tbuckley/cabot-search huggingface dataset:
Rationale for the utilization of biological targeted agents (bTAs) in the treatment of metastatic colorectal cancer (mCRC), single tertiary cancer center experience.
Authors: Ivan Barrera, Yahia A. Lakehal, Tomas Kavan, Petr Kavan
Journal: Journal of Clinical Oncology (2021)

e15589 Background: Worldwide treatment for 1st line (1LTx) mCRC included doublet or triple chemotherapy with or without bTAs. In Quebec, the anti-EGFR therapy (panitumumab or cetuximab) was only recently approved in this setting for patients RAS WT, Bevacizumab (B) not eligible. In this study we evaluated the rational and outcomes using bTAs. Methods: Retrospective study assessing mCRC pts treated with or without bTAs at any time throughout the course of therapy at the Jewish General Hospital between 2010-2018. Pts were divided in 3 groups according to their 1LTx for analysis: Chemotherapy alone (1LChA), Chemotherapy plus B (1LChB), and anti-EGFR with or without chemotherapy (1LaEGFR). The primary objective was to assess the rational of bTAs prescription based in 1LTx selection. Secondary objectives included safety, PFS and OS. Results: Among a total of 463 pts with mCRC; 196 pts (42.3%) received 1LChA, 246 pts (53.2%) 1LChB, and 21 pts (4.5%) 1LaEGFR respectively. 1LChA group, 51% omitted bTAs for physician-patient preferences, 96 pts (49%) had contraindications for B, and 79 pts (40.3%) were potentially candidates for aEGFR, but did not receive it. 152/196 (77.5%) pts continued to 2LTx and 34.8% received bTAs. As for the 3LTx, 78/196 (40%) received a treatment, 48.7% received bTAs. The most common grade 3-4 adverse events (AEs) were hypertension and bowel perforation in B, gastrointestinal (GI) symptoms and skin reaction (SR) in aEGFR. 1LChB group, 31 pts (12.6%) presented AEs related to B. 191/246 pts (77.6%) continued to 2LTx with 48 pts (25%) receiving ChB despite progression in 1LTx on this bTA and 19 pts (10%) receiving aEGFR. The most common AEs reported in 2LTx were GI symptoms and neuropathy. In 3LTx, 54/91pts (59.3%) received aEGFR therapy and 8 pts (14.8%) had SR AEs. 46 pts (18.6%) continued to 4LTx, 13/46 pts (28.2%) received aEGFR. 1LaEGFR group, the most common AEs were SR and GI symptoms. 11/21 pts (52.3%) continued to 2LTx; 5 pts (45.4%) switching bTA class and receiving ChB. 81% pts started treatment between 2017-2018 and had at least two contraindication criteria for. The median PFS for the 1LChA and 1LChB groups were 10 and 11.5 months, respectively, and were not statistically significant (p=0.22). The OS with 1LChA and 1LChB was 33.26 vs. 27.80 months (p=0.27). The PFS and OS between 1LChA and 1LaEGFR were 10 vs 11 months (p= 0.27) and 33.26 vs. 35.07 months (p=0.13). Conclusions: The outcome and tolerability of bTAs in mCRC appear similar in our institution and randomised trials. We were not able to detect any significant difference among the three groups of comparison. The 1LaEGFR available data in this subset of patients are limited. Our data highlights the importance of optimal therapeutic sequencing to prolong OS. Dedicated studies are needed in order to determine the best bTAs therapeutic strategy in mCRC.
Non-small cell lung cancer population mortality and stage shift.
Authors: Parth Bhargav Patel, Naomi Alpert, Bruce Pyenson, Emanuela Taioli, Raja Michael Flores
Journal: Journal of Clinical Oncology (2021)

