tbuckley/cabot-search huggingface dataset:
Phase III study of tislelizumab plus chemotherapy vs chemotherapy alone as first-line (1L) treatment for advanced squamous non-small cell lung cancer (sq NSCLC).
Authors: Jie Wang, Xinmin Yu, Shun Lu, Yanping Hu, Yuping Sun, Zhijie Wang, Jun Zhao, Yan Yu, Chunhong Hu, Kunyu Yang, Guosheng Feng, Kejing Ying, Wu Zhuang, Jianying Zhou, Jingxun Wu, Yanjie Wu, Xiao Lin, Liang Liang, Nong Yang
Journal: Journal of Clinical Oncology (2020)

9554 Background: Tislelizumab is an anti-PD-1 antibody engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis. Tislelizumab in combination with chemotherapy has demonstrated a manageable tolerability profile and preliminary efficacy as 1L treatment for NSCLC. Methods: In this open-label phase 3 study (NCT03594747), Chinese pts with histologically confirmed stage IIIB or IV sq NSCLC were randomized (1:1:1) to receive IV Q3W: tislelizumab (200 mg, D1) + paclitaxel (P; 175 mg/m 2 , D1) and carboplatin (carb; AUC 5, D1) ( Arm A); tislelizumab + nab-P (100 mg/m 2 ; D1, 8, and 15) and carb (AUC 5, D1) ( Arm B); or P (175 mg/m 2 , D1) and carb (AUC 5, D1) ( Arm C). Chemotherapy was administered for 4-6 cycles followed by tislelizumab. Patients were stratified by tumor stage and PD-L1 expression. The primary endpoint, PFS per RECIST v1.1, was assessed by Independent Review Committee; key secondary endpoints included OS, ORR, DoR, and safety/tolerability. Results: Across 360 pts, median PFS was significantly improved with tislelizumab plus chemotherapy ( Arms A and B) compared with chemotherapy alone ( Arm C) (Table). As of 6 Dec 2019, ORRs were higher and median DoRs were longer in Arms A and B vs Arm C. Across all arms, median OS was not reached and median number of treatment cycles were comparable. Adverse events (AEs) leading to discontinuation of any treatment were reported in 12.5%, 29.7%, and 15.4% of pts in Arms A, B, and C, respectively. The most commonly reported grade ≥3 AEs were hematologic in nature (eg, neutropenia) and consistent with known chemotherapy AEs. Serious treatment-related AEs (TRAEs) were reported in 72 pts (37.5% [ A]; 38.9% [ B]; 23.6% [ C]); TRAEs leading to death were reported in 6 pts (n=1 [ A]; n=2 [ B]; n=3 [ C]), none of which were solely attributed to tislelizumab. Conclusions: As 1L treatment for advanced sq NSCLC, addition of tislelizumab to P/carb or nab-P/carb chemotherapy significantly improved PFS and showed higher ORR and longer DoR than chemotherapy alone. The safety profile is in line with the known profiles of tislelizumab, chemotherapy, and underlying NSCLC; no new safety signals were identified with addition of tislelizumab to chemotherapy. Clinical trial information: NCT03594747 . [Table: see text]
Repurposing antimuscarinics to treat lethal chemoresistant prostate and lung cancers.
Authors: Tyler B Bland, Boyang Wu
Journal: Journal of Clinical Oncology (2020)

