999 - June 2015. We identified 327 TNBC patients who had cytologically confirmed breast and nodal disease at baseline evaluation and had preoperative ultrasound evaluation of residual disease. Ultrasound response was divided in tree categories: radiologic complete response (rCR) - complete resolution of the malignant mass); near-rCR - no discernible mass, only an isoechoic flat tumoral bed); and residual disease (RD) - a discernible mass is seen. Axillary ultrasound images were evaluated for lymph node size, cortical thickness and residual morphological type after NAC (type I-VI). Ultrasound breast and axillary findings were compared with final surgical pathology. Results: In 89 cases (27%), pCR was achieved. 74% (242/327) were unifocal and 26% (86/327) multifocal. Ultrasound rCR was seen in 11% patients (36/327). Of those, 64% (23/36) showed pCR and 36% (13/36) showed residual disease. Ultrasound near-rCR was seen in 26% (84/327). Of those, pCR was seen 49 % (41/84) and residual disease in 51% (43/84). Residual disease was seen in 63% (207/327), 12% (25/207) showed pCR and 88% (182/207) showed residual disease. Regarding axillary lymph nodes, long axis diameter mean was 1.57 cm for patients with pCR and 1.6 cm for no pCR, short axis diameter mean was 0.67 cm for pCR and 0.87 cm for no pCR. Cortical thickness mean was 2 mm for pCR versus 9 mm for no pCR. Sensitivity of ultrasound for assessment residual disease (ultrasound was considered positive if either breast ultrasound or axillary ultrasound showed residual disease) was 97%. Specificity is 22.47% with a NPV of 74% and PPV of 77%. Conclusion: Breast and axillary ultrasound performed after NACT showed low specificity but high sensitive to detect residual disease. rCR and near rCR were related with pCR in 64% and 49 % of the cases respectively. Citation Format: Adrada BE, Valero V, Reddy SM, Barcenas CH, Candelaria R, Wei W, Rauch GM. Ultrasound assessment of residual disease after neoadjuvant chemotherapy (NACT) in node positive triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-02-04.
Abstract P4-12-04: Use of complementary and integrative medicine therapies in Chilean patients with breast cancer. Experience of a private center: prevalence and characteristics of patients
Authors: C Salas, G Lopez, F Cadiz, C Barriga, P Gonzalez, S Acevedo, P Raimilla, P Pincheira, A Naing, M Quiroga
Journal: Cancer Research (2019)

Abstract Background: During the last decade several studies have been reported that the use of complementary and integrative medicine (CIM), defined as health care methods generated outside of standard Western, or conventional clinical practices has been increasing among breast cancer patients in developed countries. However, there is little information about the use of CIM in developing countries. Chile currently has no published statistics on the use of CIM in breast cancer. Methods: We conducted a cross-sectional survey between March and June 2017 in breast cancer patients treated in Clinica Alemana de Santiago to determine the prevalence of CIM use and the types of preferred CIM. We also analyzed associations between CIM and several variables including sociodemographic variables, the reasons that motivated the use of CIM and the subjective benefits that patients attributed to CIM. Statistical analysis included two tailed t–test for continuous variables, Fischer's exact test for categorical variables and logistic regression for association between CIM use and other variables. Results: 288 patients answered the survey. Among them, 98.9% were women, mostly between 41 and 50 years (40.4%). 44.9% (n = 129) reported using CIM. No association was found between the use of CIM and sociodemographic variables (sex, age, education, income). Most used CIM types were: vitamins / minerals (50.4%), herbs (48.8%), special diets (42.6%), meditation/prayers (37.2%). The reasons for CIM use were "to do everything possible" (72%), "improve immunity" (67.8%), "reduce side effects of treatment" (32.7%), recommendation by family member or friend (32.7%). Regarding CIM habits, 50.8% of patients reported having started CIM use at the time of diagnosis and only 51.6% reported about CIM use to their attending physician. Most patients reported benefits associated to CAM use (61%) but no differences were found in reported quality of life. Conclusions: Great amount of the patients reported using CIM and half of them mentioned that they shared this information with their attending physician. It is necessary incorporate to medical routines questions regarding CIM use and to educate the patients regarding the safe use of CIM and the possible interactions of these approaches with conventional clinical practices. Citation Format: Salas C, Lopez G, Cadiz F, Barriga C, Gonzalez P, Acevedo S, Raimilla P, Pincheira P, Naing A, Quiroga M. Use of complementary and integrative medicine therapies in Chilean patients with breast cancer. Experience of a private center: prevalence and characteristics of patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-12-04.
Migrant health workers’ access to healthcare
Authors: Caroline Kramarz
Journal: BMJ (2012)

Since the enlargement of the European Union in 2004, which allowed immigrants from Central and Eastern Europe to work legally in the UK, there have been regular reports of a strain on the UK’s public services.

