tbuckley/cabot-search huggingface dataset:
Abstract PD7-03: Adaptive kinome reprogramming in endocrine therapy resistant metastatic breast cancer
Authors: Derek Dustin, Guowei Gu, Doug Chan, Amanda Beyer, David Edwards, Matthew Ellis, Suzanne Fuqua
Journal: Cancer Research (2020)

Abstract Background: Approximately half of women with estrogen receptor (ER)-positive breast cancer who undergo adjuvant endocrine therapy (ET) develop disease progression and metastasis. Studies have revealed that up to 40% of metastatic patients develop tumors bearing a mutation in ESR1 which is associated with therapeutic resistance and poor prognosis. Studies have shown that cancers can undergo kinome reprogramming in response to therapy and acquired genetic alterations within the tumor. We hypothesize that expression of ESR1 mutations induces kinome reprogramming, which presents novel potential therapeutic targets to selectively treat ESR1 mutant metastatic breast cancer. Methods: We performed Kinobeads Precipitation (KiP) using broad specificity kinase inhibitors to capture and quantify by MS the level of active kinases in MCF-7 ESR1 wild-type and ESR1 Y537S mutant cells. We performed targeted siRNA screens and immunoblots to validate the hyperactivity of several of these kinases. Specific kinase inhibitors are being used to test their effects on proliferation and invasion in vitro, and in ex vivo organoid growth assays. Xenograft models are being used to evaluate the effects of the inhibitors on primary tumor growth and distant metastasis. Results: KiP analysis revealed hyperactivation of growth factor receptors, the PI3K/Akt/mTOR pathway, and MAPK pathway, in Y537S mutant cells. We tested specific inhibitors of these pathways, and have shown that the mutant cells have reduced proliferation when these pathways are targeted. We developed organoid growth assays using primary and metastatic tumors from xenograft and PDX models and found that ET in combination with these selected targeted kinase inhibitors decreased the growth of organoids. We are currently testing inhibitors in combination with ET in vivo, and preliminary results demonstrate a significant inhibition of primary tumor growth and distant metastasis. These results suggest that selective inhibition of hyperactivated “reprogrammed” kinase pathways can restore ET sensitivity in ESR1m tumors, and may show promise for use in ER-positive metastatic breast cancer patients. Citation Format: Derek Dustin, Guowei Gu, Doug Chan, Amanda Beyer, David Edwards, Matthew Ellis, Suzanne Fuqua. Adaptive kinome reprogramming in endocrine therapy resistant metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD7-03.
Erratum: Corrigendum: Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ERα metastatic breast cancer
Authors: Luca Magnani, Gianmaria Frigè, Raffaella Maria Gadaleta, Giacomo Corleone, Sonia Fabris, Mannus H Kempe, Pernette J Vershure, Iros Barozzi, Valentina Vircillo, Sung-Pil Hong, Ylenia Perone, Massimo Saini, Andreas Trumpp, Giuseppe Viale, Antonino Neri, Simak Ali, Marco Angelo Colleoni, Giancarlo Pruneri, Saverio Minucci
Journal: Nature Genetics (2017)
Selecting the surgical approach in complex reoperative partial nephrectomies: Does robotics have a role?
Authors: Sandeep Gurram, Siobhan Telfer, Winston Li, Heather Chalfin, W. Marston Linehan, Mark Wayne Ball
Journal: Journal of Clinical Oncology (2020)

658 Background: Minimally invasive surgery (MIS) has shown equal oncologic efficacy as the open approach for treating small renal masses but results in improved perioperative parameters. Surgical principles also dictate that the open technique should be considered when facing difficult surgeries though this is experience and not evidenced based. The goal of our study is to explore differences in outcomes amongst open or robotic approaches in complex reoperative partial nephrectomies. Methods: 194 patients who had prior renal surgery from 2008 to 2019 were identified, the majority of which presented with multiple tumors due to known or suspected hereditary kidney cancer syndrome. Patients were stratified into the following cohorts based on surgical history: open after open surgery, open after MIS, robotic after open surgery, and robotic after MIS. Perioperative outcomes were compared amongst cohorts. Results: Significant differences were noted in estimated blood loss (EBL), number of tumors resected, and postoperative complications as assessed by Clavien score. Univariate regression analysis of EBL showed that the number of tumors resected (p &lt;.0001, coefficient: 111 ml), number of prior renal procedures (p=.012, coefficient: 419 ml), hilar clamping (p = .015, coefficient: 840 ml), and intended surgical approach (p = .001; coefficient: 905 ml) were significant. On multivariate analysis, number of tumors resected (p&lt;.0001, coefficient: 97 ml) was the only significant factor. Univariate analysis on post-operative complications showed that number of prior surgeries (p = 0.03, OR: 1.5) and final intended approach (p &lt; .0001, OR: 4.6) were significant. On multivariate analysis, the final intended surgical approach (p = .001, OR: 4.3) was shown to be significant. Conclusions: These data show that the surgical approach of prior procedures is not a significant factor that affects perioperative outcomes, but the use of robotic surgery was associated with decreased post-operative complications in reoperative renal surgery . While open surgery will likely continue to be the standard of care for complex reoperative procedures, these data suggest that robotic surgery is safe and well tolerated in select cases.
Considering the Immune System during Fecal Microbiota Transplantation for Clostridioides difficile Infection
Authors: Alyse L. Frisbee, William A. Petri
Journal: Trends in Molecular Medicine (2020)

