tbuckley/cabot-search huggingface dataset:
CCTG BR.34: A randomized trial of durvalumab and tremelimumab +/- platinum-based chemotherapy in patients with metastatic (Stage IV) squamous or nonsquamous non-small cell lung cancer (NSCLC).
Authors: Natasha B. Leighl, Scott Andrew Laurie, Glenwood D. Goss, Brett Gordon Maxwell Hughes, Martin R. Stockler, Ming Sound Tsao, Swati Kulkarni, Normand Blais, Anil A. Joy, Mihaela Mates, Punam Rana, Sunil Yadav, Craig Underhill, Christopher W. Lee, Penelope Ann Bradbury, Andrea Hiltz, Janet Dancey, Keyue Ding, Francisco Emilio Vera Badillo
Journal: Journal of Clinical Oncology (2020)

9502 Background: First-line therapy for advanced NSCLC includes PD-1 checkpoint inhibitor (ICI) monotherapy, and in combination with chemotherapy. Combination ICI have also demonstrated better survival compared to chemotherapy (CM-227). In CCTG BR.34, we compared overall survival (OS) in patients with advanced NSCLC receiving first-line durvalumab plus tremelimumab (DT) with or without platinum doublet chemotherapy (CT). Methods: This international, open-label, randomized trial accrued 301 participants from Canada and Australia, with stage IV NSCLC, EGFR/ALK wildtype, ECOG PS 0/1. Patients were randomized to DT for 4 cycles or DT+CT (pemetrexed- or gemcitabine-platinum), with ongoing D or D + pemetrexed (non-squamous) maintenance until disease progression. Stratification factors included histology, stage IVA v. IVB and smoking status. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR = CR + PR) and adverse events (AEs). Results: At a median follow up of 16.6 months, no significant difference in OS was seen between the two treatment arms, with a median OS of 16.6 months with DT+CT v. 14.1 months with DT, (estimated HR 0.88, 90% CI 0.67-1.16). PFS was significantly improved in the DT+CT arm (stratified HR 0.67, 95% CI 0.52-0.88; medians 7.7 v. 3.2 months). ORR was higher in the DT+CT arm, 28% v. 14%, (odds ratio 2.1, p=0.001). Preplanned subgroup analysis demonstrated no significant differences in treatment outcomes by plasma TMB (&lt;20 v. ≥20 mut/Mb, Guardant OMNI), age, sex, or smoking status. There was a trend to improved OS with DT+CT in the subgroup with PD-L1 TPS≥50%, (HR 0.64, 95% CI 0.40-1.04, p=0.07). Plasma TMB&lt;20 mut/Mb was associated with shorter survival in both treatment groups (HR 1.99, 95% 1.3-3.1). Toxicity was greater in the DT+CT arm, with grade≥3 adverse events in 82% v. 70%, (p=0.02), most commonly dyspnea, nausea and cough. The incidence of immune-related adverse events was similar between arms (colitis 11%, pneumonitis 6%, endocrinopathy 21%). Grade 5 events occurred in 2.7%, (5 with DT+CT, 3 with DT). Conclusions: The addition of CT to first-line DT did not improve OS in advanced NSCLC. CT+DT improved ORR and PFS, and was associated with greater toxicity. No differential effects were seen by PD-L1 TPS nor bTMB. These data suggest that adding chemotherapy to ICI may be beneficial in those with PD-L1 TPS &gt;=50%, and warrant further analysis in independent datasets. Clinical trial information: NCT03057106 .
Autoantibodies as predictors for survival and immune-related adverse events in checkpoint inhibition therapy of metastasized melanoma.
Authors: Jessica Cecile Hassel, Hans-Dieter Zucht, Joanna Mangana, Reinhard Dummer, Claudia Pföhler, Kilian Wistuba-Hamprecht, Benjamin Weide, Lara Elena Hakim-Meibodi, Friedegund Elke Meier, Carsten Schulz, Manuel Bräutigam, Petra Budde
Journal: Journal of Clinical Oncology (2020)

