tbuckley/cabot-search huggingface dataset:
PREDICT1: An observational study for identifying blood biomarkers associated with clinical benefit from carboplatin and pemetrexed (CbP) treatment in patients with non-squamous (NS) non-small cell lung cancer (NSCLC) (CJLSG1201).
Authors: Tetsunari Hase, Kiyoshi Yanagisawa, Asuki Fukatsu, Tomoki Kimura, Eiji Kojima, Takashi Abe, Kazuyoshi Imaizumi, Yoshitsugu Horio, Tetsuya Oguri, Masashi Yamamoto, Tomohiko Ogasawara, Yasuteru Sugino, Masahiro Morise, Masahiro Nakatochi, Masahiko Ando, Masashi Kondo, Hideo Saka, Hiroshi Saito, Yoshinori Hasegawa, Takashi Takahashi
Journal: Journal of Clinical Oncology (2020)

9524 Background: At present, platinum-doublet chemotherapy or in combination with an immune check point inhibitor are standard treatment for patients with metastatic or recurrent NSCLC which lacks somatic gene alterations. Although CbP is one of the commonly used treatment options for NS-NSCLC, its clinical utility is limited due to lack of optimal biomarkers. Methods: Chemotherapy-naïve patients with pathologically proven advanced or recurrent NS-NSCLC received carboplatin (area under the curve = 5-6, at investigator’s discretion) plus pemetrexed (500 mg/m2) every 3 weeks followed by maintenance pemetrexed until disease progression. Blood samples were collected before treatment for proteomic analysis using mass spectrometry (MS). A classifier was constructed based on both an objective response assessed by radiologist independent of attending physicians in accordance with RECIST v1.1 and expression profiles of protein in a training cohort. The constructed classifier was then assessed with a validation cohort evaluating prediction accuracy of good responder, progression free survival (PFS) and overall survival (OS). Results: Of 244 patients with NS-NSCLC in a training cohort, proteomic profiles in blood from 96 patients who responded or progressed after treatment with CbP were analyzed to develop a classifier based on weighted voting. Details of the classifier will be presented at the 2020 ASCO Annual Meeting. The classifier was then applied to validation cohort (n = 94), and we successfully identified patients who benefit from the treatment (55 in good MS group) or not (39 in poor MS group). The objective response rate of the good MS group was significantly higher than that of the poor MS group (30.9% vs. 5.1%; p = 0.0018). The good MS group showed a significantly improved survival compared to the poor MS group (median PFS, 6.0 m vs. 2.3 m; hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.09-0.27; p &lt; 0.001; median OS, 25.7 m vs. 5.1 m; HR, 0.18; 95% CI, 0.1-0.34; p &lt; 0.001). Conclusions: In the present study, we successfully developed and validated a predictive classifier using proteomic analyses with blood samples collected from patients before treatment with CbP, suggesting the clinical utility of the classifier in selecting NS-NSCLC patients for treatment with CbP. Clinical trial information: UMIN000008476 .
The prognostic role of somatic BRCA mutations in ovarian cancer: Preliminary results from an observational multicenter cohort study.
Authors: Claudia Piombino, Angela Toss, Alessandra Bologna, Elisa Gasparini, Vittoria Tarantino, Maria Elisabetta Filieri, Luca Cottafavi, Filippo Giovanardi, Luigi Marcheselli, Isabella Marchi, Federica Domati, Marta Venturelli, Elena Barbieri, Giovanni Grandi, Elena Tenedini, Enrico Tagliafico, Laura Cortesi
Journal: Journal of Clinical Oncology (2020)

