tbuckley/cabot-search huggingface dataset:
Resistance to lorlatinib in <i>ROS1</i> fusion-positive non-small cell lung cancer.
Authors: Jessica Jiyeong Lin, Ted Johnson, Jochen K Lennerz, Charlotte Lee, Harper Grace Hubbeling, Beow Y. Yeap, Ibiayi Dagogo-Jack, Justin F. Gainor, Alice Tsang Shaw
Journal: Journal of Clinical Oncology (2020)

9611 Background: Lorlatinib is a potent, brain-penetrant ROS1/ALK tyrosine kinase inhibitor (TKI), which has demonstrated efficacy in advanced ROS1 fusion-positive (ROS1+) non-small cell lung cancer (NSCLC), including in patients (pts) previously treated with crizotinib. Despite initial benefit, however, most pts experience disease progression on lorlatinib. Mechanisms of resistance to lorlatinib in ROS1+ NSCLC are poorly understood. Methods: We analyzed repeat tumor biopsies derived from advanced ROS1+ lung cancer pts progressing on lorlatinib. Next-generation sequencing (NGS, n = 17) or whole exome sequencing (n = 1) was performed to detect mutations, indels, and copy number alterations. Results: Sixteen pts underwent a total of 18 repeat tumor biopsies after progression on lorlatinib. Fourteen had received prior crizotinib; two received prior crizotinib and entrectinib. Median duration of therapy on lorlatinib was 13.5 months (95% CI, 8.3-18.4). Among the 18 cases analyzed by sequencing, 7 (38.9%) harbored a ROS1 resistance mutation, including G2032R (4/18, 22.2%), S1986F/L2000V (1/18, 5.6%), L2086F (1/18, 5.6%), and G2032R/S1986F/L2086F (1/18, 5.6%). Of note, ROS1 L2086F was a novel resistance mutation not previously reported in the literature, but analogous to ALK L1256F (a lorlatinib-resistant ALK mutation). Structural modeling studies showed that ROS1 L2086F causes steric interference with binding of lorlatinib, as well as crizotinib and entrectinib. In addition to ROS1 kinase domain mutations, NGS analyses also identified MET copy number gain in a lorlatinib-resistant case, validated by fluorescence in situ hybridization as high-level focal MET amplification (MET/CEP7 copy number ratio 6.3) without a concomitant ROS1 resistance mutation. Duration of therapy on lorlatinib was significantly shorter in pts with a post-lorlatinib ROS1 resistance mutation compared to those without (8.3 vs 18.1 months; p = 0.005). Conclusions: ROS1 resistance mutations are observed in over one-third of cases progressing on lorlatinib, including the solvent front mutation G2032R and a novel L2086F mutation. These findings underscore the importance of developing next-generation ROS1 TKIs with activity against ROS1 mutations, and the need to elucidate ROS1-independent resistance mechanisms.
Device for the enumeration and continuous removal of circulating tumor cells in improving overall survival of epithelial cancer patients.
Authors: Jayant Khandare, Smriti Arora, Balram Singh, Alain D'Souza, Nitin Singh, Narendra Kale, Shubham Bhide, Amrut Ashturkar, Aravindan Vasudevan, Gourishankar Aland
Journal: Journal of Clinical Oncology (2020)