10011 Background: Increasing evidence suggests that the B cell response in cancer patients is an important component of anti-tumour immunity. Autoantibodies targeting tumour and self-antigens may serve as biomarkers of anti-tumour and auto-immunity. As they can be measured in patient' sera, they have great potential as clinical routine biomarkers. The objective of this study was to explore if autoantibodies are associated with survival and immune related adverse events (irAE) in patients with metastatic melanoma under checkpoint inhitibor (CPI) therapy. Methods: Pre-treatment serum samples from 333 metastatic melanoma patients receiving CPI therapy at 5 European centers were retrospectively used to identify autoantibody signatures for survival and irAE. We designed a cancer immunotherapy antigen array comprising 832 autoimmune and tumour antigens as well as immune and cancer pathway proteins. Statistical tests were separately performed for patients treated with anti-CTLA4 (alone or in combination) and with anti-PD1 antibody monotherapy. Cox-regression analysis and univariate statistical tests were applied for biomarker discovery. Progression free and overall survival was measured from treatment initiation to tumor progression or death date. irAE were recorded including onset date and grade (CTC-AE). Results: For each therapy group we identified a set of autoantibody reactivities in untreated melanoma patients that were associated with the development of irAEs and/or survival. The identified autoantibodies target a diverse set of antigens comprising neoantigens (p53), cancer testis antigens (MAGEB4), paraneoplastic antigens (gephyrin), autoantigens (ribosomal proteins, Nor-90) and FGFR1. Autoantigens that correlated with irAE and survival were e.g. anti-MAGEB4 and anti-FGFR1. Elevated anti-MAGEB4 pre-treatment levels were associated with longer overall survival (p = 0.002, HR = 0.77) and the development of irAEs (p = 0.002, HR = 1.27) in ipilimumab +/- nivolumab treated patients. Higher pre-treatment anti-FGFR1 antibodies were associated with shorter survival (p = 0.008, HR = 1.27) and a lower a lower frequency of irAEs (p = 0.04, HR = 0.69) in these patients. Conclusions: We identified autoantibody targets suggesting a diverse B cell response to antigens expressed in tumours and those associated with autoimmunity. Depending on the specific antigen, the immune response towards those antigens may be associated with anti-tumour or pro-tumour responses.
Current status of research in decreased high-density lipoprotein cholesterol
Authors: 吴付轩, 袁玉美
Journal: BMJ (2006)

在美国35%的男性和15%的女性存在低高密度脂蛋白胆固醇(HDL-C)血症[1].我国尚缺乏相关的流行病学资料.随着肥胖、糖尿病和代谢综合征的发病率日益增高,低HDL-C血症的发生也在增加。
Community and hospital joint management for elderly patients after percutaneous coronary intervention
Authors: Ling-ling Zhang, Li-geng Zong, Xia Gao, Dao-ying Xu
Journal: BMJ (2012)

Among 172 patients with coronary artery disease (CAD),94 received community and hospital joint management (joint group) after percutaneous coronary intervention (PCI) for Ⅰ year and 78 received community-based health education only (control group) after PCI.The compliance of medication,readmission rate,times of hospitalization,medical costs,major adverse cardiac events (MACE),and general quality of life inventory (CQOLI-74),self-rating anxiety scale (SAS) and self-rating depression scale (SDS) scores were compared between two groups.The rate of readmission,times of hospitalization,medical costs,the sores of SAS and SDS in joint group were lower than those in control group(P ＜ 0.01 or 0.05).The compliance of medication,body health dimension,psychological health dimension and social function dimension in joint group were better than those in control group,but there were no differences in material life dimension and the MACE rate between two groups(P ＞ 0.05).Community and hospital joint management can reduce the readmission rate and medical burden,and improve quality of life for elderly CAD patients after PCI.

Key words: 
Angioplasty,transluminal,percutaneous coronary; Disease management
DNA methylation profiling in patients with head and neck squamous cell carcinoma treated with immune checkpoint inhibitors.
Authors: Angelika Martina Starzer, Gerwin Heller, Erwin Tomasich, Katharina Feldmann, Teresa Hatziioannou, Stefan Traint, Christoph Minichsdorfer, Ursula Schwarz-Nemec, Maja Nackenhorst, Leonhard Muellauer, Matthias Preusser, Anna Sophie Berghoff, Thorsten Fuereder
Journal: Journal of Clinical Oncology (2020)

