tbuckley/cabot-search huggingface dataset:
Molecular correlates of PD-L1 expression in patients (pts) with gastroesophageal (GE) cancers.
Authors: Jingyuan Wang, Joanne Xiu, Anthony Frank Shields, Axel Grothey, Benjamin Adam Weinberg, John Marshall, Emil Lou, Moh'd M. Khushman, Davendra Sohal, Michael J. Hall, Francesca Battaglin, Hiroyuki Arai, Shivani Soni, Wu Zhang, Wolfgang Michael Korn, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2020)

4558 Background: The increased PD-L1 expression evaluated by combined positive score (CPS) is associated with improved efficacy of immunotherapy in GE cancers. The impact of tumor molecular alterations on PD-L1 expression is still not well-studied. We aimed to characterize specific molecular features of tumors with different CPS levels in GE cancers. Methods: 2,707 GE tumors [1,662 gastric/GE junction adenocarcinoma (GA), 856 esophageal adenocarcinoma (EA), 75 esophageal squamous (ES) and 114 GE unspecified] collected between 2000.8 and 2019.7 were analyzed using NextGen DNA sequencing (NGS), immunohistochemistry (IHC) and fragment analysis (FA) (Caris Life Sciences, Phoenix, AZ). Tumor mutation burden (TMB) was calculated based on somatic nonsynonymous missense mutations. dMMR/MSI status was evaluated by a combination of IHC, FA and NGS. PD-L1 expression measured by IHC (22c3) was evaluated by CPS scores. Molecular alterations were compared in three groups (CPS ≥ 10, H; CPS = 1~9, M; CPS = 0, L) using Fisher-Exact or Chi-square and adjusted for multiple comparison by Benjamini-Hochberg. Significance was determined by adjusted (adj) p &lt; .05. Results: Overall, CPS-H, M, and L were seen in 18% (n = 494), 28% (n = 765) and 53% (n = 1,448) of GE tumors respectively. CPS-H was the most prevalent in ES (43%) followed by GA (19%) and lowest in EA (14%). Overall, TMB was similar between CPS-L and M, but was significantly increased in H (average TMB = 8.4 vs. 8.6 vs. 11 mt/MB, adj p &lt; .0001); the effect was seen in EA and GA, but not in ES. An overall significant association between MSI/dMMR status and PD-L1 expression levels was seen (2%, 3.2% and 12% in CPS-L, M and H, adj p &lt; .05) in GE tumors; the significance was seen in GA, but not in EA or ES. Amplifications of PD-L1 (H: 1.5%, M: 0.1% and L: 0) and PD-L2 (H: 1.1%, M: 0.1%, L: 0) were the highest in CPS-H, while ASPSCR1 (H: 0, M: 0, L: 1%) and TNFRSF14 (H: 0, M: 0.4, L: 2%) were the lowest (adj p &lt; .01). Genes involved in epigenetic modification (top 5: ARID1A, ASXL1, BCL9, BCOR, CREBBP), MAPK ( KRAS, MAP2K1) and mismatch repair ( MLH1, MSH6) had the highest mutation rates in CPS-H, compared to M and L ( p &lt; .0001). In contrast, CDH1 had higher mutation rates in CPS-L (12%), compared to M and H (5% and 5%) ( p &lt; .0001). Conclusions: This is the largest study to investigate the distinct molecular landscape of pts with different PD-L1 expression levels in GE cancers. Our data may provide novel insights for pt selection (e.g. pts with gene mutations involved in epigenetic modification) and the development of rational combination immunotherapy (e.g. drugs targeting MAPK pathway).
Potentially targetable alterations identified in circulating tumor DNA (ctDNA) from patients (pts) with advanced rare cancers.
Authors: Hitomi Sumiyoshi Okuma, Kan Yonemori, Yuki Kojima, Maki Tanioka, Kazuki Sudo, Emi Noguchi, Susumu Hijioka, Keiko Wakakuwa, Ken Kato, Hitoshi Ichikawa, Akihiro Hirakawa, Aya Kuchiba, Taro Shibata, Tamie Sukigara, Kenichi Nakamura, Noboru Yamamoto
Journal: Journal of Clinical Oncology (2020)

