tbuckley/cabot-search huggingface dataset:
Frailty has significant impact on treatment selection in patients with muscle-invasive bladder cancer.
Authors: Hiromichi Iwamura, Shingo Hatakeyama, Naoki Fujita, Teppei Okamoto, Yuichiro Suzuki, Fumitada Saito, Hayato Yamamoto, Atsushi Imai, Takahiro Yoneyama, Yasuhiro Hashimoto, Chikara Ohyama
Journal: Journal of Clinical Oncology (2020)

429 Background: Although measuring frailty is important to estimate risks and to aid shared decision making, the impact of frailty on surgical indication in muscle-invasive bladder cancer (MIBC) remain unclear. We aimed to investigate the impact of frailty on treatment modality selection in patients with MIBC. Methods: Between October 2013 and September 2019, we underwent frailty evaluation in 149 patients with localized or locally advanced MIBC (T2-4N0-1M0). Frailty evaluation included modified Frailty index (mFI), Fried phenotype (FP), and frailty discriminant score (FDS). Primary purpose was comparison of frailty between the patients who underwent radical cystectomy (RC group) and trimodal therapy for bladder preservation (TMT group). Optimal cutoff values of frailty between the RC and non-RC groups was defined by receiver operating characteristic curve. Secondary purpose included overall survival (OS) comparison between in patients with frail and non-frail. Overall survival (OS) was compared using Kaplan-Meier method and Cox regression analysis. Results: Of 149, 88 and 61 patients were classified to RC and TMT group, respectively. The median age in the TMT group was significantly older than that in the RC group (80 vs. 68 years). A significantly higher prevalence of frailty was observed in the TMT group than that of the RC group in FP ≥3 (5.7% vs. 61%, P &lt; 0.001), mFI ≥2 (22% vs. 61%, P &lt; 0.001), and FDS ≥2.30 (40% vs. 72%, P &lt; 0.001). Univariate logistic regression analysis showed that frailty was significantly associated with TMT. Frailty was significantly associated with overall survival between the RC and TMT groups in the FP and FDS, whereas it was not the case in mFI. Conclusions: Frailty was significantly associated with indication of RC in patients with MIBC. Measuring frailty is important to estimate risks and to aid shared decision making.
Validation of biochemical definition of cure after low-dose rate prostate brachytherapy.
Authors: Juanita M. Crook, Chad Tang, Howard Thames, Pierre Blanchard, Jeremiah Sanders, Jay P. Ciezki, Mira Keyes, Gregory Stephen Merrick, Charles N. Catton, Hamid Raziee, Richard Stock, Frank Sullivan, Mitch Anscher, Steven J. Frank
Journal: Journal of Clinical Oncology (2020)

322 Background: Prospectively collected outcome data for 14,196 patients with localized prostate cancer treated with LDR brachytherapy (BT) from 7 institutions were analyzed. For the 80% of patients with a 4 year PSA &lt; 0.2 ng/ml, 99% were free of clinical failure at 10 years and 96% at 15 years. We sought to validate this result with 2 independent data sets from mature prospective clinical trials. Methods: In the initial analysis, patients were treated with either BT alone (61%), or in combination with external beam radiotherapy (EBRT:8%), androgen deprivation (ADT:22%) or both (9%). 42% were low risk, 50% intermediate (IR) and 8% high risk(HR). KM analysis was carried out using clinical failure (local, distant, regional or biochemical triggering salvage) as endpoints for each of 4 PSA categories: PSA&lt;0.2 ng/ml, PSA &gt;0.2 to &lt; 0.5, PSA &gt; 0.5 to &lt; 1.0, and PSA&gt;1.0 ng/ml. Results were compared to 12 year follow up data on a phase 2 trial of BT for IR prostate cancer (n=223; MDAnderson Cohort 1) and 10-year data from the BT arm of the phase 3 randomized ASCENDE RT trial (n=160, Cohort 2) for upper tier IR and HR prostate cancer. Results: The results of the initial KM analysis showed that for the 80% of patients with PSA &lt; 0.2 ng/ml at 4 years, 99% were free of recurrence at 10 years (95% CI: 98.4-99.1) and 96% at 15 years (95% CI: 95-97). The association of treatment success with PSA range was highly significant (p&lt;0.0005). Independent validation against BT alone in IR patients (Cohort 1) confirmed that 99% of patients with PSA at 4 years &lt; 0.2 ng/ml were NED at 10 years (CI: 95.8-99.9). For the unfavorable IR and HR patients receiving 12 months ADT + pelvic EBRT and BT in ASCENDE-RT (Cohort 2), PSA &lt; 0.2 ng/ml at 4 years was associated with 96.7% (CI: 89.9-98.9) being failure free at 10 years. Conclusions: As over 80% of patients achieve a PSA &lt; 0.2 ng/ml at 4 years post-LDR BT, and this is associated with 97%-99% being disease free beyond 10 years, we suggest that this biochemical definition of cure be adopted for LDR brachytherapy patients with ≥ 4 years’ follow-up.