e18527 Background: Biomarkers for response prediction to immune checkpoint inhibitors in head and neck squamous cell carcinoma (HNSCC) patients are needed for a personalized therapy regimen. Therefore, we investigated the predictive potential of inflammatory biomarkers and DNA methylation. Methods: We profiled the methylation status of 850.000 CpG sites in formalin-fixed, paraffin-embedded primary HNSCC samples collected before ICI therapy start using Infinium Methylation EPIC microarrays. Tumor-infiltrating lymphocytes (TILs) and programmed cell death ligand 1 (PD-L1) expression were analyzed employing immunohistochemistry staining. Methylation profile, TIL density and PD-L1 expression were correlated with best radiological response to ICI treatment. Results: 29 patients (median age of 61; range 28-80) years; 8 (27.6%) females, 21 (72.4%) males) with HNSCC were included. Median number of prior systemic therapies was 1 (range 0-3). Median number of ICI applications was 6 (range 1-45). 2/29 (6.9%) patients achieved an objective response (complete response or partial response) under anti-PD-1 therapy. Median progression-free survival (PFS) and median overall survival (OS) were 3.3 months (range 0-28.8) and 7.2 months (range 0-29.4), respectively. 7/29 (24.1%) patients were still alive and one of these patients was still on ICI therapy at data cut-off. Methylation analyses revealed a combination of methylation changes (both hypo- and hypermethylation) that was predictive for response to ICI. 11/27 (40.7%) patients had PD-L1 expressing tumor cells ( &gt; 1% PD-L1 expression). Median density of CD8+ TILs was 423.49 cells/mm 2 tumor (range 5.71-11528.43 cells/mm 2 ) and median density of CD3+ TILs was 794.82 cells/mm 2 tumor (range 1.68-8811.74 cells/mm 2 ). There was no correlation of PD-L1 expression, density of CD8+ or CD3+ TILs with response or disease control (p &gt; 0.05). Conclusions: In contrast to PD-L1 expression and TIL density, methylation profiles were associated with response to ICI treatment in HNSCC patients.
<i>VEGF-A</i> polymorphisms affect the pharmacologic effect of bevacizumab on VEGF-A levels in patients with metastatic colorectal cancer.
Authors: Apostolos Papachristos, Polychronis Kemos, Haralabos Kalofonos, Gregory Sivolapenko
Journal: Journal of Clinical Oncology (2020)

e15505 Background: Bevacizumab treatment presents large interpatient variability in efficacy. Mutations in VEGF-A rs699947 are associated with longer overall survival and progression free survival in bevacizumab-treated metastatic colorectal cancer (mCRC) patients. The aim of the present study was to investigate correlations between VEGF-A polymorphisms and VEGF-A levels in patients receiving bevacizumab for mCRC. Methods: 46 patients were studied. Blood samples were collected for VEGF-A (rs2010963, 1570360, rs699947) genotyping, and measurement of bevacizumab and VEGF-A levels. The Spearman's rank correlation coefficient was used to study the correlation between VEGF-A and bevacizumab levels. For the multiple analysis, we used linear regression with residual analysis and considering multicollinearity while the effects are reported with 95% confidence intervals. Results: In total 171 samples for VEGF-A and 157 for bevacizumab levels were analyzed. A very strong negative correlation between bevacizumab and VEGF-A levels (coef. = -0.625, p &lt; 0.000001) was noted. Interestingly, VEGF-A rs699947 plays an important role in the model (p = 0.0002, 95% CI 32.5-58.1) and as VEGF-A levels were found to be significantly lower in patients with mutant rs699947 (p &lt; 0.0001, 95% CI 25.2 - 53.8). Conclusions: In conclusion, genetic factors significantly affected the effect of bevacizumab on VEGF-A levels. Significantly lower VEGF levels were measured in carriers of mutant rs699947. These results may explain the favorable clinical outcomes reported in this sub-group of patients. These findings might enable clinicians to distinguish patients, who may benefit more and in a long-term. Finally, can be used to design individualized dosing schemes for bevacizumab.
为支气管哮喘患者提供全科医疗服务的探索
Authors: 李晓南, 王砾, 熊真, 卢蓉
Journal: BMJ (2004)

患者男,71岁.1989年因对油烟、冷热空气、花粉过敏,诊断支气管哮喘住院.以后反复发作,每年住院治疗2～4次,恢复期未治疗.2000年因急性心肌梗死诊断为冠心病、糖尿病、高甘油三酯血症.2001年接受全科医疗服务。
Phase III trial comparing antibody-drug conjugate (ADC) SAR408701 with docetaxel in patients with metastatic non-squamous non-small cell lung cancer (NSQ NSCLC) failing chemotherapy and immunotherapy.
Authors: Melissa Lynne Johnson, Mustapha Chadjaa, Semra Yoruk, Benjamin Besse
Journal: Journal of Clinical Oncology (2020)