e13674 Background: BRCA germline (gBRCA) mutations occur in 11-15% of women with unselected ovarian cancers (OC), whereas somatic BRCA (sBRCA) mutations occur in approximately 5-7% of cases. The impact of sBRCA mutations on OC outcome is still debated. Methods: With the aim to explore the prognostic role of sBRCA mutations, the BRCA mutational status of 149 non-mucinous and non-borderline OC and their clinical-pathological features were evaluated. BRCA1 and BRCA2 mutational profiles, either for sequence variants or copy number alterations, were evaluated by amplicon next-generation sequencing (NGS) technology. Results: 29 (19.5%) patients carried a gBRCA mutation (12.7% BRCA1 and 6.7% BRCA2). 26 (17.5%) patients presented a sBRCA mutation (6.7% BRCA1, 10% BRCA2, 0.6% BRCA1+BRCA2). Patients carrying a gBRCA mutation were slightly younger (57 years) than the others (60 years). The FIGO stage at the diagnosis was III-IV in 77.2% of cases, with no significant difference among subgroups. The most frequent histotype was serous for all the subgroups (93.1% in gBRCA, 84.6% in sBRCA, 77.7% in BRCA-negative, p = 0.08). 80.7% of sBRCA mutation carriers, 62.1% of gBRCA mutation carriers and 62.7% of BRCA-negative patients underwent upfront surgery (p = 0.46). 29.1% of sBRCA mutation carriers, 17.8% of gBRCA mutation carriers and 25.6% of BRCA-negative patients presented macroscopic residual disease after surgery (p = 0.68). Although non-statistically significant, gBRCA-associated OC were more likely to be platinum-sensitive (96.6%) than the other patients (92% in sBRCA and 87.1% in BRCA-negative patients). Overall, the median platinum-free interval (PFI) resulted shorter in sBRCA mutation patients compared to gBRCA and BRCA-negative patients (p = 0.051). No patient took PARP inhibitors as maintenance after the first line therapy. Also progression free survival 2 (PFS2) resulted shorter for sBRCA mutation patients (p = 0.008). Three sBRCA and 5 gBRCA mutation carriers took a PARP inhibitor as maintenance after the second line therapy. Finally, sBRCA mutated patients showed worse overall survival (OS) compared to the other subgroups (p = 0.014). Conclusions: Overall, 19.5% of OC patients presented a gBRCA mutation, while 17.5% of patients showed sBRCA mutations. sBRCA-related OC did not show significantly differences in clinical-pathological features (stage at diagnosis, histotype, time to surgery and residual after surgery). To our knowledge this is the first study showing shorter PFI, PFS2 and OS in patients carrying sBRCA mutations.
Offline: After COVID-19—is an “alternate society” possible?
Authors: Richard Horton
Journal: The Lancet (2020)

How do we make sense of this pandemic? The first interpretations are now appearing. Slavoj Žižek is a prolific philosopher and cultural theorist. He is the first to produce a volume of reflections—Pandemic! COVID-19 Shakes the World (Polity, 2020). Žižek doubts the epidemic will make us wiser: he insists that "we should resist the temptation to treat the ongoing epidemic as something that has a deeper meaning". Despite these cautions, we still have an important question to answer: "What is wrong with our system that we were caught unprepared by the catastrophe despite scientists warning us about it for years?" We must accept that "The coronavirus epidemic itself is clearly not just a biological phenomenon which affects humans: to understand its spread, one has to consider human cultural choices…economy and global trade, the thick network of international relations, ideological mechanisms of fear and panic." Žižek opens his investigation in China—"China thwarts the freedoms of its citizens." He endorses the view of Li Wenliang, the ophthalmologist who was censored by Wuhan authorities for sharing information about the new SARS-CoV-2 virus and who later died from COVID-19: "There should be more than one voice in a healthy society." China dealt assertively and successfully with the outbreak in Wuhan.
A phase I, first-in-human, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-3654 administered daily for 28 days to patients with advanced solid tumors.
Authors: Ignacio Garrido-Laguna, Patrick Michael Dillon, Stephen Patrick Anthony, Margit Janat-Amsbury, Nissa Ashenbramer, Steven L Warner, Lars Mouritsen, Mark L. Wade, Clifford Whatcott, David Bearss, Siqing Fu
Journal: Journal of Clinical Oncology (2020)