Clinical features and survival of patients with indolent systemic mastocytosis defined by the updated WHO classification
Authors: Jakub Trizuljak, Wolfgang R. Sperr, Lucie Nekvindová, Hanneke O. Elberink, Karoline V. Gleixner, Aleksandra Gorska, Magdalena Lange, Karin Hartmann, Anja Illerhaus, Massimiliano Bonifacio, Cecelia Perkins, Chiara Elena, Luca Malcovati, Anna B. Fortina, Khalid Shoumariyeh, Mohamad Jawhar, Roberta Zanotti, Patrizia Bonadonna, Francesca Caroppo, Alexander Zink, Massimo Triggiani, Roberta Parente, Nikolas von Bubnoff, Akif S. Yavuz, Hans Hägglund, Mattias Mattsson, Jens Panse, Nadja Jäkel, Alex Kilbertus, Olivier Hermine, Michel Arock, David Fuchs, Vito Sabato, Knut Brockow, Agnes Bretterklieber, Marek Niedoszytko, Björn van Anrooij, Andreas Reiter, Jason Gotlib, Hanneke C. Kluin‐Nelemans, Jiri Mayer, Michael Doubek, Peter Valent
Journal: Allergy (2020)

Abstract Background In indolent systemic mastocytosis (ISM), several risk factors of disease progression have been identified. Previous studies, performed with limited patient numbers, have also shown that the clinical course in ISM is stable and comparable to that of cutaneous mastocytosis (CM). The aim of this project was to compare the prognosis of patients with ISM with that of patients with CM. Methods We employed a dataset of 1993 patients from the registry of the European Competence Network on Mastocytosis (ECNM) to compare outcomes of ISM and CM. Results We found that overall survival (OS) is worse in ISM compared to CM. Moreover, in patients with typical ISM, bone marrow mastocytosis (BMM), and smoldering SM (SSM), 4.1% of disease progressions have been observed (4.9% of progressions in typical ISM group, 1.7% in BMM, and 9.4% in SSM). Progressions to advanced SM were observed in 2.9% of these patients. In contrast, six patients with CM (1.7%) converted to ISM and no definitive progression to advanced SM was found. No significant differences in OS and event‐free survival (EFS) were found when comparing ISM, BMM, and SSM. Higher risk of both progression and death was significantly associated with male gender, worse performance status, and organomegaly. Conclusion Our data confirm the clinical impact of the WHO classification that separates ISM from CM and from other SM variants.