According to the Office for National Statistics, GPs in England and Wales in 2007-8 had 605 000 new patients registered who were migrants.1 Yet, since 2000 there has only been a 2.3% annual increase in the number of GPs on average,2 so how do we know if these people are receiving adequate care?

These patients often face language barriers so practices might need to book them in for double appointments to explain procedures and treatments. This is usually done through a translator on the phone or …
All the small things
Authors: Alexander Gall
Journal: BMJ (2013)

Mendel’s Dwarf follows the fictional story of Benedict Lambert: a cynical, smart, and brilliantly funny genetic researcher, and an achondroplastic dwarf. Benedict leads us through his world: “a world of obstacles provided by the things of everyday life—chairs; laboratory benches; public toilets; buses; and, of course, people.” We look on, intrigued and compassionate, but never pitying, at this dwarf with his sharp mind and dark wit.

Benedict was born to “normal” parents, grew up in a normal house, and attended a normal school. His upbringing, however, was far from normal. A mixture of schoolyard bullying, derogatory presumptions about his intelligence, and a perpetual lack of eye contact plagued Benedict’s childhood and adolescence. Even his own father was culpable here, as Ben recalls, “Never throughout my …
Abstract P5-04-18: ARV-471, an oral estrogen receptor PROTAC degrader for breast cancer
Authors: JJ Flanagan, Y Qian, SM Gough, M Andreoli, M Bookbinder, G Cadelina, J Bradley, E Rousseau, R Willard, J Pizzano, CM Crews, AP Crew, I Taylor, J Houston
Journal: Cancer Research (2019)

Abstract ARV-471, an estrogen receptor (ER) alpha PROTAC, is a hetero-bifunctional molecule that facilitates the interactions between estrogen receptor alpha and an intracellular E3 ligase complex, leading to the ubiquitylation and subsequent degradation of estrogen receptors via the proteasome. ARV-471 robustly degrades ER in ER-positive breast cancer cell lines with a half-maximal degradation concentration (DC50) of ˜ 2 nM. PROTAC-mediated ER degradation decreases the expression of classically-regulated ER-target genes (PR, GREB1, TFF) and inhibits cell proliferation of ER-dependent cell lines (MCF7, T47D). Additionally, ARV-471 degrades clinically-relevant ESR1 variants (Y537S and D538G) and inhibits growth of cell lines expressing those variants. In an immature rat uterotrophic model, ARV-471 degrades rat uterine ER and demonstrates no agonist activity. Daily, oral-administration of single agent ARV-471 (3, 10, and 30 mpk) leads to significant tumor volume regressions of estradiol-dependent MCF7 xenografts and concomitant tumor ER protein reductions of &amp;gt;90% at study termination. Moreover, when a CDK4/6 inhibitor is combined with ARV-471 in the MCF7 model, even more pronounced tumor growth inhibition is observed (˜130% TGI), accompanied by significant reductions in ER protein levels. In an ESR1 Y537S, hormone-independent patient-derived xenograft model, ARV-471 at 10 mpk completely inhibited growth and also reduced mutant ER protein levels. Taken together, the preclinical data of ARV-471 supports its continued development as a best-in-class oral ER PROTAC-degrader. Citation Format: Flanagan JJ, Qian Y, Gough SM, Andreoli M, Bookbinder M, Cadelina G, Bradley J, Rousseau E, Willard R, Pizzano J, Crews CM, Crew AP, Taylor I, Houston J. ARV-471, an oral estrogen receptor PROTAC degrader for breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-18.
Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma
Authors: Emil Christensen, Karin Birkenkamp-Demtröder, Himanshu Sethi, Svetlana Shchegrova, Raheleh Salari, Iver Nordentoft, Hsin-Ta Wu, Michael Knudsen, Philippe Lamy, Sia Viborg Lindskrog, Ann Taber, Mustafa Balcioglu, Søren Vang, Zoe Assaf, Shruti Sharma, Antony S. Tin, Ramya Srinivasan, Dina Hafez, Thomas Reinert, Samantha Navarro, Alexander Olson, Rosalyn Ram, Scott Dashner, Matthew Rabinowitz, Paul Billings, Styrmir Sigurjonsson, Claus Lindbjerg Andersen, Ryan Swenerton, Alexey Aleshin, Bernhard Zimmermann, Mads Agerbæk, Cheng-Ho Jimmy Lin, Jørgen Bjerggaard Jensen, Lars Dyrskjøt
Journal: Journal of Clinical Oncology (2019)