3586 Background: TP-3654 is an oral, second generation, potent PIM-1 kinase inhibitor with activity against PIM 2, 3 and favorable selectivity against other kinases. These cytoplasmic serine/threonine kinases are highly expressed in many cancers and their oncogenic potential has been largely attributed to supressing apoptosis downstream of stimuli including inflammatory cytokines and other immune effectors. TP-3654 has efficacy in various hematologic and solid tumor models inducing stromal Pim-1 also has been shown to mediate various aspects of the tumor microenvironment. Thus, Pim kinases are attractive targets for the treatment of many human malignanices. Methods: A first in human, multicenter, phase 1, dose escalation study using a standard 3+3 design with a modified Fibonacci scheme to examine the safety and clinical activity of TP-3654 in patients with advanced solid tumors. Results: Ten patients were enrolled between 30Apr and 31Dec2019 receiving 480, 720, and 1080 mg respectively. Grade 3 AEs were scrotum wound infection, altered mental status, anemia, fall, and lower extremity edema, none were related to study drug and all were manageable with supportive care. There were no Grade 4 or 5 AEs and no DLTs. Median duration of SD was 5.5 months (6/10) and with prolonged SD &gt; 16wks (4/10). One CRC patient with 4 lines of prior therapy had a 22% reduction in tumor volume (SD &gt; 5+ mos). TP-3654 plasma PK values (C max , AUC) continuously increased through all 3 cohorts. Average C max (ng/mL) and AUC 0-24 (ng*hours/mL) were 195, 1965 (480mg); 357, 3310 (720mg); 735, 6922 (1080mg), respectively. PK values increased linearly with higher doses without reaching saturation. Peripheral Blood Mononuclear Cells were isolated from subjects prior and up to 24hours after treatment. Western Blot from protein lysates revealed a decrease in phosphorylation of BAD and p70s6K proteins, both regulated by PIM-1 kinase. Conclusions: These findings suggest that TP-3654 is tolerated as a monotherapy in patients with heavily pretreated, relapsed, and resistant solid tumors warranting further clinical development in selected indications.
糖尿病前期及其筛查
Authors: 辛爽清, 单忠艳
Journal: BMJ (2009)

糖尿病在世界范围内流行,发病率和患病率迅速增加,糖尿病相关的疾病和死亡已经成为一个重要的公共卫生问题,全社会为此花费非常巨大.流行病学研究显示,糖尿病并发症的风险从糖尿病前期到糖尿病的早期阶段就已经开始,若能早期诊断和治疗糖尿病前期(即糖调节受损)将会有效减少或延缓糖尿病、心血管病和微血管病的进展。
A phase II study evaluating atezolizumab (A), cobimetinib (C), and vemurafenib (V) in patients (pts) with BRAF<i>-</i>mutant melanoma and central nervous system (CNS) metastases (mets).
Authors: Paola Queirolo, Luis de la Cruz Merino, Ana Maria Abajo Guijarro, Hussein Abdul-Hassan Tawbi, Reinhard Dummer
Journal: Journal of Clinical Oncology (2020)

TPS10081 Background: CNS mets, a common complication of melanoma, are associated with poor survival prognosis (median of 4-5 months). The rationale for combining PD-L1 pathway blockade using atezolizumab (A) with the small molecule BRAF pathway–targeted inhibitors cobimetinib (C) and vemurafenib (V) for the treatment of BRAF V600 mutation–positive melanoma is based on preclinical and translational evidence supporting the synergistic antitumoral effects of these approaches. Recently, the phase 3 IMspire150 study (NCT02908672) demonstrated improved progression-free survival outcomes with A + C + V vs C + V. Methods: This phase 2 study (NCT03625141) is currently evaluating A + C + V in pts with BRAF V600 mutation–positive advanced melanoma and CNS mets. The study originally included a parallel cohort evaluating A + C in pts with BRAF V600 wild-type advanced melanoma and CNS mets. This cohort was closed at an enrollment of 15 pts after the primary analysis of the phase 3 IMspire170 study (NCT03273153), which showed no added benefit with A + C vs pembrolizumab in pts with BRAF V600 wild-type disease. Eligible pts are aged ≥18 years with histologically confirmed melanoma and magnetic resonance imaging–confirmed brain mets ≥5 mm in at least 1 dimension. In addition, pts should not have received prior systemic treatment for metastatic disease; they were required to have ECOG performance status ≤2 and adequate hematologic and end organ function. Prior stereotactic or surgical therapy of ≤10 brain mets is allowed. The primary endpoint is intracranial objective response rate (ORR) with A + C + V in BRAF V600 mutation–positive melanoma as assessed by an independent review committee. Key secondary endpoints include investigator-assessed intracranial ORR, extracranial ORR, overall ORR, safety, and quality of life. Exploratory biomarker analyses are planned. The sample size for the cohort will be approximately 60 pts. No formal statistical hypothesis is being tested in this study. The primary study analysis and the analyses of all efficacy endpoints and safety summaries will be based on data collected ≤6 months after the last pt is enrolled. Clinical trial information: NCT03625141.
神经氨酸酶抑制剂防治甲、乙型流感的疗效：随机对照试验的系统性回顾及汇总分析
Authors: NicolaJCooper, AlexanderJSutton, KeithRAbroams, AllanWailoo, DavidATurner, KarlGNicholson, 顾佳
Journal: BMJ (2003)