Letter from China: covid-19 on the grapevine, on the internet, and in commerce
Authors: Heather Mowbray
Journal: BMJ (2020)

In medically murky times in China, people are turning to rumour, hope, and faith to protect themselves from the new coronavirus. In Beijing, <b>Heather Mowbray</b> is hearing all sorts of stories about how to stop the virus—but scientific evidence for the advice is woefully absent
Real-World Evidence of Improved Patient Outcomes with Reslizumab in Adults with Severe Eosinophilic Asthma (SEA): Subgroup Analyses of Patients Using Maintenance Oral Corticosteroids (OCS) Prior to Treatment Initiation
Authors: Reynold Panettieri, Michael Wechsler, Stephen Peters, Bradley Chipps, Tanisha Hill, Rinat Ariely, Michael Depietro, Emi Terasawa, Darren Thomason
Journal: Journal of Allergy and Clinical Immunology (2020)
Axons Matter: The Promise of Treating Neurodegenerative Disorders by Targeting SARM1-Mediated Axonal Degeneration
Authors: Raul Krauss, Todd Bosanac, Rajesh Devraj, Thomas Engber, Robert O. Hughes
Journal: Trends in Pharmacological Sciences (2020)

Attempts to develop neuroprotective treatments for neurodegenerative disorders have not yet been clinically successful. Axonal degeneration has been recognized as a predominant driver of disability and disease progression in central nervous system (CNS) diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis, and Parkinson's disease, peripheral nervous system (PNS) disorders such as chemotherapy-induced, diabetic, and inherited neuropathies, and ocular disorders, such as glaucoma. In recent years, sterile alpha and TIR motif containing 1 (SARM1) has emerged as the first compelling axonal-specific target for therapeutic intervention. In this review, we discuss the role of axonal degeneration in neurodegenerative disorders, with a focus on SARM1 and the discovery of its intrinsic enzymatic function. Establishment of neurofilament light chain (NfL) as a reliable biomarker of axonal damage, and the availability of an ultrasensitive method for measuring NfL in plasma or serum, provide translational tools to make development of axonal protective, SARM1 inhibitors a viable approach to treat multiple neurodegenerative disorders.
Associations of α- and γ-tocopherol during early life with lung function in childhood
Authors: Rajesh Kumar, Ryan P. Ferrie, Lauren C. Balmert, Matthew Kienzl, Sheryl L. Rifas-Shiman, Diane R. Gold, Joanne E. Sordillo, Ken Kleinman, Carlos A. Camargo, Augusto A. Litonjua, Emily Oken, Joan M. Cook-Mills
Journal: Journal of Allergy and Clinical Immunology (2020)
98P Octreotide in Combination with Docetaxel Triggers Apoptosis by Inducing Sstr2 and Sstr5 Levels in Human Breast Cancer Cells, Mcf-7 and Mda-Mb-231
Authors: B. Karaca, U. Muslu, Z.G. Surmeli, B. Cakar, H. Atmaca, K. Asli, C. Sezgin, S. Uzunoglu, B. Karabulut, R. Uslu
Journal: Annals of Oncology (2012)
Origin of a second malignancy harboring isochromosome 12p [i(12p)] in patients with history of testicular germ cell tumor (TGCT).
