tbuckley/cabot-search huggingface dataset:
‘I’m being forced to make decisions I have never had to make before’: Oncologists and the conundrums created by COVID-19.
Authors: Chithra R. Perumalswami, Emily Chen, Carly Martin, Susan Dorr Goold, Raymond G. De Vries, Jennifer J. Griggs, Reshma Jagsi
Journal: Journal of Clinical Oncology (2021)

12001 Background: The COVID-19 pandemic has created conundrums for physicians. This study examines the experiences of oncologists who engage in complex decision-making regarding the use of chemotherapy in seriously ill persons in the context of the COVID-19 pandemic. Methods: Between January 2020 and August 2020, the authors conducted semi-structured, in-depth individual interviews with 22 purposefully sampled oncologists from practices enrolled in the Michigan Oncology Quality Consortium. Transcripts were double-coded and reconciled by consensus using qualitative data analysis software for thematic analysis. Results: Among the thematic clusters we identified, one was related to conundrums created by the COVID-19 pandemic. In this presentation, we report the results pertaining to three themes within this cluster: (1) the ethical dilemmas faced by oncologists due to the COVID-19 pandemic, (2) the need for both patients and oncologists to manage uncertainty and emotions, and (3) the importance and complexity of integrating technology and communication for seriously ill persons. Oncologists grappled with several conundrums including resource scarcity, resource allocation, delays in care, a duty to promote equity and non-abandonment, high levels of uncertainty and fear, and the importance of advanced care directives and end-of-life care planning. Non-abandonment featured as a coping mechanism for increased stress, and integration of communication with telemedicine was frequent and necessary. Conclusions: This study offers an in-depth exploration of the conundrums faced by oncologists due to the COVID-19 pandemic and how they navigated them. Optimal decision-making for seriously ill persons with cancer during the COVID-19 pandemic must include open acknowledgement of the ethical dilemmas faced, the heightened emotions experienced by both patients and their oncologists, and the urgent need for integrating technology with compassionate communication in determining patient preferences.
Recent advances in critical nodes of embryo engineering technology
Authors: Youwen Ma, Mingwei Gu, Liguo Chen, Hao Shen, Yifan Pan, Yan Pang, Sheng Miao, Ruiqing Tong, Haibo Huang, Yichen Zhu, Lining Sun
Journal: Theranostics (2021)

The normal development and maturation of oocytes and sperm, the formation of fertilized ova, the implantation of early embryos, and the growth and development of foetuses are the biological basis of mammalian reproduction. Therefore, research on oocytes has always occupied a very important position in the life sciences and reproductive medicine fields. Various embryo engineering technologies for oocytes, early embryo formation and subsequent developmental stages and different target sites, such as gene editing, intracytoplasmic sperm injection (ICSI), preimplantation genetic diagnosis (PGD), and somatic cell nuclear transfer (SCNT) technologies, have all been established and widely used in industrialization. However, as research continues to deepen and target species become more advanced, embryo engineering technology has also been developing in a more complex and sophisticated direction. At the same time, the success rate also shows a declining trend, resulting in an extension of the research and development cycle and rising costs. By studying the existing embryo engineering technology process, we discovered three critical nodes that have the greatest impact on the development of oocytes and early embryos, namely, oocyte micromanipulation, oocyte electrical activation/reconstructed embryo electrofusion, and the
A phase 2, multicenter, open-label study evaluating trastuzumab deruxtecan (T-DXd) for the treatment of solid tumors harboring specific HER2-activating mutations (DESTINY-PanTumor01).
Authors: Bob T. Li, Funda Meric-Bernstam, Soham D. Puvvada, Jacqui Rowbottom, Darren Jolliffe, Mark Gustavson, Ariadna Mendoza-Naranjo
Journal: Journal of Clinical Oncology (2021)

