tbuckley/cabot-search huggingface dataset:
Mesenchymal chondrosarcoma: An Australian multi-centre cohort study.
Authors: Madeleine Cornelia Strach, Peter S. Grimison, Richard Boyle, Paul Stalley, Elizabeth Anne Connolly, Vivek Bhadri
Journal: Journal of Clinical Oncology (2020)

e23509 Background: Mesenchymal chondrosarcoma (MCS) is a rare sarcoma that has a more aggressive course than conventional chondrosarcoma. Treatment is often multimodal with combinations of surgery, chemotherapy and radiotherapy. This study gives opportunity to evaluate prognostic factors and treatments in an Australian setting. Methods: We performed a retrospective study on patients with MCS registered on the ACCORD prospective sarcoma database from 6 Australian sarcoma centres since 2009. We collected data including baseline demographics, clinicopathological variables, treatment characteristics and survival status. We assessed outcomes of overall survival (OS), progression-free survival (PFS) and proportions of metastatic and localised patients receiving surgery, chemotherapy and/or radiotherapy. Results: We identified 20 patients diagnosed with MCS between Jan 2001 and Dec 2019. Median age was 35 years (range 20-69 years). Two (10%) had metastatic disease at diagnosis and 7 (35%) developed metastases on follow up. Median follow-up was 20 months (0.4 – 210 months). 17 (85%) patients underwent surgical resection (17 of primary, 8 of recurrence/metastasis), 10 (50%) received chemotherapy (95% anthracycline; 1 preoperative, 9 palliative), 12 (60%) received radiotherapy (7 to primary, 9 to recurrence/metastasis), and 13 (65%) received multimodality therapy. All six patients who received surgery alone remained alive at follow-up with no metastatic disease. Table shows survival estimates for the study population. There was no difference in median OS in patients who received all therapies compared to those who did not (8.4 v 7.5 years; p = 0.53). Median PFS was not prolonged in those who received all therapies compared to those who did not (37 vs 43 months, p = 0.4). Conclusions: This study demonstrates contemporary Australian treatment patterns of MCS. Understanding treatment patterns and outcomes helps promote standardisation of treatment and design of prospective trials for novel therapeutic strategies. Future analysis of prospective patients for patient and treatment factors influencing survival is planned. [Table: see text]
Distribution and drug resistance analysis of carbapenems-resistant Klebsiella pneumoniae
Authors: Yongchun Ruan, Yiqing Zhou, Lixia Yu, Haiwang Zhang, Jianyong Ma, Meixia Su, Dongfang Han, Wei He
Journal: BMJ (2018)

Objective
To investigate the clinical distribution and drug resistance of carbapenems-resistant Klebsiella pneumoniae (CRKP).


Methods
A total of 134 clinical strains of CRKP were collected from inpatients in our hospital from January 2014 to December 2016. VITEK-2 compact automatic microbiological analyzer was used to identify the bacteria and the supporting gram-negative bacterial drug susceptibility card was used for susceptibility testing. The sensitivity of other clinical commonly used antimicrobial agents was measured by K-B method. And the clinical distribution of CRKP and its resistance to antimicrobial agents were investigated and analyzed.


Results
The clinical strains of CRKP were isolated mainly from urine (n=70, 52.2%) and sputum (n=38, 28.4%). Klebsiella pneumoniae was identified in samples from the department of neurosurgery, including neurosurgery ICU (47.8%, 64/134), ICU (23.9%, 32/134), department of hepatobiliary surgery (8.2%,11/134) and department of urology (6.0%, 8/134). Among all 22 antimicrobial agents tested, the resistant rates of CRKP to 16 antimicrobial agents were >90%, especially for ampicillin it was 100%, and those to 19 antibiotics were >80%, only for tigecycline it was 23.1%. There were 16 strains of CRKP with positive extended spectrum β-lactamases (ESBLs) (11.9%). All the CRKP strains were resistant to more than three kinds of antimicrobial agents, except one strain that was resistant to two kinds.