Authors: Michael J. Hwang, Bilal A. Siddiqui, Kelly W. Merriman, Joma Uthup, John Francis Ward, Jose A. Karam, Christopher G. Wood, Louis L. Pisters, Miao Zhang, Shi-Ming Tu
Journal: Journal of Clinical Oncology (2020)

412 Background: The cumulative incidence of subsequent solid malignant neoplasm (SMN) after treatment of TGCT is about 10% over a 25-year period. i(12p) has been used to define tumor of germ cell origin. We evaluated the prevalence of i(12p) on various subsequent SMN in patients with a history of TGCT. Methods: From the Tumor Registry database at MD Anderson, we identified 655 TGCT patients who developed a second (third or fourth) malignancy between January 1990 and September 2018. Of those 114 SMN from the GI tract, GU system, chest, brain, sarcomas or melanomas between 2011 and 2017, 43 had tumor tissue available at our institution and of sufficient quality for fluorescence in situ hybridization (FISH) of i(12p). Results: Our cohort comprised 43 patients, excluding 2 cases (#6 and 7) whose SMN tested positive and their non-tumor controls negative for i(12p). Diagnosis of primary TGCT and SMN: age, mean 41 yrs (range 20-68 yrs) and 59 yrs (range 34-86 yrs), respectively, and interval of 18 yrs (range 0-57 yrs). Of those 43 cases (5 did not hybridize), 5 (11%) harbored i(12p), while 16 (37%) had additional copies of chromosome 12 without apparent gain of 12p. Conclusions: Prevalence of i(12p) on subsequent SMN in our patient cohort with a history of TGCT was 11%. Detection of i(12p) in those patients with TGCT in general and with nonseminomas in particular suggests somatic transformation, emphasizes importance of a complete surgical resection of residual teratomatous tumor after chemotherapy, and implicates a stem-cell origin and nature (e.g., plasticity, heterogeneity, dormancy) of cancer. *deceased; Rx – initial treatments; S – seminoma; NS – nonseminoma; BEP – bleomycin, etoposide, cisplatin; CEB – carboplatin, etoposide, bleomycin; XRT – radiation therapy. Groot HJ, Lubberts S, de Wit R, et al. Risk of solid cancer after treatment of testicular germ cell cancer in the platinum era. J Clin Oncol 2018;36:2504-13.
Is treat-to-target really working in rheumatoid arthritis? a longitudinal analysis of a cohort of patients treated in daily practice (RA BIODAM)
Authors: Sofia Ramiro, Robert BM Landewé, Désirée van der Heijde, Alexandre Sepriano, Oliver FitzGerald, Mikkel Ostergaard, Joanne Homik, Ori Elkayam, J Carter Thorne, Margaret Larche, Gianfranco Ferraciolli, Marina Backhaus, Gilles Boire, Bernard Combe, Thierry Schaeverbeke, Alain Saraux, Maxime Dougados, Maurizio Rossini, Marcello Govoni, Luigi Sinigaglia, Alain G Cantagrel, Cornelia F Allaart, Cheryl Barnabe, Clifton O Bingham, Paul P Tak, Dirkjan van Schaardenburg, Hilde Berner Hammer, Rana Dadashova, Edna Hutchings, Joel Paschke, Walter P Maksymowych
Journal: Annals of the Rheumatic Diseases (2020)

Objectives To investigate whether following a treat-to-target (T2T)-strategy in daily clinical practice leads to more patients with rheumatoid arthritis (RA) meeting the remission target. Methods RA patients from 10 countries starting/changing conventional synthetic or biological disease-modifying anti-rheumatic drugs were assessed for disease activity every 3 months for 2 years (RA BIODAM (BIOmarkers of joint DAMage) cohort). Per visit was decided whether a patient was treated according to a T2T-strategy with 44-joint disease activity score (DAS44) remission (DAS44 &lt;1.6) as the target. Sustained T2T was defined as T2T followed in ≥2 consecutive visits. The main outcome was the achievement of DAS44 remission at the subsequent 3-month visit. Other outcomes were remission according to 28-joint disease activity score-erythrocyte sedimentation rate (DAS28-ESR), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI) and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean definitions. The association between T2T and remission was tested in generalised estimating equations models. Results In total 4356 visits of 571 patients (mean (SD) age: 56 (13) years, 78% female) were included. Appropriate application of T2T was found in 59% of the visits. T2T (vs no T2T) did not yield a higher likelihood of DAS44 remission 3 months later (OR (95% CI): 1.03 (0.92 to 1.16)), but sustained T2T resulted in an increased likelihood of achieving DAS44 remission (OR: 1.19 (1.03 to 1.39)). Similar results were seen with DAS28-ESR remission. For more stringent definitions (CDAI, SDAI and ACR/EULAR Boolean remission), T2T was consistently positively associated with remission (OR range: 1.16 to 1.29), and sustained T2T had a more pronounced effect on remission (OR range: 1.49 to 1.52). Conclusion In daily clinical practice, the correct application of a T2T-strategy (especially sustained T2T) in patients with RA leads to higher rates of remission.