TPS3162 Background: There are substantial data suggesting that a subset of human epidermal growth factor receptor 2 (HER2)–activating mutations induce ligand-independent constitutive HER2 signaling and promote oncogenesis. Direct therapeutic targeting of HER2 has transformed the treatment of patients with HER2-overexpressing breast and gastric cancers. However, currently no targeted treatments are approved for patients with tumors harboring HER2-activating mutations. T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a membrane-permeable topoisomerase I inhibitor payload that may be selectively internalized in tumors with HER2 mutations (Li BT, et al. Cancer Discov. 2020;10:674-687). In a phase 1 study (DS8201-A-J101), T-DXd demonstrated preliminary antitumor activity in patients with tumors harboring HER2 mutations, with confirmed responses observed in 9 of 19 patients (47.4%) (Tsurutani J, et al. Cancer Discov. 2020;10:688-701). Here we describe the DESTINY-PanTumor01 trial (NCT04639219). Methods: DESTINY-PanTumor01 is an open-label, multicenter, single-arm, phase 2 study evaluating T-DXd for the treatment of patients with unresectable and/or metastatic solid tumors (excluding non-small cell lung cancer) harboring prespecified HER2-activating mutations. Patients (N≈100) are required to have progressed following prior treatment for advanced or metastatic disease or have no satisfactory alternative treatment options. Prior HER2-targeting therapy is allowed. HER2 mutation status will be determined locally using next-generation sequencing or a validated nucleic acid–based methodology. The primary endpoint is confirmed objective response rate according to independent central review per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints include duration of response, disease control rate, progression-free survival, investigator-assessed confirmed objective response rate, overall survival, safety, pharmacokinetics, and immunogenicity. Clinical trial information: NCT04639219.
Safety and efficacy of nivolumab plus recombinant human endostatin in previously treated advanced non-small cell lung cancer: A prospective and multicenter phase 2 trial.
Authors: Weize Lv, Beilong Zhong, Wenhua Zhao, Zhong Lin, Xiaofeng Pei, Zhihui Wang
Journal: Journal of Clinical Oncology (2021)

e21079 Background: Although the administration of immune checkpoint inhibitors (ICIs) and antiangiogenic agents in advanced non–small-cell lung cancer (NSCLC) has been well established, evidence supporting the combination of immune checkpoint inhibitors plus antiangiogenic drugs in previous treatment patients with advanced NSCLC is insufficient. We aimed to investigate the efficacy and safety of nivolumab combined with recombinant human endostatin (rh-Endostatin) as second-line or later treatment for advanced NSCLC. Methods: In this prospective and multicentre phase 2 trial we enrolled patients with advanced NSCLC who had not responded to standardized first-line treatment regimen from two cancer centres in China. Eligible patients were those aged 18-75 years without ICIs in first-line treatment who received nivolumab (3mg/kg, intravenous drip, day 1) every 2 weeks and rh-Endostatin (30 mg, 24-hour continous intravenous infusion，day 1–7) every 4 weeks till disease progression or discontinuation. The primary end points were objective response rate and safety. This study is registered with Chinese Clinical Trial Registry, number ChiCTR1900023664. Results: A total of 35 patients (median age, 60 years; range, 37-72 years) received nivolumab and rh-Endostatin. Median previous treated line of eligible patients was 2 lines (range, 1-7 lines). Patients received a median of 2 cycles of therapy (range, 1-14 cycles). Eleven of 33 evaluable patients achieved confirmed partial response with an objective response rate of 33.3% (11/33, 95% confidence interval [CI]: 17.2% – 49.4%) and disease control rate of 60.6% (20/33,95%CI:43.9%–77.3%). Median follow-up was 8.2 months (range: 0.9 –17.1). Median progression-free survival was 7.1 months (95% CI: 1.2m–13.0m), median overall survival was not reached and the 6-month overall survival rate was 54.5% (95% CI:37.6%–71.4%). The predominant grade 1-2 adverse events were thyroiditis, arrhythmia, hypertension. The grade 3 treatment-related adverse events were pneumonitis (3/35, 8.6%), hypertension (1/35, 2.9%) and atrial fibrillation (1/35, 2.9%), respectively. No grade 4 or 5 treatment-related adverse events were observed. Conclusions: To the best of our knowledge, this is the first prospective study that assessed nivolumab combined with rh-Endostatin as second-line or later treatment in pretreated patients with advanced NSCLC. In view of its encouraging efficacy and safety profile, nivolumab plus rh-Endostatin represents a promising treatment regimen in this patient population. Clinical trial information: ChiCTR1900023664.
A Pooled Analysis of the Xalia and Xalia-Lea Non-Interventional Studies of Rivaroxaban Versus Standard Anticoagulation in Venous Thromboembolism
Authors: Alexander G. G. Turpie, Lorenzo G Mantovani, Sylvia Katharina Haas, Reinhold Kreutz, Danja Monje, Jonas Schneider, Martin van Eickels, Miriam Tamm, Martin Gebel, Walter Ageno
Journal: Blood (2017)
Erratum to ‘Germline-focussed analysis of tumour-only sequencing: recommendations from the ESMO Precision Medicine Working Group’
Authors: D. Mandelker, M. Donoghue, S. Talukdar, C. Bandlamudi, P. Srinivasan, M. Vivek, S. Jezdic, H. Hanson, K. Snape, A. Kulkarni, L. Hawkes, J.-Y. Douillard, S.E. Wallace, E. Rial-Sebbag, F. Meric-Bersntam, A. George, D. Chubb, C. Loveday, M. Ladanyi, M.F. Berger, B.S. Taylor, C. Turnbull
Journal: Annals of Oncology (2021)