患者女,24岁.因畏寒、发热6 d,咳嗽3 d,呼吸困难1 d于2005年11月7日入院.发病前2周家中饲养的鸡、鸭陆续死亡,曾多次参与宰杀并食用.6 d前在无明显诱因下出现畏寒、低热,3 d后体温渐升至38～39 ℃,伴干咳和全身肌肉酸痛.因抗感染3 d无效,出现呼吸困难及发绀来本院就诊。
幽门螺杆菌感染与相关疾病
Authors: 王崇文, 谢勇
Journal: BMJ (2004)

自从1983年发现幽门螺杆菌(Helicobacter pylori, Hp)以来,Hp与慢性胃十二指肠疾病的关系日益受到人们的关注,目前已公认它是慢性胃炎、消化性溃疡和胃黏膜相关淋巴组织(mucoca associated lymphoid tissue, MALT)淋巴瘤的重要致病因子,并与胃癌的发生密切相关。
Association of sarcopenia with higher toxicity and poor prognosis in nasopharyngeal carcinoma.
Authors: Xin Hua, Guo Ling, Huan-Xin Lin
Journal: Journal of Clinical Oncology (2020)

6568 Background: Given the growing evidence that sarcopenia is associated with toxicity and survival in various cancers, we investigated its significance in patients with nasopharyngeal carcinoma (NPC) receiving concurrent chemoradiotherapy (CCRT). Methods: In this retrospective analysis, we studied 862 NPC patients who had received CCRT between 2010 and 2014. Sarcopenia was determined using routine pre-radiotherapy computed tomography (CT) simulation scans at the third cervical (C3) vertebral level. Receiver-operating characteristic (ROC) curve analyses were used to determine the optimal cutoff values. Propensity score matching (PSM) was applied to develop comparable cohorts of patients with or without sarcopenia. Results: A total of 862 patients were included as the primary cohort, and 308 patients were matched and regarded as the matched cohort. In the primary cohort, the five-year overall survival (OS), locoregional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) rates for the sarcopenia group vs. non-sarcopenia group were 78.2% vs. 93.6% ( P &lt;0.001), 89.4% vs. 87.9% ( P = 0.918), and 82.5% vs. 89.0% ( P = 0.007), respectively. Univariate and multivariate survival analyses revealed that sarcopenia was an independent predictor of OS ( P &lt;0.001 and P &lt;0.001) and DMFS ( P = 0.009, P = 0.034). Patients with sarcopenia experienced significantly higher rates of treatment-related toxicities compared with patients without sarcopenia ( P= 0.032). In addition, patients with sarcopenia also experienced significantly worse treatment response than those without sarcopenia ( P = 0.004). Similar results were found in a PSM cohort. Conclusions: The current findings support that sarcopenia is a promising indicator for predicting clinical outcomes in NPC patients receiving CCRT. A simple and rapid analysis on CT simulation images can provide information about the therapeutic toxicity and survival prognosis, consequently guiding personalized multi-modality interventions during CCRT.
Association of High-Potency Cannabis Use With Mental Health and Substance Use in Adolescence
Authors: Lindsey A. Hines, Tom P. Freeman, Suzanne H. Gage, Stanley Zammit, Matthew Hickman, Mary Cannon, Marcus Munafo, John MacLeod, Jon Heron
Journal: JAMA Psychiatry (2020)