e15043 Background: The presence of circulating tumor cells (CTC) in the vascular system is a tell-tale signature of metastasis in epithelial origin cancers including lung, breast, colorectal and head and neck cancers. Noteworthy, about 90% of cancer deaths are due to the progression of metastasis. Yet, cancer therapy is focussed on inhibiting tumour growth and there is a paucity of options that target metastasis. We demonstrate the POP ‘device’ that removes circulating tumour cells (CTC) from a patient’s blood to reduce the metastatic progression and improve overall survival. Methods: We designed, multi-component glass beads enriched antibody EpCAM conjugate substrates as POP blood fluidic device. We characterized the substrate and accounted for the biocompatibility using whole blood of healthy volunteers. We evaluated, the acute toxicity of substrates using rat (Wistar Albino) whole blood (CPCSEA registration number: 941/PO/Re/S/06/CPCSEA; 31/07/2019) and further studied major histopathological tissues for any toxicity. Finally, we evaluated 06 cancer patients whole blood (1.5 mL) for capturing and for the elimination of CTCs. The captured cells were immuno-stained, and the optimal fluorescence acquisition intensity was critically quantified in accounting CK18 protein over-expression. Results: The multi-component antibody EpCAM based substrate exhibited efficient CTC capture ability with a mean capture efficiency ranging from 40% to 100 % when compared to the OncoDiscover CTC test approved by CDSCO/ drug controller general of India (DCGI). Furthermore, the substrate indicated high biocompatibility primarily exhibited by the absence of haemolysis on whole human blood. Additionally, the preliminary animal experiments in rats showed a 100% survival rate and negligible toxicity to major organs. Conclusions: Removal of circulating tumor cells as a therapeutics is highly implicated in improving the overall survival of epithelial cancer patients.
Long-term cancer survival in cohorts of U.S. health professionals.
Authors: En Cheng, Donghoon Lee, Rulla M Tamimi, Susan Hankinson, Walter C Willett, Edward L. Giovannucci, Heather Eliassen, Shelley Tworoger, Stampfer Meir, Lorelei A. Mucci, Charles S. Fuchs, Donna Spiegelman
Journal: Journal of Clinical Oncology (2020)

12075 Background: Few studies have investigated long-term survival and causes of death among men and women diagnosed with major cancers. Methods: We estimated overall and cause-specific mortality rates for men diagnosed with prostate, lung and bronchus, colon and rectum, bladder, and melanoma cancer in the Health Professionals Follow-up Study between 1986-2010+, and women with breast, lung and bronchus, colon and rectum, uterine corpus, thyroid, and ovarian cancer in the Nurses’ Health Study (NHS) between 1976-2010+ and NHS II between 1989-2010+. Kaplan-Meier curves were used to calculate cumulative mortality rates at 5, 10, 15, 20, and 30 years and competing risk methods were used to calculate cumulative cancer-specific mortality rates of major causes at 5, 10, 15, 20, and 30 years. Additionally, among women 40-year mortality rates were calculated. Results: Except for lung and ovarian, most major cancer patients are more likely to die from other causes than the index cancer. We observed two basic patterns for cumulative cancer-specific mortality rates. The first pattern is greatly diminished risk of index cancer-specific mortality 10 years or more following diagnosis - for colorectal cancer, cancer-specific mortality rate increased by less than 3% between 10 to 30- or 40-year following diagnosis (among men, from 35.1% to 36.7%; among women, from 34.8% to 37.7%), and this pattern also applied to bladder, melanoma, or uterine corpus cancer. The second one is sustained, but nevertheless low, excess risk - prostate cancer-specific mortality rate increased gradually and almost linearly from 5.3% to 15.1% after diagnosis from 5 to 30 years, and for breast cancer, it increased likewise from 7.2% to 18.9% after diagnosis from 5 to 40 years. Conclusions: Except for lung and ovarian cancers, patients diagnosed with major cancers were more likely to die from causes other than cancer. Colorectal, bladder, melanoma or uterine corpus cancer patients surviving more than 10 years after diagnosis are unlikely to ever die from that disease. [Table: see text]
Impact of community healthcare service center in emergency response to natural disaster
Authors: Tian Xia, Yan Dai, Quan Gong
Journal: BMJ (2008)

The Medical Healthcare Service Center,located at the Youxian District,Mianyang City of Sichuan Province,successfully rescued the people affected by the Wenchuan earthquake and the Tangjiashan barrier lake with great help from the senior hospitals.We suggest that the community healthcare service center could play an important role in emergency response system.