e15636 Background: Advanced non-small cell lung cancer (NSCLC) and prostate cancer (PCa) remain leading causes of cancer-related deaths in the United States and worldwide. The current study investigates the ability of antimuscarinics to resensitize chemotherapy resistant NSCLC and PCa to chemotherapy-induced apoptosis. Methods: The chemotherapy drug docetaxel (DTX) resistant human NSCLC and PCa cell cultures were established to recapitulate clinical emergence of chemoresistance. These cultures were used to harvest total RNA and protein for qPCR and Western blot analyses, respectively. DTX’s ability to induce apoptosis was measured with crystal violet survival assay and TUNEL assay. Results: DTX-resistant NSCLC (A549 R ) and PCa (DU145 R ) cells show increased expression of the muscarinic acetylcholine receptors 1 and 3 (CHRM1 / CHRM3). Treatment of these DTX-resistant cells with the CHRM1 antagonist dicyclomine (Dic) or the CHRM3 antagonist darifenacin (Dari) resensitize these cells to DTX-induced cell death. This treatment repurposes Dic and Dari, which are currently used in the clinic to treat irritable-bowel syndrome and overactive bladder, respectively. Decreased cell survival was observed with crystal violet survival assay, which led to increased cell death at a lower concentration of DTX compared to cells treated with DTX alone (A549 R [DTX IC50]: DTX = No response, Dic + DTX = 5.2 nM, Dari + DTX = 2.2 nM / DU145 R [DTX IC50]: DTX = No response, Dic + DTX = 4.2 nM, Dari + DTX = 1.4 nM). Furthermore, cells treated with Dic + DTX or Dari + DTX show increased apoptosis measured by TUNEL assay compared to cells treated with DTX alone (A549 R [TUNEL positive %]: DTX = 0.9%, Dic + DTX = 22.2%, Dari + DTX = 88.2% / DU145 R [TUNEL positive %]: DTX = 3.6%, Dic + DTX = 96.4%, Dari + DTX = 90.1%). Conclusions: We show that chemoresistant NSCLC and PCa have high expression of CHRM1 and CHRM3 and that antimuscarinics effectively resensitize these lethal forms of cancer to chemotherapeutics. Our data support the rationale of repurposing these therapies to treat chemoresistant NSCLC and PCa, allowing quick entry into a Phase II clinical trial and further translation into clinical practice, in a more cost-effective and less financially risky way, to benefit cancer patients.
Platelets impact the responsiveness of immune checkpoint blockade therapy in solid tumors.
Authors: Brian P Riesenberg, Mingjia Li, Daniel Spakowicz, Rebecca Hoyd, Joal Beane, Yuanquan Yang, Filiz Oezkan, Kai He, Sandip H. Patel, Andrew Johns, Madison Grogan, Abdul Miah, Marium Husain, Erin Marie Bertino, Gregory Alan Otterson, Kari Lynn Kendra, Carolyn J Presley, David Paul Carbone, Zihai Li, Dwight Hall Owen
Journal: Journal of Clinical Oncology (2020)

e15023 Background: A growing body of evidence has linked platelets (plts) with immune suppression in the tumor microenvironment (TME). Our group has demonstrated, plts are the dominant source for TGF-β in TME and pharmacologic inhibition of plt function enhances multiple forms of immunotherapy (Sc Immunol 2017 PMID 28763790; J Immunol 2019 PMID 31358658; Sci Transl Med 2020 PMID 31915300). To further delineate this relationship, we examined the roles of plts on T cell exhaustion in a preclinical model and on response to immune checkpoint inhibitors (ICI) in a large cohort of patients (pts) with stage 4 cancers. Methods: The mouse MC-38 colon adenocarcinoma model was used in age-matched female C57Bl/6J mice. Antiplatelet therapy (APT) consisting of aspirin and clopidogrel (both at 30 mg/kg daily) was delivered p.o. and anti-PD-1 antibody (100 mg/mouse every 3 days) was administered i.p. starting on days 5 and 9 respectively. TME analysis via multispectral histology or flow cytometry was performed. Retrospective analysis was carried out on 826 pts who received ICI from 2011-2017 at the Ohio State University. Baseline plt count was collected within 7 days before initiating ICI. Repeat plt count was obtained prior to initiation of cycle 2. Normal plt counts were defined as 150,000 – 450,000/µl blood, and thrombocytosis as plt ≥450,000/µl blood. Kaplan Meier and log-rank analysis were performed to estimate median survival and determine the association with plt count. Results: In pre-clinical models, pretreatment with APT (1) synergized with PD-1 blockade to enhance T cell infiltration into MC-38 tumors resulting in immediate tumor reduction, and (2) decreased tumor infiltrating CD8 + T cell TOX expression, a transcription factor associated with T cell exhaustion (Nat Immunol 2019 PMID: 31427776). Among pts receiving ICIs, 46 (5.6%) pts with thrombocytosis had a significantly reduced median OS vs pts with normal plt counts: 6.0 (95 CI: 1.5—10.6) months (mos) vs 11.6 (95 CI: 9.7—13.4) mos (p = 0.002). Fluctuations ≥50,000 plt/mL in either direction between cycle 1 and 2 were associated with a significant reduction in median OS: 8.3 (95 CI: 6.4—10.1) mos vs 13.6 (95 CI: 11.2-16.1) mos (p &lt; 0.001). Conclusions: There is a strong association between plts and failure of ICI in both the preclinical and clinical settings, likely via modifying the amount of active CD8 + T cells infiltrating into tumors. These findings merit further study to delineate the underlying mechanism for plt-mediated immune suppression and strategies to overcome it.
Diagnostic value of brachial-ankle pulse wave velocity in coronary atherosclerosis and peripheral artery diseases
Authors: 徐远溪, 赵明中, 马文林, 郭晓铭, 罗盈怡, 胡大一
Journal: BMJ (2007)