e15540 Background: People with rare cancers have limited treatment options. In April 2017, the MASTER KEY Project, a prospective registry study with multiple clinical trials embedded, was established to promote treatment development for rare cancers. ctDNA analysis by next-generation sequencing (NGS) has provided new insight into personalized medicine; however, reports are focused on common cancers. Using our platform, we examined the feasibility of ctDNA NGS analysis for rare solid cancers. Methods: Prospectively consented pts with advanced rare cancers enrolled in MASTER KEY had ctDNA NGS testing (Guardant360, Guardant Health). Alterations were assessed for incidence according to cancer type, functional impact, and therapeutic implications. Results: From Nov 2018 to Jan 2019, 98 samples from 100 consented pts were analyzed. Diseases included soft tissue sarcoma (39); cancers of the ovary (12) and salivary gland (9); neuroendocrine tumors (8); carcinoma of unknown primary (6); carcinosarcoma (5); mesothelioma (4); gastrointenstinal stromal tumor (3); and olfactory neuroblastoma (2). All pts were Japanese, male/female = 40/58, median age 53, ECOG performance status 0/1/2/3 = 56/41/0/1, prior pharmacotherapy yes/no = 77/21. 76% of pts (75/98) had at least 1 alteration detected (median 2.8/pt; range: 0-9), with variant allelic frequency of 0.1-73.3%; 61%(60/98) of pts had a likely pathogenic variant, most commonly TP53 (43), KRAS (11), and NRAS (6); 36% (36/98) had a potentially actionable variant, such as BRCA1/2 (6), EGFR (6), PIK3CA (6), ARID1A (5), FGFR1/2/3 (4), and other homologous recombination deficiency genes. Known resistant mutations such as ROS1 G2032R and RAS mutations were detected in patients on a ROS inhibitor and a BRAF inhibitor, respectively, which suggested drug resistance prior to clinical diagnostic imaging. Mean turn-around-time from blood collection was 9.5 days. Conclusions: ctDNA testing is capable of rapidly identifying alterations that lead to clinical decision making in pts with advanced rare cancers, who have a crucial lack of treatment options compared to common cancer pts. Clinical trial information: UMIN000034394.
Health education and medical behavior intervention among healthcare providers who manage diarrhea,rickets.pneumonia,and nutritional anemia in urban children
Authors: Hong-mei Zhao
Journal: BMJ (2009)

From October 2006 to December 2008,170 medical professionals(120 from a provincial hospital,and 50 from 10 district hospitals or hygiene stations),and 400 baby watchers who took care of children(aged<3 years)with diarrhea,rickets,pneumonia,or nutritional anemia were randomly assigned to reeeive health education or medical behavior intervention.The results showed that the basic knowledge on prevention and treatment of diarrhea,rickets,pneumonia,or nutritional anemia wad improved,and oral rehydration solution utility rate was significantly increased(P<0.05 or P<0.01).The rate of breast feeding was higher,and the use of auxiliary food became more proper and timely.The use of antibiotics decreased.The baby watchers got more suggestions,and their qualification rate of medical knowledge and disease.related treatment behaviors were improved(all P<0.01). Nerwork-based health education and medical behavior intervention may have significant effects on healthcare providers who look after urban children with diarrhea,rickets,pneumonia,or nutritional anemia.

Key words: 
Child;  Health edueation
Gastric injuries in blunt abdominal trauma
Authors: Yong He, Ke-feng Dou, Hai-min Li, Yong Chen, Zhi-qing Gao
Journal: BMJ (2009)

Clinical data of 50 patients with gastric injury after blunt abdominal trauma(gastric rupture in 20 and gastric laceration in 30)were retrospectively analyzed.All the patients with gastric rupture had a satiate stomach.which was not found in the patient with gastric laceration.Forty-nine patients experienced combinant injury.The most common combinant injury of gastric laceration was liver and pancreatic injury(15/30 and 10/30),and the most frequent combinant injury of gastric rupture was spleen injury(11/20).Forty-eight patients recovered while 2 died after the treatment with gastric prosthesis.The mortality rate was 4%.Surgical operation,or prosthesis,could be the main treahnent of choice.The management of combinant injuries and complications should be imprta.