The publisher regrets that in the original publication figures 1, 2 and 3 were incorrectly presented. The correct figures 1, 2 and 3 are as follows.Figure 2Distribution of germline and somatic pathogenic variants detected upon tumour analysis. Only variants classified pathogenic/likely pathogenic AND above VAF threshold are included (blue, germline origin; red, somatic origin; numbers, total number of pathogenic variants. observed in tumour).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3Distribution of germline and somatic pathogenic variants detected upon tumour analysis for 30 high-actionability CSGs. (A) Offtumour and (B) on-tumour.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The publisher would like to apologise for any inconvenience caused. Germline-focussed analysis of tumour-only sequencing: recommendations from the ESMO Precision Medicine Working GroupAnnals of OncologyVol. 30Issue 8PreviewIt is increasingly common in oncology practice to perform tumour sequencing using large cancer panels. For pathogenic sequence variants in cancer susceptibility genes identified on tumour-only sequencing, it is often unclear whether they are of somatic or constitutional (germline) origin. There is wide-spread disparity regarding both the extent to which systematic 'germline-focussed analysis' is carried out upon tumour sequencing data and for which variants follow-up analysis of a germline sample is carried out. Full-Text PDF Open Access
Personalized Management of Pheochromocytoma and Paraganglioma
Authors: Svenja Nölting, Nicole Bechmann, David Taieb, Felix Beuschlein, Martin Fassnacht, Matthias Kroiss, Graeme Eisenhofer, Ashley Grossman, Karel Pacak
Journal: Endocrine Reviews (2021)

Pheochromocytomas/paragangliomas are characterized by a unique molecular landscape that allows their assignment to clusters based on underlying genetic alterations. With around 30% to 35% of Caucasian patients (a lower percentage in the Chinese population) showing germline mutations in susceptibility genes, pheochromocytomas/paragangliomas have the highest rate of heritability among all tumors. A further 35% to 40% of Caucasian patients (a higher percentage in the Chinese population) are affected by somatic driver mutations. Thus, around 70% of all patients with pheochromocytoma/paraganglioma can be assigned to 1 of 3 main molecular clusters with different phenotypes and clinical behavior. Krebs cycle/VHL/EPAS1-related cluster 1 tumors tend to a noradrenergic biochemical phenotype and require very close follow-up due to the risk of metastasis and recurrence. In contrast, kinase signaling-related cluster 2 tumors are characterized by an adrenergic phenotype and episodic symptoms, with generally a less aggressive course. The clinical correlates of patients with Wnt signaling-related cluster 3 tumors are currently poorly described, but aggressive behavior seems likely. In this review, we explore and explain why cluster-specific (personalized) management of pheochromocytoma/paraganglioma is essential to ascertain clinical behavior and prognosis, guide individual diagnostic procedures (biochemical interpretation, choice of the most sensitive imaging modalities), and provide personalized management and follow-up. Although cluster-specific therapy of inoperable/metastatic disease has not yet entered routine clinical practice, we suggest that informed personalized genetic-driven treatment should be implemented as a logical next step. This review amalgamates published guidelines and expert views within each cluster for a coherent individualized patient management plan.
Danuglipron (PF-06882961) in type 2 diabetes: a randomized, placebo-controlled, multiple ascending-dose phase 1 trial
Authors: Aditi R. Saxena, Donal N. Gorman, Ryan M. Esquejo, Arthur Bergman, Kristin Chidsey, Clare Buckeridge, David A. Griffith, Albert M. Kim
Journal: Nature Medicine (2021)
Evaluating the benefit of adaptive randomization in the CC-115 arm of the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT): A phase II randomized Bayesian adaptive platform trial in newly diagnosed MGMT unmethylated glioblastoma.
Authors: Rifaquat Rahman, Lorenzo Trippa, Geoffrey Fell, Eudocia Quant Lee, Isabel Arrillaga-Romany, Mehdi Touat, Jan Drappatz, Evanthia Galanis, Manmeet Singh Ahluwalia, Howard Colman, Louis B. Nabors, Jaroslaw T. Hepel, David Schiff, Mary Roberta Welch, David M. Meredith, E. Antonio Chiocca, David A. Reardon, Keith L. Ligon, Brian Michael Alexander, Patrick Y. Wen
Journal: Journal of Clinical Oncology (2021)