Key words: 
Community health centers; Emergency mdeical services
Stability of rare TP53 co-mutations in AML patients.
Authors: Kenneth Joel Bloom, Adam Idica, Dave Smart, Wendy Allen, Enya Scanlon, Jordan Clark
Journal: Journal of Clinical Oncology (2020)

7528 Background: Acute Myeloid Leukemia (AML) is a devastating disease with poor overall survival. Access to precision medicines, is revolutionizing AML care and is driving an increase in Next Generation Sequencing (NGS) utilization to determine the genomic profile of patients with AML. Advanced analysis into the interplay between mutational status for multiple genes is granting access to new targeted and precision medicine treatment options with improved outcomes. Methods: Rate of NGS adoption and TP53 mutation status were determined for a cohort of 984 AML patients tested by NGS from the Diaceutics Diagnostic Index between 2017 and 2019. Mutation rate of other genes on the same NGS panel used to determine if TP53 status was determined and compared using the z-score test for two population proportions. The stability of TP53 and co-mutation status at time of diagnosis and relapse/refractory was also analyzed. Results: We have seen a 2-fold increase in the average routine clinical practice uptake of NGS in a representative real-world patient cohort (Q3 2017, n = 144; Q3 2019, n = 290). In a cohort of 984 AML patients tested by NGS 151 (15.3%) had a TP53 mutation (Exon 4-9). Of those that had a TP53 mutation, significant negative associations were observed with mutations in seven other genes (ASXL1 p = 0.00308, CEBPA p = 0.0027, FLT3 p &lt; 0.00001, IDH1 p = 0.04338, NRAS p = 0.0012, RUNX1 p = 0.01878 and TET2 p = 0.0251). There were no statistically significant differences in TP53 mutation and other gene mutation rates between diagnosis and relapse/refractory timepoints. Conclusions: This data suggests that TP53 and other gene co-mutants may act in similar activation pathways resulting in rare detection. One possibility is that double mutants result in synthetic lethality leading to a low clonal population. Second, when co-mutated clones escape immune surveillance and regulation, it results in particularly aggressive leukemias with lower overall survival. The stability of TP53 and co-mutation is relatively stable, which has implications for testing algorithms and clinical utility as a marker of MRD. Although a clinical trial may be difficult due to low numbers of patients, a TP53 antagonist and targeted therapy may be a valuable treatment option in rare cases where co-mutation does exist. [Table: see text]
The association between hyperfibrinogenemia and clinicopathological factors, and the survival analysis of gastric cancer.
Authors: Yu Su, Xuecong Zhu, Jing Zuo, Fengling Liu, Yudong Wang, Zhisong Fan, Long Wang, Feiran Liu, Da Jiang
Journal: Journal of Clinical Oncology (2020)