Conclusion
There is a wide range of clinical distribution of CRKP, which is resistant to most of antimicrobial agents, while tigecycline still has a strong antibacterial activity to CRKP.


Key words: 
Klebsiella pneumoniae; Carbapenems; Drug resistance
癌症有遗传性吗
Authors: 杨秉辉
Journal: BMJ (2010)

由于如今癌症的发病率高和诊断技术的进步,常在一家几代人中相继、甚至有同时被发现患有癌症的情况.因此癌症的遗传问题引起人们的关注.侍统的说法是:癌症不是遗传性疾病.当然并非绝时,比如大肠癌有一部分是由大肠息肉症演变而来.而这种大肠息肉症是遗传的,被称为家族性大肠息肉症.此病患者一生中有60%的机会发生大肠癌。
Association of a STK11/KEAP1-mutation gene expression signature in lung adenocarcinoma with immune desertion in squamous cell carcinomas and mediation by NFE2L2 deregulation.
Authors: Damian Tobias Rieke, Konrad Friedrich Klinghammer, Benedikt Obermayer, Eric Blanc, Clemens Messerschmidt, Korinna Jöhrens, Frederick Klauschen, Inge Tinhofer, Dieter Beule, Ulrich Keilholz, Sebastian Ochsenreither
Journal: Journal of Clinical Oncology (2020)

3082 Background: KEAP1 and STK11 mutations are associated with resistance to immune checkpoint inhibition (ICI) in non-small cell lung cancer (NSCLC). Mechanisms are currently unknown. Methods: We examined mutation, methylation, copy number and gene expression data from the cancer genome atlas (TCGA) lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LSCC), head and neck squamous cell carcinoma (HNSCC) and cervical carcinoma (CESC) data sets as well as public single cell gene expression data from a HNSCC cohort. Pathway annotations were performed using gene set enrichment analysis. A previously published cohort of NSCLC patients treated with ICI was analyzed for the predictive value of NFE2L2 mutations on PFS. Results: Annotation of STK11 and KEAP1 mutant LUAD revealed identical gene set enrichment for mitochondrial metabolism and downregulation of the STING-pathway, immune checkpoints, and interferon signaling. A STK11/KEAP1-mutation derived gene expression signature was established in LUAD and found to be driven by NFE2L2-regulated genes. This gene expression signature was independently predictive of immune desertion in LSCC, CESC and HNSCC and associated with STING-pathway downregulation in single cell sequencing analyses in HNSCC. KEAP1 and STK11 mutations were less frequent in LSCC, CESC and HNSCC but NFE2L2 mutations were identified in 15, 6 and 5%, respectively. NFE2L2 mutant SCC exhibited upregulation of the 15-gene- signature as well as immune desertion. In NSCLC, NFE2L2 mutations were associated with significantly worse PFS with ICI. Conclusions: Alterations of KEAP1, STK11, NFE2L2 and other related genes are linked to NFE2L2 target gene upregulation and immune desertion in LUAD, CESC, LSCC and HNSCC alike. The NFE2L2 pathway should be investigated clinically as a putative negative predictive biomarker for ICI and a potential therapeutic target.
Relationship between obesity and serum soluble intercellular adhesion molecule-1 in adolescents
Authors: Chun-ming Ma, Hong Zhang, Qiang Lu, Shu-yi Wang, Fu-zai Yin, Bo-wei Liu, Dong-hui Lou, Xiao-li Liu, Rui Wang, Guang-fei Wu, Gai-ling Han
Journal: BMJ (2009)

