tbuckley/cabot-search huggingface dataset:
Escalation portion of phase II study to evaluate the safety, pharmacokinetics, and clinical activity of the PI3K/mTOR inhibitor paxalisib (GDC-0084) in glioblastoma (GBM) with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status.
Authors: Patrick Y. Wen, John Frederick De Groot, James D. Battiste, Samuel Aaron Goldlust, James Stuart Garner, Jeremy Andrew Simpson, Jelle Kijlstra, Alan Olivero, Timothy Francis Cloughesy
Journal: Journal of Clinical Oncology (2020)

2550 Background: Paxalisib (previously GDC-0084) is a potent, oral, selective, brain-penetrant, small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin. The PI3K pathway is upregulated in ~85% of GBM cases and paxalisib has shown efficacy in preclinical models. A phase I study (NCT01547546) investigated paxalisib dosed once daily in 47 patients with recurrent high-grade gliomas and established a maximum tolerated dose (MTD) of 45mg once daily. The current phase Il study aims to explore the safety, tolerability, and clinical activity of paxalisib in newly diagnosed GBM and an unmethylated MGMT promotor following surgery and temozolomide chemoradiation per Stupp regimen. Methods: Part 1 of this study is an open-label, dose-escalation phase to assess the safety, tolerability and MTD. Dose-escalation started at 60mg and progressed in 15mg increments using a 3+3 design. Part 2 is an expansion cohort recruiting 20 patients randomized to administration in fed or fasted states at the MTD. Results: Part 1 is complete and reported here. Nine patients were recruited and an MTD of 60mg was determined. DLTs were hyperglycemia and oral mucositis. AEs were generally reversible and consistent with the PI3K inhibitor class with the most common events were rash, oral mucositis, and fatigue. PK at the MTD was broadly consistent with the data published for the phase 1 study. For eight response-evaluable patients in Part I the median progression-free survival (PFS) was 8.4 months, and 25% of patients remained progression free after 15 months of follow-up. Part 2 is ongoing. Conclusions: A higher MTD of 60mg was identified in newly diagnosed GBM with unmethylated MGMT promotor status than the 45mg MTD previously identified in recurrent high-grade glioma. An encouraging PFS signal is described in this poor-prognosis, unmethylated MGMT patient population. Clinical trial information: NCT03522298 .
Distribution and frequency of patient-reported symptomatic adverse events at a comprehensive cancer center.
Authors: Jessica Cleveland, Michael J. Hassett, Sherry Lee, Isaac S. Chua, Laura Stewart Dominici, Deborah Schrag, Nadine Jackson McCleary
Journal: Journal of Clinical Oncology (2020)

e19117 Background: Systematic review of electronic patient reported outcomes (ePRO) has been shown to improve quality of life and overall survival in clinical trial. We previously demonstrated feasibility of ePRO across Dana-Farber Cancer Institute (DFCI). We sought to examine the distribution and frequency of first symptomatic adverse events (SAEs) among ePRO responders in ambulatory oncology practice. Methods: The ePRO tool uses the validated NCI developed Patient Reported Outcomes – Common Terminology Criteria for Adverse Events (PRO-CTCAE) instrument to assess attributes of 15 core SAEs (fatigue, insomnia, general pain, decreased appetite, nausea, vomiting, constipation, diarrhea, shortness of breath, numbness and tingling, rash, concentration, fever, anxiety, sadness) selected by clinician stakeholders and deployed via any internet-enabled device once every 7 days. Responses are viewable in the EHR, scored 0 to 3 using an algorithm, with scores of 3 highlighted to indicate severe grade SAEs. Results: We examined the distribution and frequency of the first 5183 unique ePRO reports for unselected patients seen in the medical, radiation and surgical oncology outpatient clinics of four pilot multidisciplinary clinics (Breast, Genitourinary, Gastrointestinal and Head and Neck) between September 2018-December 2019. Twenty one percent of eligible patients responded to ePRO (5183 of 26,084). Most respondents were female (59%), Caucasian (89%), and age 50-69 years (56% compared to 16% age &lt;50 years, 28% age ≥70; range 19-98 years). The frequency of grade 3 SAEs was pain (10%), fatigue (6%), insomnia (4%), constipation (3%), numbness and tingling/concentration/anxiety/decreased appetite (2%), diarrhea/shortness of breath/sadness (1%), and rash/fever/nausea/vomiting (none) (Table). Conclusions: We observed a consistent distribution of SAEs across cancer types, age and sex. The most frequently reported SAEs are those clinicians struggle to treat with medications - pain, fatigue, insomnia and anxiety. Research to develop effective strategies to address this constellation of SAEs should be prioritized. [Table: see text]
临床各科常见心理问题
Authors: 季建林
Journal: BMJ (2007)