e16547 Background: It is reported that hyperfibrinogenemia is commonly seen in gastric cancer. This study aim to discuss the association between fibrinogen level and preoperative clinicopathological factors and to evaluate the value as a predictor of prognosis. Methods: Retrospectively reviewed the medical records and follow-up data of patients with gastric cancer who underwent curative resection from January 2011 to December 2014 at Surgery Department of the Fourth Hospital of Hebei Medical University. Fibrinogen was measured a week before the surgery. Results: A total of 248 cases were enrolled. The means±SD of fibrinogen was 3.28±1.06g/L. Fibrinogen level was higher in older adults(≥60y), advanced tumor, poorly differentiated, deep invasion, lymph node metastasis, large tumor size and in those with high CEA, platelet count, albumin, NLR and PLR,( P&lt; 0.05). All the people were divided by the TNM staging system and found that the plasma fibrinogen was higher in stageⅡand Ⅲ (stageⅠvs. stageⅡ: 2.84±0.72g/L vs. 3.36±1.18g/L, P= 0.009;stageⅠvs. stage Ⅲ: 2.84±0.72g/L vs. 3.43±1.07g/L, P&lt; 0.001), however, there was no difference between stageⅡand Ⅲ( P= 0.662)(our study did not enrolled stage IV patients).When patients were classified into 4 groups according to the T classification, the plasma fibrinogen level gradually increased with increasing depth of cancer invasion (one way ANOVA; P= 0.002). Yet, when the patients who have lymph nodes metastasis classified according to the N classification, the differences among them did not have statistically significance ( P= 0.333). Multivariate analysis revealed that hyperfibrinogenemia had an independent association with advanced cancer (odds ratio,2.686(1.012-7.125); P= 0.047), lymph node metastasis (odds ratio,2.012 (1.012-3.125); P= 0.035) and tumor size(odds ratio,1.949 (1.099-3.454); P= 0.022). Our study aslo suggested that the patients with hyperfibrinogenemia before surgery showed a significantly lower survival rate (Log-Rank test; P&lt; 0.001), hyperfibrinogenemia was a independent predictor on the overall survival, which could predict worse clinical outcome. Conclusions: Hyperfibrinogenemia may be considered a useful biomarker to predict advanced tumor, lymph node metastasis and large tumor size and can be a good predictor of worse clinical outcome.
Blockade of TRIM59 to enhance chemosensitivity of esophageal cancer cell to cisplatin by upregulating p53 expression.
Authors: Rong Feng Liu, Jian Shi, Xiaoyang Duan
Journal: Journal of Clinical Oncology (2020)

e16509 Background: TRIM59 is the one of TRIM family characterized by an N-terminal really interesting new gene (RING)-finger domain, followed by two zinc-finger domains named B2 box and a coiled-coil (CC). Ubiquitination plays a vital role in the degradation of many kinds of proteins that function in the intracellular signaling pathway, cell cycle, DNA repair and transcriptional regulation. Because of the RING-finger domain, TRIM59 protein functions as E3 ubiquitin ligase activity and can selectively target ubiquitin-modified proteins for proteasomes or degradation. In additional, accumulating finding results have shown the TRIM proteins promote positively or negatively carcinogenesis. Here we focus on the TRIM59 protein: oncogenic activity in the promoting proliferation and metastasis of esophageal cancer cell. Methods: None. Results: Human esophageal cancer cells’ motility adopts various modes resulting in the HESC progression and poor survival of patients. We proved that TRIM59 is aberrantly up-regulated in metastatic human esophageal cancer (hESC) than adjacent normal esophageal tissue, which is on behalf of poor survival and advanced TNM state among the hESC patients. At the molecular level, we proved TRIM59 as an E3 putative ubiquitin ligase targets the p53 protein leading to the increased degradation of p53 resulting in the less chemotherapy sensitivity to cisplatin. TRIM59 knockdown in hESC cell lines reduced TRIM59 expression and promotes p53 protein level and decreased the proliferation, clone formation, migration. At the same time, hESC cell lines showed more sensitive to the cisplatin in the cell line treated with knockdown of TRIM59. These findings establish the relationship between TRIM59 and p53 and chemotherapy sensitivity of cisplatin and TRIM59 may be a promising prognostic indicator for esophageal squamous cell carcinoma (ESCA) patients. Conclusions: We have confirmed that the up-regulation of TRIM59 in human esophageal cancer tissues closely correlates with poor prognosis of patients and TRIM59 serves as an oncogene promoting the proliferation and metastasis of esophageal cancer. The study demonstrates that knockdown of TRIM59 inhibited the growth and invasion of Eca109 cancer cells and strengthened the chemosensitivity to cisplatin through the mechanism of increasing the p53 expression. These results suggest that combination of TRIM59 knockdown with cisplatin might provide a promising strategy to treat the patients with esophageal cancer.
Breast density notification with adjunctive digital breast tomosynthesis (DBT): A cost-effectiveness analysis.
Authors: Jason Semprini, Mary Vaughan-Sarrazin
Journal: Journal of Clinical Oncology (2020)