2006 Background: Adaptive randomization adjusts enrollment rates based upon early trial results, which can allow for decreased enrollment for therapies less likely to meet the primary endpoint of a trial. CC-115, a CNS-penetrant, oral inhibitor of mammalian target of rapamycin kinase (mTOR) and deoxyribonucleic acid-dependent protein kinase (DNA-PK), was evaluated in the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. As CC-115 was discontinued due to concerns about toxicity and unfavorable risk-to-benefit ratio, we sought to investigate the impact of adaptive randomization in its testing. Methods: In INSIGhT, adults with newly diagnosed MGMT-unmethylated glioblastoma and available genomic data are adaptively randomized to an experimental arm or the control arm of standard radiotherapy with concurrent and adjuvant temozolomide. Patients randomized to CC-115 received it (10mg po BID) with radiotherapy and as adjuvant monotherapy, and a safety lead-in 3+3 design was used for this arm. By simulating the INSIGhT trial with standard uniform randomization, we estimated the reduction of enrollment rate and sample size of the CC-115 arm that was attributable to adaptive randomization. Results: Twelve patients were randomized to CC-115; 58% (n = 7) patients had possible treatment-related CTCAE grade &gt; 3 toxicity. Compared to the control arm, there was no significant difference in progression-free survival (PFS, HR 0.66, 95% CI 0.32-1.36, p = 0.3) or overall survival (OS, HR 0.93, 95% CI 0.43-2.03, p = 0.8). Based on early PFS results, randomization probability to CC-115 decreased from 25% to 16%. At the time of the CC-115 arm closure, 14% of enrolled INSIGhT patients had been randomized to this arm. Compared to average expected enrollment by standard randomization, the use of adaptive randomization decreased the number of patients randomized to CC-115 by 50% (12 patients vs. 18 patients [95% CI 11-25 patients]). Conclusions: The INSIGhT trial, designed with adaptive randomization, facilitated more efficient testing of CC-115 and decreased the number of patients allocated to the CC-115 arm relative to a standard randomization design. Clinical trial information: NCT02977780.
Response to: ‘Correspondence on ‘Variants in urate transporters, ADH1B, GCKR and MEPE genes associated with transition from asymptomatic hyperuricaemia to gout: results of the first gout versus asymptomatic hyperuricaemia GWAS in Caucasians using data from the UK Biobank’’ by Takei et al
Authors: Gabriela Sandoval-Plata, Kevin Morgan, Abhishek Abhishek
Journal: Annals of the Rheumatic Diseases (2021)

Takei et al conducted a genome-wide association study (GWAS) in European individuals with gout versus asymptomatic hyperuricaemia controls. They reported nine independent genetic variants in or near ABCG2 , SLC2A9 , GCKR , ADH1B , SLC22A11 , PDX1 , MLXIPL and CNBD1 associated with gout using ‘ a more stringent ’ threshold of r2<0.01 for linkage disequilibrium (LD) clumping. Compared with our study, they found three additional loci in PDX1 (rs182200427), MLXPIL (rs7805504) and CNBD1 (rs181604403) that were not included in the non-imputed UK Biobank dataset used in our study. And more importantly, they reported a single SNP in ABCG2 (ie, rs2231142) locus associated with gout after conditioning on rs2231142.1

In our analysis, we reported 13 independent genetic variants mapped to …
Disparities in adjuvant treatment of high-grade endometrial cancer.
Authors: Logan Corey, Michele L. Cote, Julie J. Ruterbusch, Ira Seth Winer
Journal: Journal of Clinical Oncology (2021)