Abstract 333: End-Tidal Carbon Dioxide, CPR Quality and ROSC During Pediatric Cardiac Arrests in a Large Academic Children’s Hospital, 2013-2018
Authors: Jill L Sorcher, Elizabeth A Hunt, Donald H Shaffner, Justin Jeffers, Heather Newton, Sara I Jones, Oluwakemi Badaki-Makun, Jordan M Duval-arnould
Journal: Circulation (2019)

Normal 0 false false false EN-US X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Calibri",sans-serif; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;} Little evidence exists to guide end-tidal carbon dioxide (ETCO 2 ) use during cardiac arrest events in pediatric populations. Despite this, integrating physiologic feedback, including ETCO 2 , into resuscitation optimization is recognized as an important component to precision resuscitation. This was a prospective observational study of ETCO 2 , CPR quality and ROSC. The study population included any pediatric patient who received chest compressions from January 1, 2013 through July 10, 2018 in the Johns Hopkins Children’s Center. During this time, 457 arrest events of any length requiring chest compressions occurred. Of these events, 274 utilized ETCO 2 in some capacity and 198 recorded ETCO 2 on a Zoll R Series® defibrillator. Data files from 145 of these events that contained both chest compression and ETCO 2 data were successfully obtained. These 145 events contained 2200 minutes of ETCO 2 data and 2156 minutes of both chest compression and ETCO 2 data; values are reported as median [IQR]. The average ETCO 2 for all events was 21 mmHg [15-32]. ETCO 2 by age category was (0-1: 12 [0-29]; 1-8: 20 [2-35]; 8+: 10.15 [0-21]). When comparing patients who achieved ROSC &gt; 20 minutes to those who did not, we observed a significant difference in ETCO 2 between those who survived and those who did not (ROSC: 25 [15-30] vs. NO ROSC: 15 [9-22]; p&lt;0.001). Analysis to assess associations between ROSC and chest compression depth, rate, and fraction are underway. In this analysis of the largest set of pediatric ETCO 2 and resuscitation data, our findings suggest that a difference may exist in survival associated with an ETCO 2 difference between 15 and 20 mmHg.
Genomic biomarkers of response to lenvatinib/pembrolizumab (Len/Pembro) in patients with advanced renal cell carcinoma.
Authors: Chung-Han Lee, Renzo G. DiNatale, Diego Chowell, Chriag Krishna, Vladimir Makarov, Natalie Shapnik, Samuel J. Murray, Maria Isabel Carlo, Martin H Voss, Darren R. Feldman, A. Ari Hakimi, Yusuke Adachi, Yukinori Minoshima, Junji Matsui, Yasuhiro Funahashi, Rodolfo F. Perini, Kenichi Nomoto, Robert J. Motzer, Timothy An-thy Chan
Journal: Journal of Clinical Oncology (2020)

733 Background: A phase 1b/2 clinical trial indicated that len/pembro shows promise in the treatment of renal cell carcinoma (RCC) in both PD-1/PD-L1 immune checkpoint blockade (ICB)-naïve and pretreated patients (NCT02501096). The combination is being further investigated in a phase 3 clinical trial in RCC (NCT02811861). Tumor antigen presentation depends on multiple factors, including HLA diversity, which can be measured by HLA evolutionary divergence (HED). HED quantitates the capacity of a patient’s HLA genotype to present different peptide antigens. This study is investigating the genomic components of tumor antigen presentation in ICB-naïve patients who have RCC and are treated with len/pembro. Methods: Whole exome sequencing (WES) was performed on pretreatment tumor-derived DNA. Somatic mutations, tumor mutation burden (TMB), neoantigen (NA) load, germline HLA zygosity and somatic loss of heterozygosity (LOH), and HED were correlated with objective response rate (ORR) and progression-free survival (PFS). An updated clinical cutoff was March 29, 2019. Results: Twenty four (80%) of 30 ICB-naïve patients underwent WES. A top-quartile cutoff was used. Increased mean HED