e20536 Background: Lung cancer population mortality has decreased over the last decade. Smoking cessation, medical therapies, CT screening, and earlier therapeutic interventions may all contribute to this decrease. We investigate the role of stage shift on population mortality of non-small cell lung cancer (NSCLC). Methods: Data from Surveillance, Epidemiology, and End Results (SEER) were queried to assess all patients from 2006-2016 with microscopically confirmed NSCLC. Incidence based mortality was evaluated by year of diagnosis. In order to assess shifts in diagnostic characteristics, stage and histology distributions were examined by year using χ2 tests. Trends were assessed by using the average annual percentage change (AAPC), calculated with JoinPoint software. Kaplan-Meier survival analysis was also performed to assess overall survival according to stage and to compare those missing any stage to those with a reported stage. Results: Between 2006-2016, 312,382 patients in SEER were diagnosed with NSCLC. Incidence based mortality within 5 years of diagnosis for NSCLC has significantly decreased over the last decade (AAPC -3.7 (95% confidence interval (CI): -4.1 - -3.4)). When assessing stage shift, there was a significant association between year of diagnosis and stage (p &lt; 0.0001), with the percent in each year diagnosed at stage I/II increasing from 26.5% to 31.2% from 2006-2016, corresponding to a statistically significant AAPC of 1.5 (95% CI: 0.5-2.5); the percent diagnosed at stage III/IV decreased significantly from 70.8% to 66.1% (AAPC: -0.6 (95% CI: -1.0 - -0.2)). The percent missing staging information was relatively stable in this timeframe and not significant (AAPC: -1.6 (-7.4 - 4.5)). Year of diagnosis was significantly associated with tumor histology (p &lt; 0.0001). There was a statistically significant increase in the percent of those diagnosed with adenocarcinomas, from 42.9% in 2006 to 59.0% in 2016 (AAPC: 3.4 (95% CI: 2.9-3.9)). Median survival for those with stage I/II was 57 (interquartile range (IQR): 18- - ) months; for stage III/IV was 7 (IQR: 2-19) months; and for those missing stage was 10 (IQR: 2-28) months. Patients with stage I/II had significantly better survival compared to those diagnosed with stage III/IV, or missing stage (p &lt; 0.0001). Conclusions: Population-level mortality for NSCLC has decreased from 2006-2016. While advances in treatments, particularly targeted therapeutics have played a role in affecting mortality, our analysis suggests that decreased mortality is also due to a diagnostic shift from later to earlier stage lung cancer. Studies investigating the effectiveness of treatment on lung cancer mortality must take into account the confounding effect of stage shift on survival and mortality outcome.
Inhibition of SENP6 restrains cerebral ischemia-reperfusion injury by regulating Annexin-A1 nuclear translocation-associated neuronal apoptosis
Authors: Qian Xia, Meng Mao, Zhen Zeng, Zhenzhao Luo, Yin Zhao, Jing Shi, Xing Li
Journal: Theranostics (2021)

Rationale: Annexin-A1 (ANXA1) has previously been proposed to play a crucial role in neuronal apoptosis during ischemic stroke injury. Our recent study demonstrated that ANXA1 was modified by SUMOylation, and that this modification was greatly weakened after cerebral ischemia, but its effect on neuronal death and the underlying mechanism have not been fully elucidated. Methods: Mice subjected to middle cerebral artery occlusion were established as the animal model and primary cultured neurons treated with oxygen-glucose deprivation and reperfusion was established as the cell model of ischemic stroke. The Ni2+-NTA agarose affinity pull-down assay was carried out to determine the SUMOylation level of ANXA1. Co-immunoprecipitation assays was utilized to explore the protein interaction. Immunoblot analysis, quantitative real-time PCR, Luciferase reporter assay were performed to identify the regulatory mechanism. LDH release and TUNEL staining was performed to investigate the neuronal cytotoxicity and apoptosis, respectively. Results: In this study, we identified the deSUMOylating enzyme sentrin/SUMO-specific protease 6 (SENP6) as a negative regulator of ANXA1 SUMOylation. Notably, we found that SENP6-mediated deSUMOylation of ANXA1 induced its nuclear translocation and triggered neuronal apoptosis during cerebral ischemic injury. A mechanistic study demonstrated that SENP6-mediated deSUMOylation of ANXA1 promoted TRPM7- and PKC-dependent phosphorylation of ANXA1. Furthermore, blocking the deSUMOylation of ANXA1 mediated by SENP6 inhibited the transcriptional activity of p53, decreased Bid expression, suppressed caspase-3 pathway activation and reduced the apoptosis of primary neurons subjected to oxygen-glucose deprivation and reperfusion. More importantly, SENP6 inhibition by overexpression of a SENP6 catalytic mutant in neurons resulted in significant improvement in neurological function in the mouse model of ischemic stroke. Conclusions: Taken together, the results of this study identified a previously unidentified function of SENP6 in neuronal apoptosis and strongly indicated that SENP6 inhibition may provide therapeutic benefits for cerebral ischemia.
Effectiveness of surface mould brachytherapy in electron era.
Authors: Jyoti Mehta
Journal: Journal of Clinical Oncology (2021)