PURPOSE Novel sensitive methods for early detection of relapse and for monitoring therapeutic efficacy may have a huge impact on risk stratification, treatment, and ultimately outcome for patients with bladder cancer. We addressed the prognostic and predictive impact of ultra-deep sequencing of cell-free DNA in patients before and after cystectomy and during chemotherapy. PATIENTS AND METHODS We included 68 patients with localized advanced bladder cancer. Patient-specific somatic mutations, identified by whole-exome sequencing, were used to assess circulating tumor DNA (ctDNA) by ultra-deep sequencing (median, 105,000×) of plasma DNA. Plasma samples (n = 656) were procured at diagnosis, during chemotherapy, before cystectomy, and during surveillance. Expression profiling was performed for tumor subtype and immune signature analyses. RESULTS Presence of ctDNA was highly prognostic at diagnosis before chemotherapy (hazard ratio, 29.1; P = .001). After cystectomy, ctDNA analysis correctly identified all patients with metastatic relapse during disease monitoring (100% sensitivity, 98% specificity). A median lead time over radiographic imaging of 96 days was observed. In addition, for high-risk patients (ctDNA positive before or during treatment), the dynamics of ctDNA during chemotherapy was associated with disease recurrence ( P = .023), whereas pathologic downstaging was not. Analysis of tumor-centric biomarkers showed that mutational processes (signature 5) were associated with pathologic downstaging ( P = .024); however, no significant correlation for tumor subtypes, DNA damage response mutations, and other biomarkers was observed. Our results suggest that ctDNA analysis is better associated with treatment efficacy compared with other available methods. CONCLUSION ctDNA assessment for early risk stratification, therapy monitoring, and early relapse detection in bladder cancer is feasible and provides a basis for clinical studies that evaluate early therapeutic interventions.
Fever and tachypnoea in a child
Authors: Dylon Christie, Neil Chanchlani, Sormeh Salehian
Journal: BMJ (2019)

A 10 year old girl presented to her local hospital with a one week history of fever of up to 40°C, lethargy, and decreased oral intake. Her parents reported an occasional dry, non-productive cough.

She was otherwise well, born at term, and up to date with vaccinations, including Bacille Calmette Guerin. She had no unwell close contacts. She had returned from holiday in Nigeria two months previously and had taken malaria prophylaxis.

She seemed tired, but responsive. She was tachypnoeic, but not in respiratory distress. On auscultation of her chest, she had bronchial breath sounds on the left side with reduced air entry from mid to lower zone, and percussion note was dull. An examination of her ears, nose, and throat was unremarkable, and no skin rashes were seen on inspection.

Observations at presentation were temperature 40°C (normal range 36.0-37.5), heart rate 140 beats/min (normal range 60-100), and respiratory rate 38 breaths/min (normal range 12-20) with pulse oximeter saturations 97% in room air (normal range >97).

Blood results were: haemoglobin 104 g/L (normal range 112-165), white cell count 15.7×109/L (normal range 3.5-10.8), neutrophils 11.3×109/L (normal range 1.5-8.0), platelets …
“Ma’am… Can you lift your breast please?”
Authors: Pishoy Gouda
Journal: BMJ (2013)

I got to the cardiac auscultation station of my clinical examination—a station I was relatively comfortable with—and read the instructions while waiting for the buzzer to sound. When it finally rang, I opened the door and my heart sank: the patient-actor was a woman.

For the previous few weeks, my classmates and I had spent our evenings perfecting our physical examination techniques for the examination. During one of those late night practice sessions, we realised we were not confident on how to perform the cardiac examination on a female patient. Where do you put your hand when you are feeling for thrills? What do you do with the patient’s bra? If the patient’s breast is in the way, do you move it gently aside, or do you ask the patient to do so? We had a lot of questions that most clinical textbooks do not cover. Finally, we gave …