Our understanding and utilization of fecal microbiota transplantation (FMT) has jump-started over the past two decades. Recent technological advancements in sequencing and metabolomics have allowed for better characterization of our intestinal microbial counterparts, triggering a surge of excitement in the fields of mucosal immunology and microbiology. This excitement is well founded, as demonstrated by 90% relapse-free cure rates in FMT treatment for recurrent Clostridioides difficile infections. Growing evidence suggests that in addition to bacterial factors, the host immune response during C. difficile infection greatly influences disease severity. In this review, we discuss recent advancements in understanding the interplay between immune cells and the microbiota and how they may relate to recovery from C. difficile through FMT therapy.
WATChmAN: A randomized trial of virtual surveillance versus standard in-person care for clinical stage I testicular cancer.
Authors: Robert James Hamilton, Lauren Landoni, Kopika Kuhathaas, Peter W. M. Chung, Philippe L. Bedard, Padraig Richard Warde, Aaron Richard Hansen, Tran Truong, Ezra Hahn, Michael A.S. Jewett
Journal: Journal of Clinical Oncology (2020)

396 Background: Most guidelines recommend active surveillance (AS) as initial management for stage I testis cancer (TC). AS entails blood work and imaging at regular intervals requiring multiple clinic visits spanning 5 years. This can be time-consuming, difficult to adhere to, dissatisfying and costly for patients and health care systems. We innovated a secure online platform, WATChmAN (Web-based virtuAl Testicular CANcer clinic) allowing asynchronous communication between patients, results, and physician team. Methods: We are conducting an RCT (NCT03360994) where patients with stage I TC on AS are randomized to virtual care (WATChmAN), or standard in-person care. Primary endpoint is safety: examining loss-to-follow-up and compliance with AS schedules, incidence of relapse, delays in detection of relapse, and burden of relapse. Non-compliance represents a) patient-derived delay in visit; or b) follow-up visit with incomplete testing. Secondary endpoints include: patient/physician satisfaction and cost savings. Results: At present, 102 of a planned 144 patients are enrolled: 51 to virtual care, and 51 to standard in-person care. More patients in the virtual arm have been compliant with AS schedules (89% vs 73%) with shorter median compliance delays (12 vs. 14 days). To date, 10 patients have relapsed: 6 virtual (11.8%) and 4 standard (7.8%). Median time to relapse was shorter for the virtual arm (8 vs. 9.5 months), with no difference in burden of disease at relapse. Response rates to 6-month surveys were 90% and 59% for virtual and standard arms respectively. When asked if satisfied with their care, on the virtual arm 67% reported “extremely satisfied”, and 33% “satisfied” compared to 50% and 45% for the standard arm. When WATChmAN patients were asked if the application is able to provide the same excellence of care as in-person appointments, 82% reported “strongly agree” or “agree”. Conclusions: Interim results suggest virtual care in stage I TC is feasible and safe with improvements in patient satisfaction. Through semi-structured interviews and cost-effectiveness analyses, we anticipate more insight into virtual care. This may serve as a potential model for virtual care for other cancers. Clinical trial information: NCT03360994.
Deprescribing dementia drugs
Authors: Steve Iliffe, Jill Manthorpe
Journal: BMJ (2020)

Twenty years ago Prescrire International said that the effects of cholinesterase inhibitors were “only moderate and of doubtful clinical significance.”1 Nothing much has changed, judging by the French government’s decision to stop reimbursing this group of drugs, as discussed by Walsh and colleagues.2 The cholinesterase inhibitors and memantine seem effective for some people, but their benefits seem negligible in the population.3 The …
Risk factors for early mortality in patients with pulmonary tuberculosis admitted to the emergency room
Authors: R Singla, B Raghu, A Gupta, J A Caminero, P Sethi, D Tayal, A Chakraborty, Y Jain, G B Migliori
Journal: Pulmonology (2020)