e21562 Background: In India, skin cancers constitute about 1-2% of all diagnosed cancers.Surgery stays main modality of treatment with adequate surgical margin shown excellent local control rates - generally 95%.However, conditions where surgery is not feasible, brachytherapy is alternative approach.Advanced technology improved the ability to deliver safe and effective radiotherapy, resulting in renewed interest in this modality.Brachytherapy has many advantages: they can deposit a significantly higher dose within a tumor, with better sparing of adjacent normal structures over external beam radiotherapy or electron therapy, which sometimes require irradiating a large volume of tissue in order to provide adequately coverage, which in term increase toxicity. The purpose of our paper is to find out the clinical outcomes of skin tumors and superficial tumours of head and neck region treated with Surface mould brachytherapy (SMB), in terms of survival and toxicity.We report on our institution’s experience with using Co-60 based HDR SMB for the treatment of skin and head and neck superficial malignancies. Methods: A retrospective review of all patients treated with surface mould Co-60-based HDR brachytherapy at our center.A total of 23 patients, with 23 lesions, were treated during this period, and included in the analysis. A total of three of these lesions were treated with a palliative intent, and were included. The most common fractionation scheme was 35 Gy in 10 fractions given daily (52%, n = 12), though a range of doses were used, from 8/2 fractions to 36 Gy/12 fractions. Results: Median age at diagnosis was 52 (range = 28-91). The majority were Squamous cell (43%, n = 10) or Basal cell carcinomas (34%, n = 8). Most lesions were located in the head and neck region. The most commonly used RT dose was 3GyX10 fractions; all patients had individualized CT-based planning.The 5-year overall survival (OS) was 86 %( twenty patients). Three patients were died. Most deaths were from unrelated causes. Response was assessed in OPD 2-4 months post-treatment. Our complete response (CR) rate was 73.9% (seventeen patients), with partial response in three patients; two patients could not be assessed for response and one patient died due to other medical condition. We report a 2-year local control (LC) rate of 91.3%, and local recurrence was found in two patients. The procedure was well tolerated, with no grade 3 or more acute or late toxicities. There was one case of grade 3 ulcer (CTCAE). The 100% isodose line median depth was 0.5 cm, and median surface dose = 126.5%. The median V90 = 92.3%. Conclusions: Surface mould brachytherapy is a safe, effective modality for treatment of skin malignancies or tumors. Brachytherapy was overall well tolerated, with no grade 3-5 acute or late toxicities. This treatment is a good alternative option for those patients unwilling or unable to undergo surgery for their skin malignancies
Immunotherapy for MIS-C — IVIG, Glucocorticoids, and Biologics
Authors: Roberta L. DeBiasi
Journal: New England Journal of Medicine (2021)

Since the sudden emergence of multisystem inflammatory disease in children (MIS-C) in April 2020 as a novel and severe presentation of coronavirus disease 2019 (Covid-19), nearly 4000 cases of MIS-...
Increased p53 signaling impairs neural differentiation in HUWE1-promoted intellectual disabilities
Authors: Rossana Aprigliano, Merdane Ezgi Aksu, Stefano Bradamante, Boris Mihaljevic, Wei Wang, Kristin Rian, Nicola P. Montaldo, Kayla Mae Grooms, Sarah L. Fordyce Martin, Diana L. Bordin, Matthias Bosshard, Yunhui Peng, Emil Alexov, Cindy Skinner, Nina-Beate Liabakk, Gareth J. Sullivan, Magnar Bjørås, Charles E. Schwartz, Barbara van Loon
Journal: Cell Reports Medicine (2021)

Essential E3 ubiquitin ligase HUWE1 (HECT, UBA, and WWE domain containing 1) regulates key factors, such as p53. Although mutations in HUWE1 cause heterogenous neurodevelopmental X-linked intellectual disabilities (XLIDs), the disease mechanisms common to these syndromes remain unknown. In this work, we identify p53 signaling as the central process altered in HUWE1-promoted XLID syndromes. By focusing on Juberg-Marsidi syndrome (JMS), one of the severest XLIDs, we show that increased p53 signaling results from p53 accumulation caused by HUWE1 p.G4310R destabilization. This further alters cell-cycle progression and proliferation in JMS cells. Modeling of JMS neurodevelopment reveals majorly impaired neural differentiation accompanied by increased p53 signaling. The neural differentiation defects can be successfully rescued by reducing p53 levels and restoring the expression of p53 target genes, in particular CDKN1A/p21. In summary, our findings suggest that increased p53 signaling underlies HUWE1-promoted syndromes and impairs XLID JMS neural differentiation.
Frequency and Prognostic Impact of <i>ALK</i> Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1)
Authors: Angela Bellini, Ulrike Pötschger, Virginie Bernard, Eve Lapouble, Sylvain Baulande, Peter F. Ambros, Nathalie Auger, Klaus Beiske, Marie Bernkopf, David R. Betts, Jaydutt Bhalshankar, Nick Bown, Katleen de Preter, Nathalie Clément, Valérie Combaret, Jaime Font de Mora, Sally L. George, Irene Jiménez, Marta Jeison, Barbara Marques, Tommy Martinsson, Katia Mazzocco, Martina Morini, Annick Mühlethaler-Mottet, Rosa Noguera, Gaelle Pierron, Maria Rossing, Sabine Taschner-Mandl, Nadine Van Roy, Ales Vicha, Louis Chesler, Walentyna Balwierz, Victoria Castel, Martin Elliott, Per Kogner, Geneviève Laureys, Roberto Luksch, Josef Malis, Maja Popovic-Beck, Shifra Ash, Olivier Delattre, Dominique Valteau-Couanet, Deborah A. Tweddle, Ruth Ladenstein, Gudrun Schleiermacher
Journal: Journal of Clinical Oncology (2021)

