tbuckley/cabot-search huggingface dataset:
Hematological malignancies in the adolescent and young adult (AYA) population in Singapore.
Authors: Eileen Yi Ling Poon, Evelyn Wong, Wei Lin Goh, Jiancheng Hong, Victoria Wong, Daniel Quah, Yee Pin Tan, Yung Ying Tan, Selene Chan, Jason Yongsheng Chan, Nagavalli Somasundaram, Mohamad Farid Rin Harunal Rashid
Journal: Journal of Clinical Oncology (2020)

e13630 Background: Hematological malignancies is thought to be one of the more common Adolescent and Young Adult (AYA) cancers and constitute leukemias and lymphomas. However, little is known about its incidence and prevalence in Asia. We also do not have any data on its behavior or its prognosticators. The outcomes of this group of patients is also unknown when compared to the pediatrics or geriatrics, but is expected to be not as ideal. There is no consensus on whether this group of patients should be treated as pediatrics or as the older adults. We have sought to evaluate the prevalence and trends in a single large-volume tertiary cancer centre in Asia. Methods: We extracted data on all patients with cancer between 16-39 years old who were seen at our centre (National Cancer Centre Singapore) during the period of 1 st January 2015 and 31 st December 2019. In total, we had 2583 patients. We then excluded all other cancer types except those with a hematological malignancy and 5 other patients due to incomplete data. Results: There were 319 patients with a hematological malignancy. 153 (48%) were female and 166 were male(52%). Most of the patients presented between 30-39 years old (171, 53.6%). There were 54 (2.1%) leukemias and 265 (83.1%) lymphomas. Of those with leukemias, 46 (85.2%) had acute leukemia and 9 (14.8%) had chronic leukemias. Among the lymphoma patients, there were 194 (73.2%) Non Hodgkin Lymphoma (NHL) patients and 69 (26.0%) Hodgkin Lymphoma (HL) patients. There were 149 (46.7%) B Cell lymphomas and 38 (11.9%) T Cell lymphoma patients. The most common B cell Lymphomas is Diffuse Large B Cell Lymphoma (128, 85.9%) and the most common T Cell Lymphomas is Peripheral T-cell Lymphoma (28, 73.7% patients). Conclusions: AYAs with a hematological malignancy form a significant portion of the cancers we see in this age group. Yet, little information is available with regards to their clinico-pathological characteristics, especially in Asia. Work is underway to further elucidate these differences so that we can better their outcomes.
初级保健中的慢性非癌性疼痛
Authors: 毛鹏, 樊碧发
Journal: BMJ (2011)

慢性疼痛是一种伴随组织损伤或以其描述的不愉快感觉和情感体验.慢性非癌性疼痛是指持续时间超出疾病或损伤正常病程的非癌性疼痛,可伴或不伴病理过程.据统计,美国约有54万人在忍受着慢性疼痛的折磨,每年因慢性疼痛的花费高达850亿～900亿美元[1].我国虽没有统计数字,但考虑到庞大的人口,遭受慢性疼痛折磨的人数可能在5000万人以上,其中绝大多数是慢性非癌痛患者。
Wrong guidelines: why and how often they occur
Authors: Iannone Primiano, Montano Nicola, Minardi Monica, Doyle James, Cavagnaro Paolo, Cartabellotta Antonino, 王琪, 陈耀龙
Journal: BMJ (2017)

循证指南被认为是帮助医生、政策制定者和患者选择医疗方案的必备工具，也被视为无偏倚的卫生保健标准。然而，根据对其可靠性的评估，多达50%的指南被认为不值得信赖。这对患者安全、资源利用和卫生经济负担造成了严重的后果。虽然利益冲突、指南专家组构成和方法学缺陷通常被认为是影响指南可靠性的主要原因，但腐败与生物医学研究的浪费在其中发挥的作用也不容小觑。本文将对上述问题进行讨论，以期帮助读者对指南的局限性有更广泛的认识。
A new perspective of different schemes of neoadjuvant chemotherapy followed by concurrent chemotherapy and radiotherapy for locally advanced cervical cancer.
Authors: Xue Tian, Fenghu Li, Ran Li, Feiyue Yang, Jianying Chang, Jiehui Li, Lili Hu, Yanjun Du, Fan Mei, Kai Zuo, Shuying Chen
Journal: Journal of Clinical Oncology (2020)