Mortality of patients with pulmonary tuberculosis (TB) admitted to emergency departments is high. This study was aimed at analysing the risk factors associated with early mortality and designing a risk score based on simple parameters. This prospective case-control study enrolled patients admitted to the emergency department of a referral TB hospital. Clinical, radiological, biochemical and microbiological risk factors associated with death were compared among patients dying within one week from admission (cases) and those surviving (controls). Forty-nine of 250 patients (19.6%) experienced early mortality. Multiple logistic regression analysis showed that oxygen saturation (SaO2) ≤90%, severe malnutrition, tachypnoea, tachycardia, hypotension, advanced disease at chest radiography, severe anaemia, hyponatremia, hypoproteinemia and hypercapnia were independently and significantly associated with early mortality. A clinical scoring system was further designed to stratify the risk of death by selecting five simple parameters (SpO2 ≤ 90%, tachypnoea, hypotension, advanced disease at chest radiography and tachycardia). This model predicted early mortality with a positive predictive value of 94.88% and a negative predictive value of 19.90%. The scoring system based on simple parameters may help to refer severely ill patients early to a higher level to reduce mortality, improve success rates, minimise the need for pulmonary rehabilitation and prevent post-treatment sequelae.
Giant proerythroblasts in pure red cell aplasia due to parvovirus B19 infection in a patient with rheumatoid arthritis
Authors: Kirsteen Harper, Louisa McIlwaine, Mike Leach, Barbara J. Bain
Journal: American Journal of Hematology (2020)

A 72-year-old woman with rheumatoid arthritis presented with fatigue and chest pain and was noted to have a hemoglobin concentration of 43 g/L with absolute reticulocytopenia (3 × 109/L, normal range 50-100). The white cell and platelet counts were normal. The blood film showed no specific features. A bone marrow aspirate showed an absence of normal erythroid precursors with normal granulopoiesis and megakaryopoiesis. There were a number of extremely large cells up to 50 μm in diameter with deeply basophilic cytoplasm, occasionally with vacuolation (top left and center, ×100 objective). Some nuclei had inclusions and multiple bare nuclei from these giant cells were also apparent (top right, ×100). The bone marrow trephine biopsy confirmed the presence of giant proerythroblasts with an absence of more mature erythroid precursors (hematoxylin and eosin, ×50, bottom left; immunoperoxidase for glycophorin A, ×50 bottom center). Immunoperoxidase for parvovirus viral capsid antigens VP1 and VP2 showed positivity in the nuclei of the giant proerythroblasts (×50, bottom right). No parvovirus B19 IgM or IgG antibodies were detected but PCR for parvovirus DNA was positive. Parvovirus B19 is a single stranded DNA virus that specifically infects red cell precursors. Pure red cell aplasia caused by this virus is associated with the presence of giant proerythroblasts, often with viral inclusions (“lantern cells”) in the bone marrow. This diagnosis should be considered in immunosuppressed individuals with apparent red cell aplasia as protracted infection and severe anemia can result from their inability to clear the virus. Serology may be negative and PCR analysis is often required for detection of the virus in these patients. The patient reported here was receiving methotrexate, sulphasalazine, hydroxychloroquine and golimumab (anti-TNFα) therapy for her rheumatoid arthritis. Treatment with intravenous immunoglobulin resulted in reticulocytosis within 2 weeks of administration. The authors declare no potential conflict of interest.
Type I Interferon Response Dysregulates Host Iron Homeostasis and Enhances Candida glabrata Infection
Authors: Michael Riedelberger, Philipp Penninger, Michael Tscherner, Markus Seifert, Sabrina Jenull, Carina Brunnhofer, Bernhard Scheidl, Irina Tsymala, Christelle Bourgeois, Andriy Petryshyn, Walter Glaser, Andreas Limbeck, Birgit Strobl, Guenter Weiss, Karl Kuchler
Journal: Cell Host & Microbe (2020)
Marker lesion study of oral FGFR inhibitor BGJ398 in patients with FGFR3-altered intermediate-risk nonmuscle-invasive bladder cancer.
Authors: Eugene K. Cha, Gopa Iyer, Samuel Aaron Funt, Ashley Marie Regazzi, Jasmine Francis, M.H. Heinemann, Irina Ostrovnaya, Guido Dalbagni, Dean F. Bajorin, Bernard H. Bochner, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2020)