医学服务的对象是有思想感情的患者,所以不能机械地治疗某种疾病.临床医师在诊治患者时,应该注意其身心反应,才能使患者身体及心理健康全面恢复.在临床工作中,必须对躯体疾病在患者心理和社会功能上的效应给予关注,尤其重要的是识别部分患者在躯体疾病期间所出现或伴发的心理与精神障碍。
条块结合的全科服务团队管理模式研究与实践
Authors: 蒋羽萍, 张莲芳, 张齐苑, 周志衡, 王家骥
Journal: BMJ (2012)

广州市黄埔区红山街社区卫生服务中心自从2009年起构建条块结合的全科服务团队管理模式.分析2006 -2010年中心运行状况结果显示,全科团队服务提高了社区卫生服务的效果,推动了本地区社区卫生服务的发展；但存在全科医生队伍水平不高,绩效考核有待完善的问题,所以条块结合的全科团队管理模式值得在社区卫生服务机构中探索。
Role of patient navigation in improving access to radiotherapy treatment in a limited resource setting.
Authors: Carolina Martins Vieira, Lindsay Krush, Paul E. Goss, Angelica Nogueira Rodrigues
Journal: Journal of Clinical Oncology (2020)

e19019 Background: Approximately 60% of cancer patients in low- and middle-income countries (LMICs) require radiotherapy (RT), with RT contributing 40% of curative treatment for cancers. Timely RT impacts prognosis. There are several difficulties in accessing RT in the Brazilian public health system: deficit of devices, obsolete machines, heterogeneous distribution of services, lack of investment in human resources and socioeconomic obstacles. Thus, it becomes necessary to optimize available resources. Although there are examples of successful patient navigation (PN) programs in vulnerable populations in high-income countries (HICs), data is scarce for LMICs. Considering the high incidence of cancer, complex difficulties in accessing treatment, and the positive results of PN in HICs, it was decided to evaluate this tool to improve RT access in the public system in Brazil. Methods: This pilot study was carried out in in a public school hospital in Belo Horizonte, Brazil, in partnership with the Global Cancer Institute, with a historical cohort as the control arm. The primary objective was to evaluate the changes in the time from definitive diagnosis to the start of treatment with the implementation of PN. Secondary objectives included: evaluating changes in the time between the beginning and end of RT, identification of the obstacles to access care, and quality of life data. Candidates for the program would be those considered for neoadjuvant or definitive RT, without previous cancer treatment. Results: 124 patients were included in the retrospective arm (12 excluded) and 73 in the navigation arm (1 excluded). Most had loco-regionally advanced disease, the most prevalent sites being esophagus, head, neck, and rectum. PN decreased the median time from biopsy result to the beginning of RT from 108 to 74 days (p &lt; 0.001). PN also decreased the time between biopsy results and referral to RT (53 to 40.5 days, p = 0.011); between the referral and the first consultation in the RT (25 to 13 days, p &lt; 0.001) and between the referral and the end of the RT (98 to 78 days, p &lt; 0.003). There was an increase in the proportion of patients who started RT within 60 days (maximum period established by law to start cancer treatment), from 20.5% in the retrospective arm to 38.5% in the prospective arm (p = 0.026). PN in this context showed no impeditive costs ( &lt; $140 USD per patient) with a satisfaction rate greater than 90% from patients. Conclusions: In an oncological context of socioeconomic vulnerability, PN is a financially viable and efficient tool to optimize access to timely radiotherapy.
自发性气胸术中发现肺癌一例
Authors: 王砚东, 魏善志, 付强, 王林南, 王利民
Journal: BMJ (2005)