目的 探究肱踝脉搏波速度(baPWV)与冠状动脉粥样硬化病变和外周动脉狭窄病变程度的相关性及其在动脉硬化疾病中的诊断价值.方法 选取心内科住院患者中45～92岁接受冠状动脉造影术(CAG)的患者共272例,部分患者同时接受了下肢动脉造影术.测量患者左右两侧baPWV,同步测量四肢血压,计算出两侧的踝臂指数.根据冠状动脉狭窄的严重性(按照Gensini评分法评估)分4组比较患者的踝臂指数及baPWV;根据baPWV分5组比较患者的踝臂指数;根据下肢动脉造影结果分4组探讨动脉狭窄程度与踝臂指数及baPWV的相关性;并对冠心病罹患的危险因素进行回归分析.结果 冠状动脉狭窄重度病变组踝臂指数(1.04±0.22)显著低于对照组,baPWV(1822±434)cm/s则显著高于对照组及轻度病变组;baPWV重度升高组踝臂指数异常比例(13.9%)高于其余各组;下肢动脉狭窄程度与踝臂指数呈负相关,与baPWV呈正相关.均P＜O.05或P＜0.01.logistic回归分析显示,baPWV过高、踝臂指数过低、高血糖和吸烟是冠心病罹患的危险因素.结论 baPWV＞1800 cm/s提示有较严重冠状动脉事件可能,＞2100 cm/s提示有外周动脉疾病(PAD)可能.baPWV对于预判冠心病发生及严重程度有重要意义,是继踝臂指数之后又一个预测外周动脉疾病的指标。
Detection of prostate cancer and determination of its significance using explainable artificial intelligence.
Authors: Okyaz Eminaga, Andreas Loening, Andrew Lu, James D Brooks, Daniel Rubin
Journal: Journal of Clinical Oncology (2020)

5555 Background: The variation of the human perception has limited the potential of multi-parametric magnetic resonance imaging (mpMRI) of the prostate in determining prostate cancer and identifying significant prostate cancer. The current study aims to overcome this limitation and utilizes an explainable artificial intelligence to leverage the diagnostic potential of mpMRI in detecting prostate cancer (PCa) and determining its significance. Methods: A total of 6,020 MR images from 1,498 cases were considered (1,785 T2 images, 2,719 DWI images, and 1,516 ADC maps). The treatment determined the significance of PCa. Cases who received radical prostatectomy were considered significant, whereas cases with active surveillance and followed for at least two years were considered insignificant. The negative biopsy cases have either a single biopsy setting or multiple biopsy settings with the PCa exclusion. The images were randomly divided into development (80%) and test sets (20%) after stratifying according to the case in each image type. The development set was then divided into a training set (90%) and a validation set (10%). We developed deep learning models for PCa detection and the determination of significant PCa based on the PlexusNet architecture that supports explainable deep learning and volumetric input data. The input data for PCa detection was T2-weighted images, whereas the input data for determining significant PCa include all images types. The performance of PCa detection and determination of significant PCa was measured using the area under receiving characteristic operating curve (AUROC) and compared to the maximum PiRAD score (version 2) at the case level. The 10,000 times bootstrapping resampling was applied to measure the 95% confidence interval (CI) of AUROC. Results: The AUROC for the PCa detection was 0.833 (95% CI: 0.788-0.879) compared to the PiRAD score with 0.75 (0.718-0.764). The DL models to detect significant PCa using the ADC map or DWI images achieved the highest AUROC [ADC: 0.945 (95% CI: 0.913-0.982; DWI: 0.912 (95% CI: 0.871-0.954)] compared to a DL model using T2 weighted (0.850; 95% CI: 0.791-0.908) or PiRAD scores (0.604; 95% CI: 0.544-0.663). Finally, the attention map of PlexusNet from mpMRI with PCa correctly showed areas that contain PCa after matching with corresponding prostatectomy slice. Conclusions: We found that explainable deep learning is feasible on mpMRI and achieves high accuracy in determining cases with PCa and identifying cases with significant PCa.
误诊癫痫六年
Authors: 吴明昌
Journal: BMJ (2005)