Objective To evaluate the relationship between obesity and serum soluble intercellular adhesion molectde-1 (sICAM-1) in adolescents. Methods Totally, 158 adolescents aged 13-15 years were divided into three groups based on their body mass index (BMI) , 80 in control group, 44 in overweight group and 34 in obesity group. Height, weight, waist circumference (WC) and blood pressure were measured for all of them and sICAM-1 was assayed from fasting venous blood collected. Results BMI, WC and systolic blood pressure were significantly higher in overweight group than those in control group (P < 0. 01). BMI, WC, systolic blood pressure and diastolic blood pressure were significantly higher in obesity group than those in overweight group (P<0. 05). Level of sICAM-1 was significantly higher in obesity group than that in control group (P <0.05). Their sICAM-1 showed positive correlation with BMI (r = 0.168, P=0.035) and WC (r=0. 179, P =0.025). Multiple linear regression analysis using sICAM-1 as a dependent variable showed that WC (β= 0.009, 95% CI 0. 001-0.018, P=0.025) was an independent predictors for sICAM-1 adjusted for age, sex, BMI and blood pressure. Conclusions Results mentioned above suggest that endothelial dysfunction associates with obesity, particularly with abdominal obesity. sICAM-1 can be used as an early marker of atherosclerosis in adolescents.

Key words: 
Obesity;  Intercellular signaling peptides and proteins;  Adolescent
The role of TGF-β pathway in immune regulation as a potential biomarker of immunotherapy across pan-cancer.
Authors: Yongmei Yin, Yan Liang, Zhengyi Zhao, Yuzi Zhang, Jing Zhao, Longgang Cui, Guoqiang Wang, Yuezong Bai, Shangli Cai
Journal: Journal of Clinical Oncology (2020)

e15187 Background: The transforming growth factor beta (TGF-β) signaling pathway has been reported to be involved in both tumor suppression and tumor promotion. However, the role of TGF-β pathway in immune regulation for cancer patients and its influences on immunotherapy efficacy have not been systematically investigated. Methods: Available data of whole-exome sequencing, mRNA expression, baseline characterization and prognosis information of 10,912 pancancer patients were adopted from The Cancer Genome Altas (TCGA) to explore the role of TGF-β pathway in immune regulation. Formalin-fixed, paraffin-embedded tissue samples from 6,717 Chinese patients with over 17 tumor types were assayed by next-generation sequencing with a panel with 381 cancer related genes as a validation cohort (3DMed cohort). Datasets from the public MSK cohort (N = 1,610) was used to explore the association of TGF-β pathway in patient survival. Results: The highest prevalence of single nucleotide variation (SNVs) in TGF-β pathway fell in digestive system tumors in both TCGA and 3DMed cohorts, including colon adenocarcinoma pancreatic adenocarcinoma, rectum adenocarcinoma, and stomach adenocarcinoma. TGF-β pathway SNVs was significantly correlated with high microsatellite instability, high tumor mutational burden (TMB-H) status and high neoantigen burden (TNB-H) ( p&lt; 0.001) across all tumor types. Notably, the correlation of pathway alternation and TMB or TNB remained significance in microsatellite stable patients ( p&lt; 0.001). Alternations of the pathway genes were associated with significant different expression patterns of immune-related genes such as the up-regulation of CD28, CD40, and CCL5, etc. Consistently, significant higher levels of CD8 ( p&lt; 0.001), dendritic cells ( p&lt; 0.001), and neutrophil cells ( p&lt; 0.001) were observed in the pathway mutated samples. Patients with TGF-β pathway mutations exhibited significant worse prognosis than the wild-type patients regardless of interventions (overall survival, HR 1.20, 95% CI 1.08-1.33; p= 0.001). However, when treated with immune checkpoint inhibitors, superior survival benefit was observed in patients in the mutation group versus the wild-type group (overall survival, HR 0.73, 95% CI 0.61-0.88; p= 0.001). Conclusions: Our study has provided clues for the role of TGF-β pathway in immune regulation in patients with solid tumors and revealed the potential predictive role of TGF-β pathway alternation in cancer immunotherapy.
E2F cell cycle pathway score as a predictive biomarker of ER+/HER2- breast cancer response to neoadjuvant chemotherapy.
Authors: Masanori Oshi, Yoshihisa Tokumaru, Eriko Katsuta, Li Yan, Itaru Endo, Kazuaki Takabe
Journal: Journal of Clinical Oncology (2020)