患者男,24岁,因突发右胸痛伴胸闷12 h入院.既往史:1年前曾因左侧自发性气胸于我院行左侧肺大疱切除、肺修补术.查体:右侧胸部语颤减弱,叩诊呈鼓音,听诊呼吸音消失.正位胸片示:右肺野可见无肺纹理透光区,肺组织被压缩至肺门区.经患者及家属知情同意,在全麻下行右侧开胸探查术.术中见右肺上叶尖段有一灰白色破裂大疱;前段见一高粱粒大粉红色结节,质韧,表面光滑,界限清.分别予缝扎、切除、送病理.术后病理回报:(右肺上叶前段小结节)低分化鳞状细胞癌;(右肺上叶)肺大疱.经患者及家属知情同意,在全麻下行右肺上叶切除术,并清扫肺门、纵隔淋巴结.病理回报:右肺上叶无癌细胞残留,淋巴结无转移癌.该患者术后随访3年无复发。
Effect of androgen deprivation therapy combined with nivolumab on the systemic antitumor immune response in castration-sensitive prostate cancer.
Authors: Matthew Dallos, Matthew Chaimowitz, Mark N. Stein, Emerson A. Lim, Jessica Hawley, Scott T. Tagawa, David M. Nanus, William Kevin Kelly, Charles G. Drake
Journal: Journal of Clinical Oncology (2020)

e17503 Background: To date, immunotherapy has limited efficacy in castration-resistant prostate cancer. However, we previously reported that androgen deprivation therapy (ADT) has significant immunomodulatory effects and can induce a complex immune cell infiltrate before castration-resistance develops. Therefore, we designed an ongoing clinical trial to assess the effects of immunotherapy plus ADT in men with recurrent castration-sensitive prostate cancer (CSPC) (NCT03689699). We hypothesized that PD-1 blockade given at the time of castration could induce systemic anti-tumor immune responses with epitope spreading and modulate key circulating cytokine networks. Methods: 15 patients with recurrent CSPC were treated with nivolumab (480mg) every 4 weeks for 8 weeks followed by nivolumab plus degarelix for an additional 16 weeks. Sera was collected at 3 time points: pre-treatment, after nivolumab alone (8 weeks) and at completion of therapy with nivolumab plus degarelix (24weeks). To assess the therapeutic effects on systemic humoral immune responses and to evaluate for induction of epitope spreading, we analyzed treatment-induced serum IgGs against an array of self-antigens over time. We also performed a 44-parameter electrochemiluminescence assay to measure the effects of therapy on innate cytokines and the Th1/Th2 and Th17 pathways. Results: ADT combined with PD-1 blockade led to significant changes in systemic immunity including induction of humoral antigen spread with IgG responses to secondary tumor antigens including PSA, KLK2, K-Ras and modulation of key circulating cytokines. We observed a significant increase in mean levels of IFN-gamma (8.68 +/- 10.74 pg/ml vs 9.53 +/- 7.36 pg/ml), an increase in IL-10 (0.37 +/- 0.29 pg/ml vs 0.66 +/- 0.53 pg/ml) and a decrease in IL-8 (106.7 +/- 275.47 pg/ml vs 25.49 +/- 23.09 pg/ml) when comparing cytokine levels before and after nivolumab plus degarelix respectively. Conclusions: ADT plus nivolumab led to significant changes in systemic immunity and overall appeared to promote a pro-inflammatory state. This immune response also appeared tumor specific with induction of humoral responses against secondary tumor antigens. However we also observed changes in targetable immunosuppresive cytokines like interleukin-8 and are currently testing whether ADT plus combined PD-1 and IL-8 blockade can further promote robust anti-tumor immune responses in prostate cancer. Clinical trial information: NCT03689699 .
Targeted PCR <i>vs</i> NGS for molecular diagnostic in solid tumors and liquid biopsies. How to choose in real-life.
Authors: Jean-Louis Merlin, Pauline Gilson, Marie Husson, Alexandre Harle
Journal: Journal of Clinical Oncology (2020)