患儿男,4岁在骑自行车摔倒时发生小抽搐,瞬间自愈,家长未予重视.7岁上学后与同学打架或看电视惊吓时常有抽搐发作,当地诊断为癫痫,一直服用苯妥因钠,抽搐减少,每半年或1年发作2～3次,若停药则每月或每日有发作。
Magnetic Resonance Imaging Alteration of the Brain in a Patient With Coronavirus Disease 2019 (COVID-19) and Anosmia
Authors: Letterio S. Politi, Ettore Salsano, Marco Grimaldi
Journal: JAMA Neurology (2020)

This case report describes a 25-year-old female radiographer with no significant medical history who had been working in a coronavirus disease 2019 (COVID-19) ward who presented with a mild dry cough that lasted for 1 day, followed by persistent severe anosmia and dysgeusia.
Adaptive dose optimization trial of stereotactic body radiation therapy (SBRT) with or without GC4419 (avasopasem manganese) in pancreatic cancer.
Authors: Elizabeth Charlotte Moser, Sarah E. Hoffe, Jessica Frakes, Todd Anthony Aguilera, Mona Karim, Lauren Elizabeth Colbert, Shalini Moningi, Ching-Wei David Tzeng, Peter F. Thall, Shubham Pant, Manoop S. Bhutani, Melissa Brookes, Jon Holmlund, Joseph M. Herman, Cullen M. Taniguchi
Journal: Journal of Clinical Oncology (2020)

TPS4670 Background: Local progression causes up to 30% of deaths from pancreatic cancer (PC) and is also a significant source of morbidity. Stereotactic body radiotherapy (SBRT) offers the potential for improved therapeutic index over standard fractionation, but current regimens of 5 fractions of 5-7 Gy/fraction are constrained by nearby organ tolerance and offer only palliation without improving survival. Safe dose escalation may be necessary to improve SBRT efficacy. Avasopasem, a superoxide dismutase mimetic, selectively converts superoxide (O2•-) to hydrogen peroxide (H 2 O 2 ) and oxygen. O2•-initiates normal tissue damage due to RT. Avasopasem is in a Phase 3 trial (NCT03689712) to reduce RT-induced oral mucositis in head and neck cancer, based on positive results in a randomized Phase 2 trial for that indication (Anderson, JCO 2019). Avasopasem improved the survival of mice receiving 8.5 Gy x 5 to the upper abdomen. Cancer cells are less tolerant to elevated H 2 O 2 , and more tolerant to elevated O2•-, than normal cells, and avasopasem demonstrated mechanism-dependent synergy with high dose-fraction RT in a human tumor xenograft with inducible expression of catalase (Sishc, AACR 2018). Thus, adding avasopasem to SBRT may increase both the efficacy and the safety of the latter. Methods: 48 patients with locally advanced PC, who have completed medically-indicated induction chemotherapy, are randomized 1:1 to placebo or avasopasem, 90 mg IV, prior to each of 5 consecutive daily (M-F) SBRT fractions. A phase I/II Late Onset Efficacy/ Toxicity tradeoff (LO-ET) based adaptive design adaptive model drives assignment of SBRT dose escalation in each arm based on a dual endpoint (Gr 3-4 GI toxicity or death; local stable disease or better) by 90 days post SBRT. The planned dose levels are 10, 11 and 12Gy x 5 fractions (BED10 = 100,112.5 and 132Gy, respectively) as an integrated boost to the gross tumor volume (GTV). Primary endpoint: Maximum tolerated dose of SBRT with avasopasem or placebo. Secondary endpoints progression-free survival, response rate, and acute (90 day) and late (12 month) radiation toxicity with avasopasem vs placebo. Exploratory correlative studies include ctDNA, tumor exome/transcriptome sequencing, and immune profiling. Clinical trial information: NCT03340974 .
Long-term results of selective internal radioembolization (SIRT) to control progressive liver metastases of gastro-intestinal stromal tumors (GIST) beyond treatment with tyrosine kinase inhibitors (TKI).
Authors: Peter Hohenberger, Nils Rathmann, Karen Buesing, Franka Menge, Steffen Diehl
Journal: Journal of Clinical Oncology (2020)