In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied ALK genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact.Diagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine ALK amplification status (n = 330), ALK mutational profile (n = 191), or both (n = 571).Genomic ALK amplification (ALKa) was detected in 4.5% of cases (41 out of 901), all except one with MYCN amplification (MNA). ALKa was associated with a significantly poorer overall survival (OS) (5-year OS: ALKa [n = 41] 28% [95% CI, 15 to 42]; no-ALKa [n = 860] 51% [95% CI, 47 to 54], [P < .001]), particularly in cases with metastatic disease. ALK mutations (ALKm) were detected at a clonal level (> 20% mutated allele fraction) in 10% of cases (76 out of 762) and at a subclonal level (mutated allele fraction 0.1%-20%) in 3.9% of patients (30 out of 762), with a strong correlation between the presence of ALKm and MNA (P < .001). Among 571 cases with known ALKa and ALKm status, a statistically significant difference in OS was observed between cases with ALKa or clonal ALKm versus subclonal ALKm or no ALK alterations (5-year OS: ALKa [n = 19], 26% [95% CI, 10 to 47], clonal ALKm [n = 65] 33% [95% CI, 21 to 44], subclonal ALKm (n = 22) 48% [95% CI, 26 to 67], and no alteration [n = 465], 51% [95% CI, 46 to 55], respectively; P = .001). Importantly, in a multivariate model, involvement of more than one metastatic compartment (hazard ratio [HR], 2.87; P < .001), ALKa (HR, 2.38; P = .004), and clonal ALKm (HR, 1.77; P = .001) were independent predictors of poor outcome.Genetic alterations of ALK (clonal mutations and amplifications) in HR-NB are independent predictors of poorer survival. These data provide a rationale for integration of ALK inhibitors in upfront treatment of HR-NB with ALK alterations.
Where are the women and underrepresented minorities in medicine? Race/ethnicity and gender representation in oncology journals’ editorial boards.
Authors: Shruti Rajesh Patel, Ivy Riano, Gabriella Geiger, Jacqueline Pimienta, Inas Abuali, Angela Ai, Adriana Ramirez Roggio, Natasha Dhawan, Nazli Dizman, Alexandra Lizette Salinas, Narjust Duma
Journal: Journal of Clinical Oncology (2021)

11007 Background: The proportion of women &amp; underrepresented groups in medicine (URM) in the field of hematology and oncology remains low, particularly in academic leadership positions. Editorial board appointments allow physicians to have a substantial impact on the nature of the published scholarly work and serve as a platform for academic opportunities. We aimed to assess gender and race/ethnicity representation in editorial board positions in hematology and oncology journals. Methods: Editorial leadership board members from 60 journals from oncology, hematology, radiation oncology, and surgical oncology were reviewed, 54 journals were included in the analysis. Gender and race/ethnicity were determined based on publicly available data for editor-in-chief (EiC) and second-in-command (SiC) (including deputy, senior, or associate editors). Descriptive statistics and chi-squared were estimated. Results: A total of 793 editorial board members are included in the analysis. 72.6 % were men and 27.4 % were women. 71.3% of editorial leadership were non-Hispanic white with Asian editorial board members representing the second largest majority at 23.3%. The editorial position was significantly different among men and women (p = 0.038) with women filling only 15.9% (10/63) of the EiC positions. Of these 10 women, the racial breakdown was 90% white and 10% Asian. In the prevalence odds ratio (pOR), women were about half as likely to be in the EiC position compared with men [pOR: 0.47, 95%CI (0.23, 0.95, p = 0.03)]. Women represented 28.4% (207/730) of SiC editorial positions. White editors had the highest representation at 71.0% in the SiC editorial positions, followed by Asian editors at 16.0%. Notable differences were seen in gender proportions between journal specialties (p = 0.001); with surgical oncology and hematology having the lowest female representation at 11.9% and 22.7%, respectively. Conclusions: Women and UIM are markedly underrepresented in leadership roles on Editorial Boards in hematology and oncology journals. Importantly, the representation of minority women physicians in EiC positions is at an inexorable zero which is a sign of unconscious attitudes that may exclude women and minorities from certain positions. It is imperative that we work to move towards a more diverse and inclusive editorial board to ensure critical perspectives are heard and scientific discovery is fostered.[Table: see text]
Mobile health and privacy: cross sectional study
Authors: Gioacchino Tangari, Muhammad Ikram, Kiran Ijaz, Mohamed Ali Kaafar, Shlomo Berkovsky
Journal: BMJ (2021)