e12593 Background: Although the survival rate of patients diagnosed with breast cancer has greatly improved over the last decades, the metastatic stage of the disease remains incurable. Estrogen receptor positive (ER+)/human receptor 2 negative (HER2-) breast cancers accounts for approximately 70% of metastatic breast cancers and, it is responsible for most of the deaths from the disease. Another issue of ER+/HER2- breast cancer is its poor response to neoadjuvant chemotherapy (NAC). Recently, several clinical trials have shown that endocrine therapy plus FDA-approved cyclin-dependent kinases (CDK) 4/6 inhibitors have improved the treatment response to patients with advanced ER+/HER2 breast. The CDK 4/6 is an important E2F-related factor. Therefore, we hypothesized that E2F pathway is predictive biomarker for treatment response of ER+/HER2- breast cancer. Methods: METABRIC dataset was used for training cohort. And TCGA breast cancer as well as four neoadjuvant therapeutic cohorts were used as validation cohort. The E2F pathway score was calculated by Gene Set Variant Analysis (GSVA). Results: Tumors with high E2F pathway score enriched cell proliferation and cell cycle pathway related gene sets (G2M, MYC v1, and v2, MITOTIC, MTORC1, PI3K AKT MTOR, and DNA repair; FDR &lt; 0.001). The high E2F pathway score was significantly associated with TNBC and HER2+ (p &lt; 0.001), which are known to be clinically aggressive, and advanced stage (p &lt; 0.001) and high grade (p &lt; 0.001). The score also correlated with copy mutation (r = 0.605, p &lt; 0.01). The patients, who had early recurrence before 5 years, had significantly high score rather than non-recurrence patients (p &lt; 0.001). Moreover, these results were validated in TCGA cohort. The high E2F pathway score group had a higher pCR rate than the low score group with ER+/HER2- breast cancer (p &lt; 0.001). Interestingly, the tumors in high score group expressed higher CDK pathway related molecules compared to low score group. Conclusions: The E2F pathway score was found to be a predictive biomarker for neoadjuvant chemotherapy in ER+/HER2- breast cancer patients.
Contrast-enhanced ultrasonography as a diagnostic supplement for contrast-enhanced CT scan for small hepatocellular carcinoma with liver cirrhosis
Authors: 朱晓琳, 侯文静, 张晟, 徐勇, 李强
Journal: BMJ (2011)

Objective To evaluate contrast-enhanced ultrasonography (CEUS) in diagnosis of small hepatocellular carcinoma (SHCC) ( ≤ 2. 0 cm) with liver cirrhosis after contrast-enhanced CT (CECT) examination. Methods Forty five patients with liver cirrhosis received CECT and CEUS examinations before operation or needle biopsy and the diagnosis was confirmed by pathological examination.CEUS and CECT findings of 51 liver space-occupying lesions from 45 patients were retrospectively analyzed.Results Among all 51 lesions detected CEUS and CECT found 49 and 35, respectively. The typical characteristics of SHCC were fast-in and fast-out and fast-in and slow-out. The sensitivity of CEUS and CECT in diagnosis of SHCC was 88. 9% (32/36) and 69. 4 % (25/36) respectively ( x2 = 3. 02, P =0. 08);the diagnostic accuracy was 84. 3 % (43/51 ) and 56. 9% (29/51 ) respectively ( x2 = 1.46, P =0. 22). Among 16 lesions missed by CECT, 12 were detected by CEUS. Conclusions CEUS and CECT show the similar diagnostic rate for typical SHCC ,however, CEUS is more sensitive for atypical lesions. With high time resolution, CEUS have advantages for follow-up study of benign liver lesions.