e15576 Background: Molecular diagnostic is now part of routine diagnosis in many solid tumors and multiple technical options are available from extensive sequencing (NGS) to fully-automated targeted PCR (FAPCR). Tumor tissue testing is the gold standard, liquid biopsy is becoming a valuable option. Methods: 417 FFPE tumors, and 28 liquid biopsies were analyzed from 233 non small cell lung cancer (NSCLC), 177 colorectal cancer (CRC), 35 melanoma (MEL) in an ISO 15189 certified, French NCI molecular genetics platform. FAPCR analyses were performed individually, every day, using CE-IVD kits for the exclusive analysis of KRAS, NRAS, BRAF and EGFR mutations in NSCLC, CRC and MEL. NGS analyses were performed weekly as 12 or 24 sample runs using custom multiple gene panel capture sequencing. In all cases, prior to analysis, the specimens were macrodissected to warrant tumor cell content &gt; 10% after examination of hematoxylin eosin stained slide by a pathologist. For liquid biopsy, cfDNA was extracted within 3 days from blood samples collected in cfDNA BCT tubes and analyzed using CE-IVD EGFR mutation kits. Time to results was recorded from registration of the specimen to validation of the results. Results: All FFPE tumors were analyzed using either FAPCR (N = 321) or NGS (N = 110) according to the clinician choice. Less than 2% of samples were not analyzable because of tumor cell content &lt; 10% or degradated DNA. Median time to results was 6 days for FA-PCR (range 1-19) and 18 days for NGS (range 7-28). No significant difference was observed between NSCLC, CRC and MEL. Most cases of delay &gt; median were related to pre-analytical defects and the need for a second specimen. For liquid biopsies, time to result was 6 days (range 1-18). The mutation rates were respectively, 13% for EGFR in NSCLC, 57% for KRAS/NRAS/BRAF in CRC and 69% for BRAF/NRAS in MEL. Using NGS led to the identification of additional molecular targetable alterations that were not analyzed by FAPCR in 44% of NSCLC, 22% of CRC and 14% of MEL. Among the 28 liquid biopsies analyzed mostly at progression under anti-EGFR TKI, EGFR mutations including T790M, were detected in 61% of the cases. Conclusions: Independently of cost-effectiveness, using PCR reduces time to results and can accelerate the initiation of targeted therapy but restricts the range of analysis, while extensive NGS delays time to results but identifies additional biomarkers that could be useful for therapeutic stratification. Using liquid biopsy testing could be an alternative and allow dynamic molecular diagnostic at 1st line and during follow-up.
Responding to the COVID-19 Pandemic
Authors: Jonathan M. Metzl, Aletha Maybank, Fernando De Maio
Journal: JAMA (2020)

The Need for a Structurally Competent Health Care SystemThe coronavirus disease 2019 (COVID-19) pandemic has exposed the consequences of inequality in the US.Even though all US residents are likely equally susceptible to infection with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus that causes COVID-19 disease, the resulting illness and the distribution of deaths reinforces systems of discriminatory housing, education, employment, earnings, health care, and criminal justice. 1,2The patterns of COVID-19 illuminate centuries of support systems that the US did not build and investments it did not make.Each stage of the pandemic, from containment, to mitigation,toreopening,highlightstheextenttowhichcertain populations were rendered vulnerable long before the virus arrived.As a result, marginalized, minoritized, and communities of low wealth have been at highest risk, with disproportionate death rates among African American, Latinx, and Native American populations across the US. 3,4ociodemographic differences in COVID-19 morbidity and mortality highlight an unavoidable reality facing the US health care system as it strives to fulfill its mission to promote health and well-being, and to treat disease.At its core, the practice of medicine is based on individual-level interactions among clinicians,
Somatic and germline mutation profiles of Chinese breast cancer patients younger than 35.
Authors: Ning Liao, Guo-Chun Zhang, Xiaoqing Chen, Weikai Xiao, Jianguo Lai, Yulei Wang, Bo Chen, Chong-Yang Ren, XueRui Li, Kai Li, Ling-Zhu Wen, Li Cao, Minghan Jia, Guangnan Wei, Jiali Lin, Min Li, Analyn Lizaso, Han Han-Zhang, Hao Liu, Jing Liu
Journal: Journal of Clinical Oncology (2020)