was associated with improved PFS, while HLA homozygosity or LOH trended toward worse PFS. Loss-of-function mutations in PBRM1 (PBRM1 LOF) trended toward improved PFS. However, TMB and NA load were not correlated to PFS. No genomic biomarkers were correlated to ORR. Conclusions: Increased HLA diversity was associated with improved PFS, while decreased HLA diversity may be associated with worse PFS. PBRM1 mutation may be associated with improved PFS; however, TMB and NA load were not correlated to outcomes. These findings warrant further examination in larger datasets to rule out possible artifacts from multiple testing in a small cohort. Clinical trial information: NCT02811861. [Table: see text]
RNA-Seq of Gastrointestinal Biopsies During Oral Immunotherapy Reveals Changes in IgA Pathway
Authors: Wenming Zhang, Gopal Dhondalay, Ramona Hoh, Dana Tupa, Bryan Bunning, Nielsen Fernandez-Becker, Neeraja Kambham, Scott Boyd, Stephen Galli, Sandra Andorf, Monali Manohar, Sharon Chinthrajah, Kari Nadeau
Journal: Journal of Allergy and Clinical Immunology (2020)
Safety and efficacy of restarting immune checkpoint inhibitors after clinically significant immune-related adverse events in metastatic renal cell carcinoma
Authors: Sarah Abou Alaiwi, Wanling Xie, Amin H Nassar, Shaan Dudani, Dylan Martini, Ziad Bakouny, John A Steinharter, Pier Vitale Nuzzo, Ronan Flippot, Nieves Martinez-Chanza, Xiao Wei, Bradley A McGregor, Marina D Kaymakcalan, Daniel Y C Heng, Mehmet A Bilen, Toni K Choueiri, Lauren C Harshman
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Immune checkpoint inhibitors (ICI) induce a range of immune-related adverse events (irAEs) with various degrees of severity. While clinical experience with ICI retreatment following clinically significant irAEs is growing, the safety and efficacy are not yet well characterized. Methods This multicenter retrospective study identified patients with metastatic renal cell carcinoma treated with ICI who had &gt;1 week therapy interruption for irAEs. Patients were classified into retreatment and discontinuation cohorts based on whether or not they resumed an ICI. Toxicity and clinical outcomes were assessed descriptively. Results Of 499 patients treated with ICIs, 80 developed irAEs warranting treatment interruption; 36 (45%) of whom were restarted on an ICI and 44 (55%) who permanently discontinued. Median time to initial irAE was similar between the retreatment and discontinuation cohorts (2.8 vs 2.7 months, p=0.59). The type and grade of irAEs were balanced across the cohorts; however, fewer retreatment patients required corticosteroids (55.6% vs 84.1%, p=0.007) and hospitalizations (33.3% vs 65.9%, p=0.007) for irAE management compared with discontinuation patients. Median treatment holiday before reinitiation was 0.9 months (0.2–31.6). After retreatment, 50% (n=18/36) experienced subsequent irAEs (12 new, 6 recurrent) with 7 (19%) grade 3 events and 13 drug interruptions. Median time to irAE recurrence after retreatment was 2.8 months (range: 0.3–13.8). Retreatment resulted in 6 (23.1%) additional responses in 26 patients whose disease had not previously responded. From first ICI initiation, median time to next therapy was 14.2 months (95% CI 8.2 to 18.9) and 9.0 months (5.3 to 25.8), and 2-year overall survival was 76% (95%CI 55% to 88%) and 66% (48% to 79%) in the retreatment and discontinuation groups, respectively. Conclusions Despite a considerable rate of irAE recurrence with retreatment after a prior clinically significant irAE, most irAEs were low grade and controllable. Prospective studies are warranted to confirm that retreatment enhances survival outcomes that justify the safety risks.
The Low-FODMAP Diet Helps IBS Symptoms, but Questions Remain
Authors: Anita Slomski
Journal: JAMA (2020)

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