11538 Background: Liver and peritoneum are the main area of metastatic spread in GIST. Liver resection does not play a role for hepatic metastases in comparison to f.e. colorectal cancer. If hepatic metastases are the only or major area of tumor progression and are resistant to available TKIs due to a missing mutation in KIT/PDGFRA/SDH ( ‘wildtype’) or after treatment with 1 st /2 nd /3 rd /4 th line therapy, interventional radioembolization with yttrium-90 ( 90 Y) microspheres are promising treatment options, as radiation doses as high as 200Gy can be applied locally. We analyzed the long-term results of SIRT with respect to hepatic-progression-free survival (HEP-PFS) in a consecutive cohort of patients.. Methods: From 1/2008 to 1/2018, 25 pts (12f, 13m) with biopsy proven liver metastases of GIST which were the only (n = 13) or the dominant site of progression (n = 12) were treated by SIRT. Median age at GIST diagnosis had been 51.8 yrs and when receiving SIRT was 57.6yrs (range, 18–75yrs). The mutational status was ‘wildtype’ (n = 7, 2 NF-1), exon 11 (n = 7), exon 11+2 nd mutation (n = 6), exon 9 (n = 3), exon 9+2 nd mut (n = 1), and, exon 13 (n = 1). All patients except of two had prior TKI therapy: 1 line n = 3, 2 lines n = 11, 3-4 lines n = 9. Follow-up after SIRT was done via dynamic MRI and contrast-enhanced (CE)-CT, the median follow-up is 30.6 mos (range, 12-100mos) and all patients were followed until death. Results: The median hepatic-progression free survival (HEP-PFS) after SIRT was 17 months (range, 5-53+, 95%CI 11.8-22.1 mos). Of the patients with concomitant extrahepatic disease, the extraHEP-PFS was median 10 months. Twelve patients received next-line TKI therapy for progressive extrahepatic disease, whereas six patients required this for progressive liver metastases. When comparing the results according to the mutational status, patients with a ‘wildtype’ tumor showed a better median HEP-PFS of 19 mos (range, 12-53+, 95%CI 16.7-21.2 mos.) in comparison to KIT exon 9/11/13 mutated patients with only 14 months (range, 4-34 mos., 95%CI 6.5-21.4 mos), p &lt; 0.11 (Wilcoxon). Conclusions: 90Y radioembolization (SIRT) offers a safe and effective treatment for patients with liver metastases of GISTs being the dominant site of tumor progression and with no drug treatment options available. In patients known to have no mutation in KIT/PDGFRA (wt, also NF-1 associated) it looks whether the results might be even more promising and SIRT could be used in early treatment lines.
Results of a phase Ib trial evaluating the safety and clinical activity of sapanisertib (TAK 228) in combination with serabelisib (TAK 117) and paclitaxel in patients with advanced ovarian, endometrial, or breast cancer.
Authors: Casey B. Williams, Kirstin Anne Williams, Amy K. Krie, Pradip De, Nandini Dey, Brian Leyland-Jones, David Starks, Luis Alexander Rojas-Espaillat
Journal: Journal of Clinical Oncology (2020)