Abstract Objectives To investigate whether and what user data are collected by health related mobile applications (mHealth apps), to characterise the privacy conduct of all the available mHealth apps on Google Play, and to gauge the associated risks to privacy. Design Cross sectional study Setting Health related apps developed for the Android mobile platform, available in the Google Play store in Australia and belonging to the medical and health and fitness categories. Participants Users of 20 991 mHealth apps (8074 medical and 12 917 health and fitness found in the Google Play store: in-depth analysis was done on 15 838 apps that did not require a download or subscription fee compared with 8468 baseline non-mHealth apps. Main outcome measures Primary outcomes were characterisation of the data collection operations in the apps code and of the data transmissions in the apps traffic; analysis of the primary recipients for each type of user data; presence of adverts and trackers in the app traffic; audit of the app privacy policy and compliance of the privacy conduct with the policy; and analysis of complaints in negative app reviews. Results 88.0% (n=18 472) of mHealth apps included code that could potentially collect user data. 3.9% (n=616) of apps transmitted user information in their traffic. Most data collection operations in apps code and data transmissions in apps traffic involved external service providers (third parties). The top 50 third parties were responsible for most of the data collection operations in app code and data transmissions in app traffic (68.0% (2140), collectively). 23.0% (724) of user data transmissions occurred on insecure communication protocols. 28.1% (5903) of apps provided no privacy policies, whereas 47.0% (1479) of user data transmissions complied with the privacy policy. 1.3% (3609) of user reviews raised concerns about privacy. Conclusions This analysis found serious problems with privacy and inconsistent privacy practices in mHealth apps. Clinicians should be aware of these and articulate them to patients when determining the benefits and risks of mHealth apps.
The Decline in e-Cigarette Use Among Youth in the United States—An Encouraging Trend but an Ongoing Public Health Challenge
Authors: Briana M. Choi, Ivo Abraham
Journal: JAMA Network Open (2021)

Teresa W. Wang, PhD; Andrea S. Gentzke, PhD; Linda J. Neff, PhD; Emily V. Glidden, MPH; Ahmed Jamal, MBBS; Eunice Park-Lee, PhD; Chunfeng Ren, PhD; Karen A. Cullen, PhD; Brian A. King, PhD; Karen A. Hacker, MD
Applications of single-cell sequencing in cancer research: progress and perspectives
Authors: Yalan Lei, Rong Tang, Jin Xu, Wei Wang, Bo Zhang, Jiang Liu, Xianjun Yu, Si Shi
Journal: Journal of Hematology & Oncology (2021)

Single-cell sequencing, including genomics, transcriptomics, epigenomics, proteomics and metabolomics sequencing, is a powerful tool to decipher the cellular and molecular landscape at a single-cell resolution, unlike bulk sequencing, which provides averaged data. The use of single-cell sequencing in cancer research has revolutionized our understanding of the biological characteristics and dynamics within cancer lesions. In this review, we summarize emerging single-cell sequencing technologies and recent cancer research progress obtained by single-cell sequencing, including information related to the landscapes of malignant cells and immune cells, tumor heterogeneity, circulating tumor cells and the underlying mechanisms of tumor biological behaviors. Overall, the prospects of single-cell sequencing in facilitating diagnosis, targeted therapy and prognostic prediction among a spectrum of tumors are bright. In the near future, advances in single-cell sequencing will undoubtedly improve our understanding of the biological characteristics of tumors and highlight potential precise therapeutic targets for patients.