e17572 Background: To examine surgical outcomes, patterns of adjuvant therapy, and survival for non-Hispanic Black (NHB) women compared to non-Hispanic White (NHW) and Hispanic (HS) women who have undergone surgery for high grade endometrial cancer in the Medicare population. Methods: We utilized the SEER-Medicare linked database to identify women who underwent surgery as a primary treatment for uterine grade 3 endometrioid adenocarcinoma, carcinosarcoma, clear cell carcinoma, or serous carcinoma between the years 2000 and 2015. Multinomial logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for receiving a treatment delay or not receiving adjuvant treatment (compared to those who received adjuvant treatment within 12 weeks) adjusted for clinical and demographic characteristics. Overall survival (OS) stratified by race/ethnicity, route of surgery, operative complications, and type and timing of adjuvant therapy were analyzed using the Kaplan-Meier method. Cox Proportional hazards regression was used to estimate hazard of death by race/ethnicity adjusted for known predictors, as well as surgical outcomes and adjuvant therapy patterns. Results: 12, 201 women met study inclusion criteria. NHB patients had a significantly worse five-year overall survival (OS) than HS and NHW patients (30.9 months vs 51.0 months vs 53.6 months, respectively). Approximately 8.6% of patients who received adjuvant treatment experienced a treatment delay (632/7, 282). Delay in treatment of greater than or equal to 12 weeks was significantly different by race/ethnicity (p=0.034), with 12% of HS, 9% of NHB, and 8% of NHW women experiencing a delay. After adjustment for number of complications, age, histology (endometrioid v. non-endometroid), FIGO stage, marital status, comorbidity count, surgical approach, lymph node dissection, and urban-rural code, HS had a 71% increased risk of treatment delay (OR 1.71, CI 1.23-2.38) for all stages of disease. In the same model, NHB race was independently predictive of decreased use of adjuvant treatment for FIGO stage II and higher (OR 1.32, CI 1.04-1.68). NHB race, number of perioperative complications, and non-endometrioid histology were predictive of worse OS in univariate models. Treatment delay was not independently predictive of worse 1- or 5-year survival at any stage. Conclusions: NHB race is predictive of worse 5-year survival across all stages and is also associated with omission of adjuvant treatment in ≥FIGO Stage II high grade endometrial cancers. HS ethnicity was associated with treatment delay across all stages. In unadjusted analyses, patients who experience treatment omission or delay experienced poorer OS, but these factors were not independently associated in multivariate analyses.
Radiographic progression-free survival as a surrogate endpoint of overall survival in men with metastatic castrate-resistant prostate cancer.
Authors: Susan Halabi, Akash Roy, Qian Yang, Wanling Xie, William Kevin Kelly, Christopher Sweeney
Journal: Journal of Clinical Oncology (2021)

5057 Background: Radiographic progression-free survival (rPFS) is commonly used as a co-primary endpoint in randomized clinical trials in men with metastatic castrate-resistant prostate cancer (mCRPC). However, rPFS has not been established as a valid surrogate endpoint of overall survival (OS) in men with mCRPC. Here, we hypothesized that rPFS is a reliable surrogate for OS in mCRPC. We also explored whether PFS is a valid surrogate endpoint of OS at the aggregate trial level. Methods: We performed a systematic search of the literature encompassing the period January 2004-December 2020 using PubMed and clinical trials.gov to identify completed phase III trials in mCRPC post-docetaxel. Eligible trials had to be randomized phase III therapeutic trials that reported OS, PFS or rPFS. OS was measured from the date of random assignment to date of death from any cause or date of last follow-up. rPFS was defined as the time from random assignment to date of disease progression on CT and/or Tc bone scan per trial definition or death from any cause, whichever occurred first. PFS included PSA progression as a component of the composite endpoint. Trial level surrogacy was evaluated by fitting linear regression on the treatment effect of rPFS (or PFS) and OS (in other words, the weighted linear regression of the log(hazard ratio) of OS on the log(hazard ratio) of rPFS). It was pre-specified that rPFS would be considered a valid surrogate for OS if R² was 0·7 or higher. Results: We identified 33 in men with mCRPC post docetaxel approval. We assessed the association between PFS and OS in 29,456 patients from 30 trials. Overall, a moderate correlation was observed at the trial level between OS and PFS ( R 2 = 0.46, 95 %CI = 0.20-0.68) in these trials. In 18 trials with 16,818 mCRPC patients where rPFS was considered as a key endpoint, a moderate correlation between the treatment effects on rPFS and OS was observed at the trial level ( R 2 = 0.65, 95% CI = 0.23-0.87). Conclusions: This meta-analysis demonstrates moderate correlation between treatment effects of rPFS and OS in patients with mCRPC. However, rPFS did not meet the pre-specified surrogacy threshold of 0.7. Clinical trial information: several.
Surgeon is struck off after failing to tell employers that he was being investigated
Authors: Clare Dyer
Journal: BMJ (2021)

A surgeon has been struck off for failing to tell employers that he was being investigated for sending home an emergency department patient who died two days later, and for carelessly keeping and storing confidential patient information at his home.

Kamal Abusin, 61, missed a “red flag” indicative of bowel perforation before discharging the patient, a medical practitioners tribunal found. But while the tribunal held that this amounted to serious misconduct, it noted that it was a single incident nearly five years ago and that his current references were good. It decided that his fitness to practise was not impaired by the misconduct.

Abusin was also found guilty of serious misconduct when, on at least five …