554 Background: Limited studies have investigated the molecular underpinnings driving breast cancer development in Chinese younger women. Based from our previous data, more Chinese women are diagnosed with early-onset breast cancer than in the West. In our study, we aim to investigate the comprehensive mutational profile of Chinese women 35 years old and younger (≤35y) diagnosed with breast cancer. Methods: Targeted sequencing was performed on surgically-removed tumor tissues and blood samples collected from 589 women diagnosed with stage I-III breast cancer of various molecular subtypes at the Guangdong Provincial People’s Hospital (GPDH) using a gene panel interrogating 520 cancer-related genes. We compared the data of 53 women aged ≤35y from our cohort to the data from 33 breast cancer patients aged ≤35y included in The Cancer Genome Atlas (TCGA) dataset. Results: Among the women aged ≤35y with early-stage breast cancer from both cohorts, our cohort had more number of hormone receptor-positive (HR+) patients (GPDH, 72% vs. TCGA, 61%, P&lt; 0.001). Analysis revealed an overall mutation detection rate of 98% in our cohort, with mutations affecting genes involved in the PI3K pathway (47%) and cell cycle pathway (23%). TP53 and PIK3CA were the most commonly mutated genes, with mutation rates of 51% and 25% from our cohort. No statistical difference in mutation profile was found between GPDH and TCGA cohorts. Moreover, germline mutations considered as pathogenic and likely pathogenic (P/LP) in breast cancer susceptibility genes including BRCA1 (n = 4), BRCA2 (n = 2), PALB2 (n = 1), PMS2 (n = 1), PTEN (n = 1), and ATM (n = 1) were detected from 18.9% (10/53) of the patients from our cohort. Women aged ≤35y had significantly more germline BRCA1 mutations than patients &gt; 35y from our cohort (7.5%, 4/53 vs. 2.1%, 11/536 P= 0.049). Conclusions: Our study has identified the involvement of PI3K and cell cycle as the two key pathways in the early development of breast tumors in younger women. In addition, our results also support the role of P/LP germline mutations in breast oncogenesis in Chinese patients with early-onset breast cancer, indicating the need to include a more comprehensive germline mutation screening in our population.
Characteristics of EGFR uncommon mutations in Chinese cancer patients.
Authors: Minghui Wang, Shuben Li, Hongbiao Wang, Jianjiang Xie, Junhang Zhang, Yun Li, Kunsong Li, Jian Huang, Chunyan Cheng, Kai Wang
Journal: Journal of Clinical Oncology (2020)

e13527 Background: Exon 19 deletions and exon 21 L858R substitutions are the most common mutations of epidermal growth factor receptor (EGFR) in cancers, and the remaining other mutations are called uncommon mutations. Recent studies have shown the clinical relevance of EGFR uncommon mutations with tyrosine kinase inhibitors (TKI) therapies and immunotherapies. Therefore, understanding the distribution and characteristics of EGFR uncommon mutations in cancers would provide evidence for future design of trials and drug development. Methods: Next-generation sequencing data were obtained from 3,026 Chinese tumor samples which have been identified with EGFR mutations. Single nucleotide variations (SNV), short and long insertions/deletions (indel), copy number variations and gene rearrangements were assessed. All tests were carried out in a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory in Shanghai, China. Results: EGFR mutations including 32% L858R substitutions, 28% exon 19 deletions, and 40% uncommon mutations were detected in this cohort. EGFR uncommon mutations were most frequently detected in lung cancers, followed by esophageal and gastric cancers. The uncommon mutations of EGFR including 54% SNVs, 30% amplifications, and 9% rare types of mutations such as rearrangement, long indels and complex mutations were detected. The SNVs in exon 18 to 21 which encode the tyrosine kinase domain of EGFR consisted of 16% EGFR mutations. Among them, the mostly frequently SNV was G719X in exon 18 and had 3% EGFR mutations. Mutations in other function domain of EGFR, including extracellular EGF binding domain (0.8%), transmembrane domain (0.03%) and intracellular autophosphorylation domain (0.7%) were also detected. Conclusions: Our data indicated that EGFR uncommon mutations were widely distributed in a variety of cancer types in Chinese patients, mostly in lung cancers. SNVs in the tyrosine kinase domain were the most frequent uncommon mutations. These data will provide clues for future clinical studies.
Urodynamics in diabetic patients complicated with benign prostatic hyperplasia
Authors: Yadong Liu, Xiaoming Lu, Guoyang Zhou, Jinfeng Wang, Jiuhu Yin, Liping Wang, Binbin Dong, Zhongqing Wei
Journal: BMJ (2018)