Key words: 
Abdominal injuries; Stomach
全科医生接诊语言沟通技巧
Authors: 许子彬
Journal: BMJ (2007)

接诊是医生为诊疗的目的与患者接触、信息交流的过程,是医患接触的第一环.接诊时医患的良好沟通,给患者留下良好的印象,对后续的诊疗工作产生重大影响.语言是接诊时最基本的沟通方式,使用频率最高、最直接,因而最重要。
Enhancement of the therapeutic effects of oncolytic vaccinia virus by using autologous and allogeneic cell-based delivery platforms.
Authors: Boris Minev, Antonio F. Santidrian, Ivelina Minev, Duong Nguyen, Dmitriy Zamarin, Francesco Marincola, Dobrin Draganov Draganov
Journal: Journal of Clinical Oncology (2020)

e15271 Background: Clinical trials with oncolytic viruses for cancer treatment have shown limited efficacy due to viruses’ rapid clearance by patients’ innate and adaptive immune systems. In a recent first-in-human clinical trial, we confirmed the safety and feasibility of our approach to enhance oncolytic vaccinia virus (OVV) delivery and improve tumor targeting by utilizing an autologous cell-based cell delivery system (auto-OVV). We also developed an allogeneic cell-based platform (SuperNova1c - SNV1c) aiming to protect and potentiate OVV’s antitumor effects in large patient populations. Methods: We evaluated the immunomodulatory potential of auto-OVV by an extensive time-course analysis of cytokines in patients’ plasma (Luminex profiling) and peripheral blood immune cells (flow cytometry). We also analyzed the ability of SNV1c to protect the OVV from antibody/complement inactivation in vitro and in vivo following intratumoral injection in various mouse tumors. The immune cell infiltrations of the injected tumors were also analyzed. Results: Therapy with auto-OVV induced a coordinated activation of cytokine, T cell and NK responses in patients as early as 1 day, peaking around 1-week and lasting for up to 1-month post treatment. Effective OVV amplification in cancer patients correlated with significant changes of multiple innate and adaptive immune parameters. Patient stratification into groups with transient versus persistent viral DNA was linked to opposing and mutually exclusive patterns of robust activation of NK versus T cell responses, respectively. SNV1c showed significantly enhanced protection of OVV in vitro and led to statistically significant tumor growth inhibition as compared to control non-treated tumors or to naked OVV-treated tumors. Importantly, local administration of SNV1c induced systemic therapeutic effects. Five days after SNV1c administration, tumor infiltrating lymphocytes from both treated and untreated tumors showed increased CD4 and CD8 T-cell infiltrations, decreased Tregs, and improved effector to Treg ratios, associated with tumor growth inhibition at both treated and untreated tumor sites. Conclusions: This study establishes the timeline of treatment-related immunological changes and identifies potential immunological correlates associated with the OVV persistence in vivo. We also demonstrate the ability of our cell-based platforms to protect and potentiate OVV by circumventing innate and adaptive immune barriers, resulting in enhanced oncolytic virotherapy.
Decision tree model with tumor immune function genes for predicting response to anti-PD1 therapy in renal cell carcinoma.
Authors: Xingang Bi, Zhiwen Luo, Xinyu Bi
Journal: Journal of Clinical Oncology (2020)