3604 Background: The link between taxane resistance and activation of PI3K/AKT/mTOR signaling suggests that by inhibiting this pathway in combination with anti-microtubule agents like paclitaxel may improve treatment outcomes in many malignancies. To investigate this further we combined the TORC 1/2 inhibitor sapanisertib (TAK-228), the PI3Kα isoform inhibitor serabelisib (TAK-117), and paclitaxel in a phase I trial to determine the safety, efficacy, and RP2D. Methods: Open label, cohort study using a traditional 3+3 dose escalation design with a maximum of 5 dosing cohorts. A dose expansion of cohort 4, the recommended RP2D, is planned for February 2020. Results: Enrollment to the DLT evaluation has been completed and the clinical results are summarized in Table. Sixteen patients have been enrolled; a majority were heavily pretreated and resistant to paclitaxel. Overall, the combination was safe and tolerable. One DLT occurred due to renal dysfunction in cohort 5. 360 adverse events have been reported, but only 28 (8%) grade 3 or 4 events. The most common events were leukopenia and non-febrile neutropenia. Two patients required dose reductions as a result of pneumonitis. The ORR is currently 46% in 13 evaluable patients. CBR is 69% and PFS is currently at 10 months. Two patients achieved a CR and three patients remain on treatment. Conclusions: The combination proved to be well tolerated in the doses and schedules used in cohorts 1-4 and exhibited very promising clinical activity in heavily pretreated patients. This regimen could prove to be a highly effective treatment option and a phase 2 study is warranted at the RP2D. Clinical trial information: NCT03154294 . [Table: see text]
Risk factors of cardiocerebrovascular events in diabetic patients with metabolic syndrome
Authors: Yuling Li, Liangxiang Zhu, Qi Yuan, Wei Sun, Shuo Chen, Rong Kang, Wenhui Gao
Journal: BMJ (2015)

Objective
To investigate the risk factors of cardiocerebrovascular events in type 2 diabetic (T2DM) patients with metabolic syndrome (MS).


Methods
Total 376 patients with type 2 diabetes, including 258 cases with metabolic syndrome and 118 cases without metabolic syndrome, entered in community diabetes management program in 2008 and followed up for 6 years. The body mass index (BMI), blood pressure, blood lipids, fasting blood glucose, postprandial 2 h blood glucose, glycated hemoglobin (HbA1c), the incidence of liver and kidney function and other indicators were measured in a 6-month interval, the cardiovascular events were documented.


Results
At the end of follow-up: BMI, waist circumference, hip circumference, systolic blood pressure, postprandial blood glucose, high density lipoprotein levels of T2DM patients with MS were higher than those of T2DM patients (P<0.05). The systolic pressure, HbA1c and low density lipoprotein levels of T2DM with MS patients were decreased by 2.99 mmHg (1 mmHg=0.133 kPa), 0.43%, and 0.50 mmol/L, respectively (P<0.05); those of T2DM patients were decreased by 1.58 mmHg, 0.01% and 0.68 mmol/L, respectively (P<0.05). The incidence rate of cardiocerebrovascular events in T2DM group was 5.1%(6/118), that in T2DM with MS was 13.2%(34/258), Kaplan-Merier analysis showed that Cum Hazard rate of cardiovascular diseases between two groups was significantly different (χ2=3.877, P=0.049). The Cox survival analysis showed that the risk rate of cardiocerebrovascular events in T2DM with MS patients was 2.21 times higher (95%CI: 1.02-4.73) than diabetic group. After adjustment of gender, age, education level, metabolic syndrome, the risk was 2.31 times (95%CI: 1.01-5.28) higher than diabetic group.


Conclusion
The diabetic patients with metabolic syndrome increase the risk of cardiocerebrovascular events, and the management of T2DM with MS patients need to be strengthened.


Key words: 
Cardiovascular diseases; Diabetes mellitus, type 2; Metabolic syndrome; Community health services