7072 Background: Dense breasts increase a woman's risk of developing cancer while also raising the likelihood of a missed diagnosis from traditional mammography screening. Digital Breast Tomosynthesis (DBT) has been shown to identify positive breast cancer more accurately in women with dense breasts, but no study has estimated the cost-effectiveness of this screening mode under a notification requirement. Methods: Taking the perspective of a healthcare system, we estimated the incremental cost-effectiveness ratio (ICER) of providing DBT as an alternative to mammography for 40-year old women. Model parameters reflecting risk of breast cancer, detection rates, and costs were estimated from recent meta analyses, Tufts’ CEA registry, and Medicare Fee Schedules. We used probabilistic Markov Models to estimate the ICER under uncertainty, and a time-variant model in which breast density and cancer risk change over time. Additionally, a heterogeneity analysis included all women between the ages of 40-65, while also using 1 st and 2 nd degree family history to calculate cancer risk. Results: In the probabilistic model, adjunctive DBT has a cost differential of $12,203, with an increase of 0.0382 quality-adjusted life years (ICER = $319,491/QALY) compared to mammography. This result was most sensitive to the probability of a missed diagnosis for women with dense breasts. At a willing-ness to pay of $50,000, adjunctive DBT had a 57% chance of being more costly and less effective than standard mammography. Conversely, DBT only had a 20% chance of being cost-effective and a 9.9% chance of being less costly and more effective. The time-variant model reported an ICER of $174,218, but adjunctive DBT became even more cost-effective after expanding the population and including family history of cancer (ICER_All Ages = $157,146; ICER_FamHist = $153,388). Conclusions: Breast density notification laws which provide additional screening via DBT are not cost-effective at a willingness to pay of $50,000. Policymakers, however, should note that many modern cancer therapeutics also exceed this threshold. As an adjunctive screening technique, DBT would result in fewer deaths and increase quality of life, but the effect is minimal and carries a high cost. Including breast density within greater risk stratification protocols, however, may prove highly cost-effective, especially for older women with a family history of cancer.
Misdiagnosed allergic granulomatous vasculitis as bronchial asthma: 1 case and literature review
Authors: Ruiying Wang, Jianying Xu, Lei Wang
Journal: BMJ (2014)

The clinical characteristics of Churg-Strauss syndrome (CSS) were summarized to improve the understanding of disease and reduce its misdiagnostic rate. Report clinical data, treatment and follow-up of one confirmed case and review the domestic reports of CSS before 2013. Among 94 reported cases, most had initial respiratory symptoms and increased eosinophil was found in peripheral blood of 95.74% patients.


Key words: 
Allergic granulomatous vasculitis; Diagnostic errors
Efficacy and toxicity of immunotherapy with immune checkpoint inhibitors in gynecologic cancers.
Authors: Michelle Kuznicki, Amy Joehlin-Price, Peter Graham Rose, Haider Mahdi
Journal: Journal of Clinical Oncology (2020)