510 Background: FGFR3 alterations are prevalent in non-muscle-invasive bladder cancer (NMIBC). We conducted a marker lesion study of the oral FGFR inhibitor BGJ398 in patients with intermediate-risk NMIBC. Methods: Patients with recurrent clinical high-grade papillary NMIBC following intravesical BCG were eligible. FGFR3 alteration status was determined via testing of pre-treatment or archival tumor tissue. BGJ398 was administered at 125 mg PO daily for a 3 week on, 1 week off schedule (1 cycle). Response was determined after 2 cycles (at 7 weeks). Patients with a complete response (CR) had the option to continue therapy. Results: We enrolled four patients on trial, which we closed secondary to low accrual. Three patients had a CR at the 7-week evaluation. The other patient had a smaller, necrotic lesion after prematurely discontinuing treatment at 4 weeks. Clinically significant toxicities included eye disorders, skin and nail disorders, and elevations in LFTs. Two patients required dose reductions for toxicities. Two patients discontinued treatment before the 7-week evaluation, one for Grade 2 skin toxicity and the other for Grade 3 LFT elevation. All other toxicities were Grades 1 and 2. The other two patients continued treatment beyond a CR at 7 weeks but stopped after 3 and 4 cycles (after 11 and 16 weeks) for vision/skin toxicities and nail infection/mucositis, respectively. Conclusions: The oral FGFR inhibitor BGJ398 showed antitumor activity in a marker lesion study of patients with recurrent high-grade papillary NMIBC. Treatment was discontinued secondary to toxicities in all subjects, after a range of 4 to 16 weeks. Further investigation may be warranted for lower doses of oral BGJ398 or other formulations, such as intravesical delivery. Clinical trial information: NCT02657486. [Table: see text]
Human rhinovirus HRV16 induces antiviral responses and inhibits regeneration of human lung microvascular endothelium
Authors: Maciej Chalubinski, Mateusz Gawrysiak, Adrian Gajewski, Aleksandra Szulc, Malgorzata Pawelczyk, Aleksandra Likonska, Robert Szewczyk, Magdalena Chmiela, Marek Kowalski
Journal: Journal of Allergy and Clinical Immunology (2020)
Exenterative surgery to improve quality of life on men with locally advanced, symptomatic castration-resistant prostate cancer.
Authors: Friederike Haidl, Florian Hartmann, David A. Pfister, Axel Heidenreich
Journal: Journal of Clinical Oncology (2020)

77 Background: Invasion of the urinary bladder and/or the rectum by locally advanced castration sensitive (CSPC) or castration resistant PCA (CRPC) can result in debilitating symptoms with a significant negative impact on the patient’s well-being. Local progression might develop despite the application of new life prolonging agents. It was the purpose to retrospectively review the surgical and oncological outcome following pelvic exenteration surgery (PES) for locally advanced and symptomatic CRPC. Methods: Retrospective, single-centre, dual surgeon study of 103 men with symptomatic locally progressive and symptomatic CS- and CRPC treated between 2008 and 2019. Primary endpoint was symptomatic free survival (SFS) and the secondary endpoint were overall survival (OS) and complications defined by Clavien-Dindo criteria. Statistical tests were two-tailed with a p-value &lt;0.05 considered to indicate significance. Symptom-free survival and cancer specific survival were calculated using Kaplan-Meier analysis. Results: 9 (8.7%), 71 (68.8%) and 21 (22.4%) patients underwent radical prostatectomy, radical cystoprostatectomy or anterior and posterior exenteration, resp. After a median follow-up of 36.5 (3 – 123) months, the SFS at 1 and 3 years was 89.2% (n=89) and 64.1% (n=66). The median SFS was 27.9 months. 78.6% of the patients were symptom-free during their remaining lifetime. OS at 1 and 3 years was 92.2% and 43.7%, respectively, and the median OS was 33.6 months. Clavien-Dindo grade 2, 3 and 4 complications developed in 31 (30.6%), 12 (12%) and 8 (8.1%), respectively. Conclusions: PES is a technically feasible approach in well-selected patients resulting in symptom relief of &gt; 90% of patients which covered almost 80% of the remaining life time. Adequate preoperative imaging studies, endoscopic evaluation and extensive surgical experience is mandatory to achieving a benefit for the individual patient with improvement of quality of life.
Patient-reported outcomes from the phase III IMpassion130 trial of atezolizumab plus nab-paclitaxel in metastatic triple-negative breast cancer
Authors: S. Adams, V. Diéras, C.H. Barrios, E.P. Winer, A. Schneeweiss, H. Iwata, S. Loi, S. Patel, V. Henschel, S.Y. Chui, H.S. Rugo, L.A. Emens, P. Schmid
Journal: Annals of Oncology (2020)
High-exosomal AKR1C3 mRNA expression as a marker of poor efficacy of abiraterone in metastatic PCa patients.
Authors: Sha Zhu, Guangxi Sun, Xingming Zhang, Jindong Dai, Junru Chen, Xudong Zhu, Haoran Zhang, Yuchao Ni, Jinge Zhao, Zhipeng Wang, Pengfei Shen, Hao Zeng
Journal: Journal of Clinical Oncology (2020)