Cannabis use is consistently linked to poorer mental health outcomes, and there is evidence that use of higher-potency cannabis increases these risks. To date, no studies have described the association between cannabis potency and concurrent mental health in a general population sample or addressed confounding using longitudinal data.To explore the association between cannabis potency and substance use and mental health outcomes, accounting for preceding mental health and frequency of cannabis use.This cohort study used data from the Avon Longitudinal Study of Parents and Children, a UK birth cohort of participants born between April 1, 1991, and December 31, 1992. Present data on outcomes and exposures were collected between June 2015 and October 2017 from 1087 participants at 24 years of age who reported recent cannabis use.Self-reported type of cannabis most commonly used in the past year, coded to a binary exposure of use of high-potency cannabis or lower-potency cannabis.Outcomes were reported frequency of cannabis use, reported cannabis use problems, recent use of other illicit drugs, tobacco dependence, alcohol use disorder, depression, generalized anxiety disorder, and psychotic-like experiences. The study used secondary data; consequently, the hypotheses were formulated after data collection.Past-year cannabis use was reported by 1087 participants (580 women; mean [SD] age at onset of cannabis use, 16.7 [3.0] years). Of these, 141 participants (13.0%) reported the use of high-potency cannabis. Use of high-potency cannabis was associated with increased frequency of cannabis use (adjusted odds ratio [AOR], 4.38; 95% CI, 2.89-6.63), cannabis problems (AOR, 4.08; 95% CI, 1.41-11.81), and increased likelihood of anxiety disorder (AOR, 1.92; 95% CI, 1.11-3.32). Adjustment for frequency of cannabis use attenuated the association with psychotic experiences (AOR 1.29; 95% CI, 0.67-2.50), tobacco dependence (AOR, 1.42; 95% CI, 0.89-2.27), and other illicit drug use (AOR, 1.29; 95% CI, 0.77-2.17). There was no evidence of association between the use of high-potency cannabis and alcohol use disorder or depression.To our knowledge, this study provides the first general population evidence suggesting that the use of high-potency cannabis is associated with mental health and addiction. Limiting the availability of high-potency cannabis may be associated with a reduction in the number of individuals who develop cannabis use disorders, the prevention of cannabis use from escalating to a regular behavior, and a reduction in the risk of mental health disorders.
Brugada综合征患者自动心脏复律除颤器植入后误服奎宁一例
Authors: 张艳春, 董剑廷
Journal: BMJ (2011)

患者男,43岁,因抽搐伴神志不清2次曾于2006年7月30日入院,诊断为Brugada综合征,并行自动心脏复律除颤器植入术(ICD植入术).之后至2009年6月共发作室性心动过速16次,其间规律服用胺碘酮、美托洛尔.2009年6月再次因心悸入住我科,好转出院后停用胺碘酮、美托洛尔,而自行服用从香港购买的奎尼丁(英国Actavis药厂生产),口服200～600 mg,1次/d,共服用1年零6个月,之后患者至今未发作心律失常.后来我院复诊时医生发现其所服奎尼丁实为奎宁.患者服用奎宁前后心电图。
Effect of detection of epigenomic changes in plasma-derived cell-free DNA on multicancer classification.
Authors: Anna Bergamaschi, David Haan, Jeremy Ku, Yuhong Ning, Chris Ellison, Gulfem Guler, Tierney Phillips, Erin McCarthy, Michael Antoine, Albert Nguyen, Aaron Scott, Paul Lloyd, Alan Ashworth, Kelly Bethel, Samuel Levy
Journal: Journal of Clinical Oncology (2020)

1539 Background: Epigenomic changes in DNA methylation patterns are more precisely delineated by active demethylation events as marked by 5-hydroxymethylation (5hmC) of cytosine residues. 5hmC appears to be dynamically modulated in tumor tissues and can be employed as a cancer biomarker. Strategies which interrogate 5hmC genome-wide patterns in a liquid biopsy context may provide efficient and precise technology for early cancer screening and detection. In this study we identified genome-wide 5hmC changes in plasma based circulating free DNA (cfDNA) from breast, colorectal, lung, pancreatic and prostate cancer patients versus non-cancer individuals. Methods: cfDNA was isolated from plasma, enriched for the 5hmC fraction using novel click-chemistry protocol for labelling followed by sequencing and alignment to a reference genome to construct features sets of 5hmC patterns. Regularized classification models were constructed to classify cancer samples apart from non-cancer. Results: &gt; 500 non-cancer individuals and &gt; 500 cancer patients across five cancer types (breast, colorectal, lung, pancreas and prostate) were included in this study. About 60% of the cancer samples were early stage disease (I or II). The ability to classify non-cancer versus cancer patients was evaluated by 5-fold cross validation of our trained prediction models. Our models were able to classify all breast cancer with a test auROC of 0.86 while prediction model classification for ER negative samples had an auROC of 0.92. Colorectal performance auROC was 0.9; lung auROC = 0.92, pancreatic auROC = 0.97 and prostate auROC = 0.91. Overall sensitivity range, when allowing 2% false positive, was between 85% and 52%. Further using 5hmC signal in blood we were able to identify several signaling pathways specifically relevant to the biology of the cancers investigated. Conclusions: These findings further demonstrate that 5hmC changes in cfDNA enable non-invasive detection of breast, colorectal, lung pancreatic, and prostate cancers. Further, 5hmC signals enabled the identification of a suite of cancer signaling pathways differentially enriched in cancers versus non-cancers. These data suggest that dynamic changes in tumor cell methylation, detectable through 5-hydroxymethylation, are contained in the circulating blood and signal active disease biology.