e18092 Background: There is limited data on outcomes for gynecologic cancer patients treated with immune checkpoint inhibitors (ICI) outside the scope of clinical trials. Here we present our Institutional experience with a cohort of endometrial (EC) and ovarian cancer (OC) treated with ICI. Methods: 59 patients who received ICI were included (23 OC and 36 EC). Progression-free (PFS) and Overall survivals (OS) were determined by Kaplan-Meier (KM) curve and log rank test. Comparison of duration of response (DOR) and stable disease (DOSD) was done with unpaired t-test or one-way ANOVA. Rates of objective response (ORR) including partial response (PR) and complete response (CR), and stable disease (SD) were compared by Fischer’s exact test. Results: Median age was 66 years. 23 patients were microsatellite stable (MSS), 23 microsatellite instability high (MSI-H). Median number of prior lines was 2 (0-11). PFS and OS for EC and OC were overlapping; therefore outcomes for both were combined [(PFS 6.4m OC vs 7.3 m EC, p = 0.61), (OS 15.9 m OC vs 14.2 m EC, p = 0.78)]. Response rates consisted of 20.3% PR, 8.5% CR, 37.3% SD. Differences in responses were noted for clear cell carcinoma (CC) (33.3% PR, 11.1% CR, 33.3% SD) and MSI-H (36.4% PR, 18.2% CR, 22.7% SD) compared to MSS (11.8% PR, 0% CR, 47% SD). MSI-H had higher ORR vs. MSS (54.1% vs 11.8%, p = 0.0078). CC trended toward improved ORR vs. MSS (44.4% vs 11.8%, p = 0.14). PFS was improved for MSI-H vs. MSS (10m v 5.0m, p = 0.03). OS for CC compared to any other histology was improved (NR vs 12.8m respectively, p = 0.009). 5 recurrent MSI-H EC patients received ICI as first line monotherapy. Responses included 4 PR and 1 SD (80% ORR, 100% clinical benefit). PFS was 9.2m (3.3-13.3). 80% remained progression-free at last follow up. Overall, 38.9% experienced toxicity: hypothyroidism (15%), dermatitis (5%), pneumonitis (10%), LFT elevation (2%), amylase/lipase elevation (3%), colitis or diarrhea (5%), uveitis (2%) or nephritis (5%). 10% of patients required discontinuation of ICI secondary to toxicity. Trends for PFS and OS favored improved outcomes in patients with toxicity vs. no toxicity [(PFS 12.9m vs 5.6m, p = 0.07), (OS 22.9m vs 13.1m, p = NS)] respectively. Conclusions: In this study, immunotherapy with ICI outcomes favor MSI-H and CC compared to MSS disease. CC had promising OS compared to other histology types. ICI showed promising efficacy in MSI-H EC with 100% clinical benefit rate in chemonaive patients. First line ICI should be investigated in these patients. Positive correlation between toxicity and outcome is noted and will be further investigated.
危重症手足口病患儿临床特征及危险因素分析
Authors: 陈建江, 洪玉玲, 李薇, 林树林
Journal: BMJ (2011)

手足口病是由肠道病毒感染引起的一种急性传染病,多数为轻症,呈自限性,在1周内痊愈.但少数患儿发展为重症,常合并脑炎、脑膜炎、肺水肿或心肌炎等严重并发症,病情进展迅速,病死率高[1-2].本文回顾性分析本院184例重症或危重症手足口病患儿的临床特征、相关辅助检查结果及高危因素,为早期诊断危重症手足口病提供临床依据。
消化科临床精粹(一)
Authors: 吴东, 朱峰, 陈嘉林
Journal: BMJ (2010)

一、胃食管反流病(GERD)的患者经常就诊于呼吸科 GERD是消化系统常见病,约15%～44%的正常人每月发生一次反流症状.值得注意的是,虽然烧心、反酸是GERD最常见的症状,但也有少数患者消化系统以外的临床表现更为突出,为此就诊于其他科室,尤其是呼吸科。
胃肠激素紊乱与重症急性胰腺炎胃肠动力障碍的机制
Authors: 王强, 王湘英
Journal: BMJ (2012)

重症急性胰腺炎(severe acute pancreatitis,SAP)是一种发病急、病情重、发病机制复杂的急腹症,死亡率高达20％～30％[1].SAP常合并胃肠道动力障碍,伴随胃肠动力障碍而致的并发症,包括麻痹性梗阻、腹腔间隔室综合征、胃肠道屏障功能损害、肠道细菌移位和毒素吸收、败血症,甚至全身性炎症反应综合征和多器官功能衰竭综合征[2-4]等.因此,尽早恢复胃肠动力对SAP的发展与转归有重要意义。