TPS9625 Background: Despite recent advances in the treatment of NSQ NSCLC, including the integration of immune checkpoint inhibitors (ICI) into first-line treatment of all patients, novel therapies are necessary at disease progression. Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), a cell-surface glycoprotein, is overexpressed in several tumor types, including NSQ NSCLC; ~20% of patients express high CEACAM5 levels. SAR408701 is an ADC combining a humanized antibody targeting CEACAM5 with the potent cytotoxic maytansinoid derivative DM4 and is expected to selectively deliver DM4 to CEACAM5-expressing cancer cells. In an interim analysis of a first-in-human study (NCT02187848) in patients with NSQ NSCLC and CEACAM5 expression in ≥50% of tumor cells, SAR408701 administered 100 mg/m² every 2 weeks showed an objective response rate (ORR) of 23% and a favorable safety profile (Gazzah A et al J Clin Oncol. 2019;37:15, 9072). Methods: In this randomized, open-label, phase 3 trial, patients receive either SAR408701 100 mg/m² IV every 2 weeks or the standard of care treatment docetaxel 75 mg/m² IV every 3 weeks. Randomization is stratified on ECOG performance status (PS), previous ICI treatment (sequential vs combination), and geographical region. Patients are ≥18 years with metastatic NSQ NSCLC after platinum-based chemotherapy and ICI treatment (anti-PD-1/PD-L1 monoclonal antibody), express CEACAM5 in ≥50% of tumor cells at ≥2+ intensity (central testing), and have ECOG PS 0–1. Exclusion criteria include untreated brain metastases, history of corneal disorders, and prior treatment with docetaxel, maytansinoid derivatives, or CEACAM5-targeting drugs. Tumor imaging occurs at baseline and every 8 weeks until disease progression. Primary endpoints are progression-free survival (PFS; RECIST v1.1 by independent blinded review committee) and overall survival (OS), both analyzed by Kaplan-Meier method, stratified log-rank test, and stratified Cox proportional hazard model. Study success is defined either on PFS or OS, with a strong type-I error control for multiple hypotheses. Secondary endpoints are ORR and duration of response (RECIST v1.1), health related quality of life (EORTC QLQ-C30 and EORTC QLQ-LC13), and safety (adverse events graded by NCI CTCAE v5). Approximately 554 randomized patients (277 per arm) is adequate to reach both PFS and OS events. The study opened in Nov 2019, and as of Feb 7, 2020, 20 sites in 8 countries are activated. Clinical trial information: NCT04154956 .
Pre-treatment predictors of immune-mediated hepatitis in non-small cell lung cancer patients treated with immune-checkpoint inhibitors: A retrospective study.
Authors: Dmitrii Shek, Scott A. Read, Matteo S. Carlino, Adnan Nagrial, Bo Gao, Golo Ahlenstiel
Journal: Journal of Clinical Oncology (2020)

e15136 Background: Immune-checkpoint inhibitors (ICIs) have become standard of care for patients with non-oncogenic driven metastatic non-small cell lung cancer (NSCLC); a feat that has dramatically changed prognosis for these patients. Nevertheless, ICIs can cause immune-related adverse events (irAEs) requiring steroid administration or treatment cessation. This cohort study aimed to examine the incidence of ICI related hepatitis and determine potential predictors of immune-mediated hepatitis. Methods: We retrospectively collected clinicopathological data from 139 patients with metastatic NSCLC treated at Westmead and Blacktown Public Hospitals between 2017 and 2019. Blood tests results were collected longitudinally with a particular focus on liver function tests (LFTs). Further, parameters associated with acute or chronic liver hepatitis were statistically analyzed regarding their association with toxic elevation of LFTs. In particular we were interested in body weight, liver fibrosis (measured by AST to Platelet Ratio Index [APRI] and Fib-4 score), AST/ALT ratio, albumin, globulin, direct/indirect bilirubin, gamma-glutamyl transferase, ratio of serum protein (SP) to total bilirubin (TB) and C-reactive protein. Results: ICIs were more effective in terms of overall (p = 0.0001) and progression-free (p = 0.007) survivals compared to chemotherapy. Pre-treatment blood tests revealed no abnormalities in LFTs, however, at week 9 we first detected elevated LFTs in 29% (n = 18) and 6.5% (n = 5) of ICI and chemotherapy groups, respectively (p = 0.0003). Multivariate regression found that abnormal transaminases at week 9 significantly correlated with high pre-treatment ratio of SP/TB (p = 0.001) in the ICI group only. Specifically, a pre-treatment SP/TB ratio of was &gt; 5 associated with increased ALT at week 9 (odds ratio 92%; positive and negative predictive values: 74% and 97% respectively; sensitivity 94%; specificity 86%). Interestingly, no other significant correlations with elevated transaminases at week 9 were established. Conclusions: In this real-world cohort, we confirmed that ICI therapy results in improved PFS and OS comparing to chemotherapy alone. Moreover, a pre-treatment ratio of SP/TB &gt; 5 was significantly associated with elevated LFTs at week 9 suggesting that it may have a predictive role.
视触叩听急腹症:体格检查是支柱
Authors: 吴东, 韩显林, 朱峰
Journal: BMJ (2012)