e17084 Background: No current models can predict prognosis as well as immunotherapy benefits in renal cell carcinoma (RCC). The current study was undertaken to develop and validate a simple decision tree model to predict survival and immunotherapy benefits in patients with RCC. Methods: Analysis on RNA expression in a reported clinical trial dataset identified tumor immune function genes differentially expressed between anti-PD-1 response and non-response RCC. The analysis on these genes in different populations and platforms to develop a Bi-Luo (BL) DTM. The predictive performance of the BL DTM on the prognosis and the immunotherapy outcome in RCC was comprehensively analyzed and validated. Then, the mechanism of BL classification on the immune microenvironment in RCC was extensively analyzed. Results: Immunologic genes expression alteration resulted in the sensitivity for anti-PD-1 therapy in RCC. Twelve tumor immune function genes were enriched based on anti-PD-1 response. Survival analysis and machine learning algorithms on 12 genes established a BL classification based on 545 RCC samples to differentiate patients into low risk (BL1) and high risk of poor survival (BL2) groups ( P &lt; 0.0001). The BL classification was a better independent prognosis indicator ( P = 0.004). TIDE algorithm predicted the response of two subgroups to immune checkpoint blockade, and BL1 was more promising to respond to anti-PD-1 therapy ( P = 0.00003268). Our BL classification was visualized in a 3 genes-DTM (F2RL1, TNFRSF and WHSC1) with a high prediction accuracy (AUC = 0.84) in an external validation cohort. Furthermore, in a small-scale immunotherapy clinical trial dataset, our BL DTM had a high specificity (0.86) to identify the non-response RCC in anti-PD-1 therapy. Gene expression of immune inhibiting factors in BL2 subtype was higher than BL1 subtype (all P &lt; 0.01), but less in tumor mutation burden ( P = 0.009). Moreover, we found that BL2 subtype had higher fractions of Tregs ( P &lt; 0.001), CD8+ T cells ( P = 0.037) and lower fractions of resisting memory CD4+ T cells ( P &lt; 0.001) than BL1 subtype. And most HLA subtype genes, namely HLA-G, HLA-E, HLA-DR, HLA-DQ and HLA-DP, were significantly down-regulated in BL2 subtype (all P &lt; 0.05). Conclusions: Our BL based DTM could predict survival and has potential for identifying RCC patients who could not benefit from anti-PD-1 immunotherapy. Non-response of RCC to anti-PD-1 immunotherapy is strongly related to the down-regulation of the immune response.
Extensive Remodeling of the Immune Microenvironment in B Cell Acute Lymphoblastic Leukemia
Authors: Matthew T. Witkowski, Igor Dolgalev, Nikki A. Evensen, Chao Ma, Tiffany Chambers, Kathryn G. Roberts, Sheetal Sreeram, Yuling Dai, Anastasia N. Tikhonova, Audrey Lasry, Chunxu Qu, Deqing Pei, Cheng Cheng, Gabriel A. Robbins, Joanna Pierro, Shanmugapriya Selvaraj, Valeria Mezzano, Marla Daves, Philip J. Lupo, Michael E. Scheurer, Cynthia A. Loomis, Charles G. Mullighan, Weiqiang Chen, Karen R. Rabin, Aristotelis Tsirigos, William L. Carroll, Iannis Aifantis
Journal: Cancer Cell (2020)
Results of treating children with medulloblastoma in Azerbaijan of 2020.
Authors: Naila Agayar Mammadova, Malikov Ramin Nizami, Aleskerova Gunel Alik, Ismailzade Reiman Sadikh, Nasirli Asif Akif, Khalafova Leyla Pamir
Journal: Journal of Clinical Oncology (2020)