The clinical and urodynamic data of 37 patients with benign prostate hyperplasia (BPH) and 30 diabetic patients complicated with BPH (BPH+DM) admitted between Jan 2014 and July 2017 were analyzed retrospectively. The International Prostate Symptom Score (IPSS), maximal flow rate (Qmax), post-voiding residual urine volume (PVR), maximum cystometric capacity (MCC), first desire to void (FDV), pressure of detrusor maximum (Pdet, max), bladder outlet obstruction index (BOOI), bladder contraction index (BCI) were compared between BPH group and BPH+DM group. According to BOOI-BCI linear regression, 22 cases (group A) and 15 cases (group B) of BPH patients were above and below the linear curve; while there were 14 cases (group C) and 16 cases(group D)of BPH+DM patients above and below the curve, respectively. The mean±SD FDV, MCC, Pdet, max, PVR, BOOI, BCI were (172.7±93.0)ml vs. (300.5±118.4)ml (P 0.05), (2.6±1.1)ml/s and (3.7±1.3) ml/s (P 0.0 5), (2.4±1.0)ml/s and (3.8±1.4)ml/s (P<0.05), respectively. The study indicates that the therapeutic effect is better for the patients blow BOOI-BCI regression linear curve compared to the patients above the linear curve.


Key words: 
Prostatic hyperplasia; Diabetes mellitus; Urodynamics; Diagnosis
Ultra-accurate Duplex Sequencing for the assessment of pretreatment ABL1 kinase domain mutations in Ph+ ALL
Authors: Nicholas J. Short, Hagop Kantarjian, Rashmi Kanagal-Shamanna, Koji Sasaki, Farhad Ravandi, Jorge Cortes, Marina Konopleva, Ghayas C. Issa, Steven M. Kornblau, Guillermo Garcia-Manero, Rebecca Garris, Jake Higgins, Gabriel Pratt, Lindsey N. Williams, Charles C. Valentine, Victor M. Rivera, Justin Pritchard, Jesse J. Salk, Jerald Radich, Elias Jabbour
Journal: Blood Cancer Journal (2020)

Mutations of ABL1 are the dominant mechanism of relapse in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). We performed highly accurate Duplex Sequencing of exons 4-10 of ABL1 on bone marrow or peripheral blood samples from 63 adult patients with previously untreated Ph + ALL who received induction with intensive chemotherapy plus a BCR-ABL1 TKI. We identified ABL1 mutations prior to BCR-ABL1 TKI exposure in 78% of patients. However, these mutations were generally present at extremely low levels (median variant allelic frequency 0.008% [range, 0.004%-3.71%] and did not clonally expand and lead to relapse in any patient, even when the pretreatment mutation was known to confer resistance to the TKI received. In relapse samples harboring a TKI-resistant ABL1 mutation, the corresponding mutation could not be detected pretreatment, despite validated sequencing sensitivity of Duplex Sequencing down to 0.005%. In samples under the selective pressure of ongoing TKI therapy, we detected low-level, emerging resistance mutations up to 5 months prior to relapse. These findings suggest that pretreatment ABL1 mutation assessment should not guide upfront TKI selection in Ph + ALL, although serial testing while on TKI therapy may allow for early detection of clinically actionable resistant clones.