Key words: 
Liver cirrhosis ;  Liver neoplasms ;  Ultrasonography,interventional ;
Regulation of dynamic BACE1 trafficking in neurons
Authors: Virginie Buggia-Prévot, Celia G Fernandez, Sean Riordan, Kulandaivelu S Vetrivel, Vinod Udayar, Aureliane Elie, Margaret Lefkow, Jelita Roseman, Xavier Meckler, Sohinee Bhattacharyya, Manju George, Jack Waters, Vytautas P Bindokas, Angèle T Parent, Lawrence Rajendran, Hamid Band, Robert Vassar, Gopal Thinakaran
Journal: Molecular Neurodegeneration (2013)

Proteolytic processing of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase generates Aβ peptides. APP is constitutively trafficked through the secretory and endocytic pathways in cultured cells and neurons. The identities of cellular organelles and sorting pathways involved in amyloidogenic processing of APP have been extensively investigated. Although a consensus has not yet emerged, there is a general agreement from biochemical and genetic studies on the importance of endocytic APP trafficking for Aβ production. In neurons, APP is trafficked anterogradely along peripheral and central axons, and proteolytically processed during transit. Recent in vivo studies estimated that ~70% of Aβ released in the brain requires ongoing endocytosis, and synaptic activity regulates the vast majority of this endocytosis-dependent Aβ. BACE1 cleavage is thought to be the rate-limiting step in amyloidogenic processing of APP. Little, however, is known about endocytic BACE1 sorting and dynamic transport in neurons. We investigated BACE1 trafficking in cultured hippocampal neurons using live-cell imaging and selective labeling. This approach revealed dynamic neuronal transport of internalized BACE1 in dendrites and axons. BACE1 was transported in vesicles that were positive for markers of recycling endosomes. Dominant-negative expression and siRNA knock-down of proteins involved in endocytic transit revealed that BACE1 is dynamically transported in recycling endosomes and this process significantly contributes to amyloidogenic APP processing. Our results suggest that BACE1 trafficking in neuronal recycling endosomes is likely relevant for presynaptic Aβ production and contributes to Alzheimer’s disease pathogenesis.
Solitary Breast Metastasis From Thyroid Papillary Carcinoma Revealed on Whole-Body Radioactive 131I Scan
Authors: Dris Kharroubi, Carine Richa, Clotilde Saie, Linda Chami, Charlotte Lussey-Lepoutre
Journal: Clinical Nuclear Medicine (2020)

Breast metastasis from thyroid papillary carcinoma is an exceptional situation. Here, we present the diagnostic approach and the management of a 19-year-old woman with single breast metastasis from thyroid carcinoma. There was no extra thyroidal extension, neoplastic emboli, or lymph node invasion. The metastasis was revealed by whole-body radioactive I scan, explored by a fine-needle aspiration, and confirmed by elevated thyroglobulin in situ.
PSGL-1 is a novel macrophage checkpoint in immuno-oncology.
Authors: Dominika Nowakowska, Ryan Phennicie, Kevin Kauffman, Mohammad Zafari, Kathryn Rooney, Brian O’Nuallain, Steve Sazinsky, Joe Wahle, Igor Feldman, Tatiana Novobrantseva
Journal: Journal of Clinical Oncology (2020)