认真细致的体格检查对于早期发现并正确诊断急腹症极为重要.急腹症的查体包括判断一般情况、评估生命体征、针对性的腹部查体以及相关其他部位的必要检查.完整细致的体格检查,并辅以动态观察体征的变化,不仅有利于及时做出诊断,还有助于建立良好和谐的医患关系。
Utilizing single-cell-subtype analysis via advanced microdissection methods and the impact on precision medicine.
Authors: Donald Joseph Johann, Sarah Laun, Owen Stephens, Robert Weigman, Ikjae Shin, Adam Roberge, Valerie Greisman, Matthew V Steliga, Jason Muesse, Erich Peterson, Michael Emmert-Buck, Michael Tangrea
Journal: Journal of Clinical Oncology (2020)

e15571 Background: Improving the utilization of tumor tissue from diagnostic biopsies is an unmet medical need. This is especially relevant today in the rapidly evolving precision oncology field where tumor genotyping is essential for the indication of many advanced and targeted therapies. National Comprehensive Cancer Network (NCCN) guidelines now mandate molecular testing for clinically actionable targets in certain malignancies. Patients diagnosed with advanced non-small cell lung cancer (NSCLC) are commonly of an older age and have significant co-morbidities. This frequently causes clinical dilemmas regarding the ability to obtain adequate amounts of tissue for tumor genotyping. In these cases, the tumor tissue may have been obtained by an image-guided biopsy, and the diagnosis of NSCLC proper determined via cytology. In certain instances, adequate tissue for tumor genotyping and/or a more advanced mutational analysis to identify oncogenic drivers may not be available. Methods: Following pathology review, formalin fixed paraffin embedded (FFPE) specimens were subjected to advanced immuno-based laser capture microdissection (LCM), DNA was extracted and prepped for droplet digital PCR (ddPCR) and run with a series of positive and negative controls. Results: Utilizing advanced stage lung cancer as an example, an improved genotyping approach for solid tumors is possible. The strategy involves optimization of the microdissection process and analysis of a large number of identical target cells from FFPE specimens sharing similar characteristics, in other words, single-cell subtype analysis. The shared characteristics can include immunostaining status, cell phenotype, and/or spatial location within a histological section. Conclusions: Synergy between microdissection and ddPCR enhances the molecular analysis. We demonstrate a methodology that illustrates genotyping of a solid tumor from a small tissue biopsy sample in a time and cost-efficient manner, using immunostain targeting as an example.
A rational approach to nivolumab dosing using cost analysis.
Authors: Alex Renner, Suraj Rajesh Samtani, Carlos Salinas, Carlos Rojas, Mauricio Emanuel Burotto Pichun
Journal: Journal of Clinical Oncology (2020)

e15101 Background: Immune checkpoint inhibitors have changed the landscape in oncology, offering durable responses and improved survival across several tumor types. A significant problem in many countries is access to these drugs, as the yearly treatment cost can exceed $100,000. One of the alternatives to reduce the total cost of therapy is to optimize the dosing strategy. Nivolumab was initially approved with a 3mg/kg Q2W dosage, later fixed dose nivolumab 240mg Q2W was also approved. Fixed dose regimens can lead to unnecessarily high doses for patients under 80 kg. Methods: We performed a cost analysis using weight data from 53 patients diagnosed with melanoma or metastatic renal cell carcinoma who were treated with nivolumab at our institution. With that information we generated a model which calculated the total cost if they were to receive the 240mg fixed dose regimen, versus a a cost-saving strategy as follows: all patients weighing up to 79.9Kg were to be dosed at 3mg/kg, while patients 80kg or more were to use the fixed 240mg dose. Since nivolumab is available in 100mg, 40mg and 240mg vials, there is dose wastage when using the 3mg/kg calculation, this was considered for the cost analysis. Results: The median weight of our patients was 73.6kg (range 56,0kg - 103,1kg). Analyzing individual patient data, 75% of them would receive a higher dose if treated with the fixed dose regimen, versus 3mg/kg dosing. Among them, the median comparative overdosage is 50,9mg (range 3.0mg - 87.0mg). Considering drug wastage, and a USD 12.96 per mg local price for nivolumab, treating our 53 patients with the proposed model for one year would result in USD 366.886 in cost savings, versus using the 240mg fixed dose regimen, equivalent to a 9.3% of the total treatment costs. Conclusions: Expanding access to immunotherapy is a challenge for health systems. We have shown a potential 9.3% cost savings using a rational dosing regimen for nivolumab, which could be very important in cost-constrained scenarios which many countries are facing. Considering the world average weight is 62.0kg, it is plausible than even greater cost savings could be realized in many other locations around the globe.