e14519 Background: Medulloblastoma (a primitive neuroectodermal tumor of the posterior cranial fossa) is the most common CNS tumor in children; it takes 20-30% of all brain tumors. In about 40% of cases of primary detected tumors, there are already metastatic lesions of the brain and spinal cord. Treatment of medulloblastoma is a difficult problem. It requires a multidisciplinary approach and modern technical support of the medical institution. Only after the opening of the children's oncology department of the National Oncology Center in 2012, it became possible for children with a medulloblastoma to use modern treatment by HIT-2000 and HIT 2015 protocols. Methods: For the period 2012-2020, a total amount of 45 children were treated with a diagnosis of medulloblastoma (34 boys, girls-11). The average age of children was 12 years. Complete removal of the tumor was reached in 27, subtotal removal of 18 patients. Taking into account the age, the histological variant and the size of the residual tumor after surgery, the patients were divided into high and medium risk groups. Treatment according to the average risk group was carried out in 27 patients and high risk group - in 18. Craniospinal radiation therapy was carried out in 45 patients in the prescribed manner (SOD 25-30 Gy for the entire CNS and additionally for the posterior cranial fossa 25-30 Gy). In parallel with radiation therapy, vincristine is used, in dose of 1.5 mg / m2 weekly, only 8 times, followed by 8 courses of maintenance chemotherapy (cisplatin 70 mg / m2, lomustine 75 mg / m2 and vincristine 1.5 mg / m2). Results: Children in general satisfactorily tolerated both chemo- and radiotherapy. No serious complications of treatment were noted. During the observation period ( 8 years), relapses were observed in 5 children out of 45 treated, in 3 there was a progression during treatment, 8 children died. Thus, out of 45 children, 37 are alive with no signs of illness. 8-year survival rate was 82% ± 7%. Conclusions: The introduction and subsequent modification of modern foreign protocols into the practice of our center made it possible for the first time to achieve quite good results for this difficult category of patients.
Sequential treatment with pazopanib followed by nivolumab in patients with renal cell carcinoma: Updated interim results of the non-interventional study PAZOREAL.
Authors: Jens Bedke, Martin Boegemann, Martin Schostak, Christiane Hering-Schubert, Manfred Welslau, Jan Schleicher, Alexander Petzoldt, Christian Doehn, Carsten Gruellich, Peter-Juergen Goebell, Thomas Steiner, Elisa Degenkolbe, Sven Hanson, Viktor Grünwald
Journal: Journal of Clinical Oncology (2020)

e17075 Background: Real-world evidence is urgently needed to monitor the translation of new treatment approaches into routine clinical practice as well as to improve cancer treatment and survivorship care. Methods: PAZOREAL is a prospective, multicenter, non-interventional study to evaluate effectiveness, tolerability, safety, and quality of life (QoL) in patients (pts) with advanced or metastatic renal cell carcinoma (mRCC) treated with 1st-line pazopanib (PAZO) followed by 2nd-line nivolumab (NIVO). The primary variable was time on drug (TD) in the respective treatment (Tx) lines. Other endpoints include overall survival (OS), safety and QoL evaluated by EQ-5D-5L. Results: Between December 2015 and September 2017, 414 pts were enrolled and 388 pts started first-line PAZO Tx, 136 pts subsequently received NIVO as second-line Tx. At time of data-cut (30 Sep 2019) median TD was 6.5 months (95%CI 5.7-7.6) for 1st-line PAZO and 4.6 months (95%CI 3.3-6.0) for 2nd-line NIVO. 9.0% of 1st-line PAZO pts and 5.9% of 2nd-line NIVO pts achieved a complete response and disease control rate was 58.0% (95% CI 53.0-62.8) and 44.9% (95% CI 36.8-53.2) for PAZO or NIVO, respectively. Median OS was 32.6 months (95% CI 28.0-38.9) for all pts, 32.6 months (95%CI 28.2-NA) for pts with 2nd-line NIVO and 32.3 months (95%CI 18.8-NA) for pts with other 2nd-line Tx. The most commonly reported treatment emergent AEs were diarrhea (37.2%), nausea (21.7%) and fatigue (19.1%) for PAZO Tx and diarrhea (8.8%), peripheral edema (5.9%) and dyspnea, fatigue, nausea, rash, vomiting (5.1% each) for NIVO. 66 pts (17.1%) discontinued PAZO and 7 pts (5.1%) discontinued NIVO due to related TEAEs. During 1st-line PAZO Tx, mean EQ-5D-5L utility scores initially decreased slightly by time, returned to baseline level and remained stable afterwards. During 2nd-line NIVO Tx the utility scores initially increased by time and remained stable thereafter. Similar tendencies were reported for mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Conclusions: The interim results of the PAZOREAL study confirm favorable clinical trial outcomes, the good benefit-risk profile and the sustained QoL in pts with mRCC in a real-world setting. The sequential treatment with PAZO followed by NIVO is effective and well tolerated. Clinical trial information: NIS-Nr.: 6687.
Cancer's role in chemotherapy-induced neuropathy.
Authors: Stephen Nick Housley, Paul Nardelli, Allison B. Wang, Ann Marie Flores, Eric J. Perreault, Tim Cope
Journal: Journal of Clinical Oncology (2020)