e15090 Background: Macrophages are both antigen presenting and effector cells of the innate immune system and play an important role in tissue homeostasis as well as in activation and modulation of the adaptive immune response in disease. They display phenotypic heterogeneity in different tissue environments but can be broadly subdivided into pro-inflammatory M1 macrophages, which promote immune response, and anti-inflammatory M2 macrophages, which are associated with immune suppression. Under steady-state conditions, the populations of immune-stimulatory and immune-regulatory macrophages are balanced, but disruption of this balance can result in disease. In the tumor microenvironment, tumor-associated macrophages (TAMs) acquire an M2-like phenotype and maintain suppression of the immune system and promotion of tumor progression. Methods: For functional screening of anti-PSGL-1 antibodies, monocytes were isolated from peripheral blood mononuclear cells (PBMC) obtained from healthy donors and differentiated into M2 macrophages in the presence or absence of anti-PSGL-1 antibodies. On day 8 of the assay, phenotypic profile of cells was analyzed by flow cytometry and chemokines / cytokines were measured by Luminex. Mixed-lymphocyte reaction assay, SEB assay and an ex vivo tumor model were used to further assess antibody functionality in a multi-cellular assay format. For T cell assays, purified T cells from PBMC were stimulated in the presence or absence of anti-PSGL-1 antibodies and responses were characterized by flow cytometry and Luminex. Results: We have identified PSGL-1 as a novel macrophage checkpoint. Our work demonstrates that targeting PSGL-1 via an antagonistic antibody re-polarizes human primary M2 macrophages to a more M1-like state both phenotypically and functionally. We observe this M2-to-M1 switch to have an impact on immune cell communication in complex multi-cellular assays. Moreover, targeting of PSGL-1 in an ex vivo tumor system demonstrates that anti-PSGL-1 treatment can increase pro-inflammatory cytokine and chemokine production known to be associated with beneficial clinical response. These effects can be predominantly attributed to macrophage modulation, as antibody targeting PSGL-1 on purified T cells has a very small, if any, impact on their activation and effector function. Conclusions: Our results demonstrate that treatments inducing macrophage phenotypic switches can promote an immune response in a tumor setting across multiple tumor types and provide support for targeting the novel macrophage checkpoint PSGL-1 across multiple cancer indications.
PIOS ratio: predicting the best response of non-small-cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors.
Authors: Foteinos-Ioannis D. Dimitrakopoulos, Achilleas Nikolakopoulos, Anastasia E Kottorou, Elias Liolis, Theodora Frantzi, Ioannis Pyrousis, Foteini Kalofonou, Angelos Koutras, Thomas Makatsoris, Haralabos Kalofonos
Journal: Journal of Clinical Oncology (2020)

e21507 Background: With the exception of programmed death ligand 1 (PD-L1) expression and Tumour Mutational Burden (TMB), which have entered clinical practice, no other clinically useful predictive biomarker for immune checkpoint inhibitors (ICIs) has been established in the daily practice. The purpose of this study was to develop a novel, non-interventional and clinically useful predictive score for NSCLC patients with advanced disease treated with ICIs. Methods: Eighty-nine patients with advanced and histologically confirmed NSCLC (stages III and IV), treated with immunotherapy (nivolumab, pembrolizumab, atezolizumab), were enrolled in the current study. Clinicopathological data as well response rates and clinical outcome data were collected. Based on this data and using a regression model, we developed a predictive score (Patras Immunotherapy Score-PIOS) with regard to the best response to ICIs. Best overall responses (BOR) were based on the immune-based therapeutics (iRECIST) criteria. Results: Four of the studied parameters -Performance Status (PS), Body Mass Index (BMI), age and lines of treatment (LOT)- were incorporated in our formula (PS *BMI/ LOT*age) giving rise to PIOS. This score was strongly associated with BOR, with patients of a good response (SD, PR or CR) having higher PIOS compared to patients with progression disease (PD) (p&lt;0.001). The association remained significant when we used a four-tier model (PD, SD, PR and CR) for BOR (p&lt;0.001). PIOS predictive significance also persisted using a binary logistic regression analysis (p=0.001). Conclusions: This study suggests that PIOS, which combines 4 baseline clinical parameters, may help to identify NSCLC patients with increased probability to be benefitted from ICIs treatment. Further evaluation and possibly combination with other factors may multiply its clinical significance.
Progress of imaging diagnosis of gouty arthritis
Authors: Qiaonan Liu, Weiren Ding, Lin Liu, Xuhong Peng, Fenghui Yu, Xiang Peng
Journal: BMJ (2019)

The incidence of metabolic rheumatism gout has been increasing with a trend of more younger patients and atypical symptoms. Typical gout is easy to be diagnosed, but it is difficult for atypical cases. Finding uric acid crystal in articular fluid by polarizing light microscope is a gold standard of diagnosis, but it is an invasive diagnostic method and difficult to be widely used. The patients need further imaging examination for assistance of diagnosis and guide of follow-up treatment. This article reviews the research progress of different imaging methods used for diagnosis of gouty arthritis.


Key words: 
Arthritis, gouty; Ultrasonography; Tomography, X-ray computed; Magnetic resonance imaging