196 Background: Aldo-keto reductase family 1 member C3 (AKR1C3) has been proved to be an important part in the androgen biosynthesis process. Previous researches have showed that immunohistochemical (IHC) AKR1C3 expression is a prognosticator in prostate cancer (PCa) patients treated with abiraterone. This study is to find out the relationship between exosomal AKR1C3 mRNA expression and the efficacy of abiraterone in metastatic PCa patients. Methods: Blood samples of metastatic prostate cancer patients during different disease stages were collected. We isolated the exosomes and extracted the RNA for analysis of AKR1C3 by ddPCR. Absolute target mRNA concentration was measured by ddPCR as copies per milliliter (copies/20ul). Clinical data were collected for all patients. Primary study endpoint was progression-free survival (PFS). Statistical analyses were performed with SPSS 25.0. Results: Exosomal AKR1C3 mRNA expression was positive in 71.9% (41/57) patients, and high expression (defined as ≥ 20 copies/20μl) was found in 12.3% (7/57) patients. High exosomal AKR1C3 mRNA expression was not related to positive IHC AKR1C3 expression ( P=0.723). Patients with high exosomal AKR1C3 expression and negative IHC AKR1C3 expression harbored only 4.866 months’ median progression-free survival (PFS) compared with the whole cohort (9.37 months). High exosomal AKR1C3 expression is significantly associated with shorter PFS (median PFS 8.036 months, p&lt;0.001). Multivariate Cox regression analysis revealed that high exosomal AKR1C3 expression was an independent prognosticator of abiraterone treatment efficacy (OR: 8.891, 95%CI: 1.309-61.631, P=0.026). In subsequently subgroup analyses, high exosomal AKR1C3 expression demonstrates particularly high hazard ratio in multiple subgroups (patients with baseline PSA &gt;100 ng/mL, ALP &gt;71 IU/L, HGB &gt;120 g/L, and patients receiving abiraterone as first-line therapy in castration resistant prostate cancer). Conclusions: Exosomal AKR1C3 level is an independent adverse prognosticator in metastatic PCa patients receiving abiraterone treatment, especially when abiraterone was used as first-line therapy in castration resistant prostate cancer.
Orally applied bacterial lysate in infants at risk for atopy does not prevent atopic dermatitis, allergic rhinitis, asthma or allergic sensitization at school age: Follow‐up of a randomized trial
Authors: Siri Roßberg, Theresa Keller, Katja Icke, Valentina Siedmann, Imke Lau, Thomas Keil, Susanne Lau
Journal: Allergy (2020)

The allergy preventive effects of gut immune modulation by bacterial compounds are still not fully understood.We sought to evaluate the effect of bacterial lysate applied orally from the second until seventh months of life on the prevalence of allergic diseases at school age.In a randomized, placebo-controlled trial, 606 newborns with at least one allergic parent received orally a bacterial lysate consisting of heat-killed Gram-negative Escherichia coli Symbio and Gram-positive Enterococcus faecalis Symbio or placebo from week 5 until the end of month 7. A total of 402 children were followed until school age (6-11 years) for the assessment of current atopic dermatitis (AD), allergic rhinitis (AR), asthma and sensitization against aeroallergens.AD was diagnosed in 11.0% (22/200) of children in the active and in 10.4% (21/202) of children in the placebo group. AR was diagnosed in 35% (70/200) of children in the active and in 38.1% (77/202) children in the placebo group. Asthma was diagnosed in 9% (18/199) of children in the active and in 6.6% (13/197) of children in the placebo group. Sensitization occurred in 46.5% (66/142) of participants in the active and 51.7% (76/147) in the placebo group.An oral bacterial lysate of heat-killed Gram-negative Escherichia coli and Gram-positive Enterococcus faecalis applied during the first 7 months of life did not influence the development of AD, asthma and AR at school age.