e24064 Background: For the constellation of neurological disorders known as chemotherapy-induced neuropathy, mechanistic understanding, and treatment remain deficient. This might be due to the fact that studies on the effects of chemotherapies on the nervous system have utilized experimental models that exclude cancer perhaps due to the presumption that chemotherapy alone explains the neuropathology. However, the convergence of cancer and chemotherapy on the same biological processes seems likely to yield non-linear interactions. This led us to hypothesize that clinically relevant neuropathy emerges from codependent actions of cancer and chemotherapy. Methods: We established a clinically-relevant animal model of chronic sensory neuropathy in rats with cancer (adenomatous polyposis coli in rat colon: Apc +/Pirc ) and age-matched animals without cancer ( Apc WT ) that were randomly assigned to receive a human-scaled course of oxaliplatin (OX) or control treatment (4 groups). We quantified behavioral deficits during precision ladder walking, a validated measure of locomotor performance. Neuronal signaling was measured during terminal in vivo experiments to examine the response of sensory neurons to physiologically-relevant stimuli. We defined statistical significance as when 95% of a highest density interval (HDI) of posterior probabilities do not overlap (hierarchical Bayesian modeling). Results: Apc +/Pirc +OX (n = 11) rats exhibited significantly higher error rate (19.2±5.6%, 95%HDI) during precision ladder walking in comparison to Apc WT +control (2.4±2.7%: n = 9) or Apc +/Pirc +control (2.5±2.9%: n = 7) and significantly exceeded the error rate observed in animals treated with OX alone (8.4±3.1%: n = 10). In contrast to the observations in all other groups, we found drastically impaired neuronal signaling in Apc +/Pirc +OX rats which manifested as significantly reduced sensitivity and attenuated static and dynamic firing patterns (95%HDI). Conclusions: We present the first evidence that chronic neuropathy cannot be explained by the effects of chemotherapy alone but instead depend on non-linear interactions between cancer and chemotherapy. This understanding is a prerequisite for developing meaningful treatment or prevention of neuropathy.
Building and development of training center in Weifang community health service center of Shang hai Pudong New Area
Authors: Yaling Li, Xiaoyang Han, Dongmei Luo, Zhaohui Du
Journal: BMJ (2017)

介绍上海市浦东新区潍坊社区卫生服务中心实训中心的建设情况，包括软硬件设施及其主要在教学和考核两方面的功能和目的，以及浦东新区全科医生临床能力水平考核的形式及实训中心未来发展的建议。提示社区实训中心是未来全科医生培养、继续教育的一个重要平台，能够提供更加符合全科医生能力建设实际的临床技能训练项目，但这些工作都尚处于起步探索阶段。
Construction and development of regional in-service training platform for general practitioners in Shanghai Jiading district
Authors: Liang Chen, Jing Zhou, Tao Wang, Lina Gong, Qiang Li, Xiuping Xia, Weiwei Zhang
Journal: BMJ (2018)

The regional education platform is important in the training and continuing education for general practitioners, which provides clinical training program to upgrade the competence of general practitioner, but it is still in the initial stage. This article introduces the construction and development of in-service training and education platform for general practitioners in Shanghai Jiading district, and introduces the specific function and main features of the platform.


Key words: 
In-service training; General practitioners