e18011 Background: To observe the clinical effect, survival time and toxicity and side effects in unoperated cervical cancer patients treated with different schemes of neoadjuvant chemotherapy (NACT) followed by concurrent chemotherapy and radiotherapy (CCRT). Methods: A retrospective analysis was performed in 120 patients who were followed up until they died or being followed up at least 5 years. The treatment schedules consisted of 2 cycles of intravenous paclitaxel 135-175 mg/m 2 plus cisplatin 60-80mg/m 2 (TP group, 62 patients) or lobaplatin 30mg/m 2 (TL group, 58 patients) every 21 days. Patients were then submitted to CCRT. Chemotherapy regimen of CCRT was cisplatin 40 mg/m 2 (TP group) or lobaplatin 30mg/m 2 (TL group) weekly. External beam radiation therapy (total 50.4-56.35Gy, 28 fractions, 180-215cGy per fraction daily) was administered using the3D-CRT or IMRT followed by intracavitary brachytherapy (5Gy per fractions, mostly 5 fractions, Ir192 based). Results: The proportion who had a complete/partial response was 81.7% after NACT, and 99.2% after all treatment. In all patients, the one-year, three-year and five-year survival rates were 99.2%, 81.7% and 69.2% respectively. In TP group vs. TL group, the 3-yr and 5-yr survival rates were 85.5% vs.77.6% (χ 2 = 1.248, p = 0.264) and 75.8% vs. 63.8% (χ 2 = 2.059, p = 0.151) with no significant difference. In mass size ≥ 5cm group vs. &lt;5cm group, 3-yr survival rates were 88.0% vs.77.1% with no significant difference (χ 2 = 2.296, p = 0.130), but 5-yr survival rates were 82.0% vs.61.4% (χ 2 = 5.878, p = 0.015) with significant difference. The 3-yr and 5-yr OS rates between stage IIB and stage IIIB were not significantly different, respectively 83.1% vs. 70.6% (χ 2 = 2.083, p = 0.149) and 67.7% vs. 64.7% (χ 2 = 0.090, p = 0.765) . In TP group, grade 3 or 4 digestive reaction was obviously more frequent than TL group, respectively 54.3% vs. 1.8%(p = 0.000). Neutropenia and thrombocytopenia are more common in TL group than TP group, respectively 48.3% vs. 30.6%(p = 0.0.048) and 44.8% vs. 1.6%(p = 0.000). Conclusions: For patients with severe digestive system reaction or contraindications of cisplatin, lobaplatin was might be used as an alternative drug. A prospective research is undergoing in our hospital. NACT may improve the prognosis of patients with large-scale mass. A undergoing prospective study protocol was approved by the Ethics Committee of hospital number 2017-02 and was registered in ClinicalTrial.gov as ChiCTR-IIR-17011559.
夜间低氧血症对高血压患者血压昼夜节律和尿香草扁桃酸水平的影响
Authors: 曹梅, 李南方
Journal: BMJ (2004)

对70例高血压伴打鼾且体重指数≥25 kg/m2的患者进行夜间持续经皮血氧饱和度监测及24 h动态血压监测,同时收集夜间8 h尿液和24 h总尿液检测香草扁桃酸水平.结果显示高血压合并中、轻度低氧血症患者多数血压昼夜节律消失,血压水平较血氧饱和度正常组增高显著(P<0.05);夜间8 h尿香草扁桃酸水平同夜间血压水平显著正相关(r=0.52、0.534,P<0.05).提示高血压合并夜间低氧血症患者因夜间周期性缺氧致儿茶酚胺释放增多,使夜间血压升高、血压昼夜节律消失。
Relationship between blood glucose excursion and cognitive performance in diabetic patients over 60 years old
Authors: Xiao-yan Zhang, Yuan Zhong, Gao-zhong Huang, Jie-hua Zhu, Zhe Zhao, Hua Zhang, Ting-jun Hu
Journal: BMJ (2010)

Objective To explore relationship between excursion of blood glucose levels and cognitive performance in diabetic patients over aged 60 years.Methods A total of 108 diabetic patients over aged 60 years were recruited in this study and they wore under continuous blood glucose monitoring system (CGMS) for three days to evaluate excursion of their mean blood glucose (MBG) level and its standard deviation (SD).All the participants accepted cognitive function tests during continuous blood glucose monitoring, including mini mental status examination (MMSE), Montreal cognitive assessment (MOCA) and clock drawing test (CDT).Relationship of the SD of blood glucose level and cognitive performance in the three cognitive tests was assessed.Data were analyzed with CGMS software version 3.0.Results The SD reversely correlated with scores of MMSE (r = - 0.324, P ＜ 0.01 ) and CDT ( r =-0.325, P = 0.001 ), but they did not significantly correlate with MOCA scores (r = -0.212, P =0.081 ).Statistically significant difference was observed between the SD and scores of all three cognitive tests adjusted for glycosylated hemoglobin Alc (HbAlc) level (r = -0.387, -0.046 and -0.292, P =0.029, ＜0.001 and ＜ 0.001, respectively).The SD reversely correlated with scores of MMSE, MOCA and CDT adjusted for MBG (r= -0.314, -0.466 and -0.345, P ＜0.01, respectively).Results of multivariate linear regression analysis showed that the SD reversely correlated to scores of MMSE, MOCA and CDT (β = - 0.378, - 0.224 and - 0.346, all P ＜ 0.05).Conclusions Excursion of blood glucose levels can influence their cognitive performance in diabetic patients over aged 60 years, leading to decrease in their overall cognitive function and activities as its excursion large enough.

Key words: 
Diabetes mellitus, type 2;  Blood glucose, excursion;  Cognitive dissonance
Therapeutic drug monitoring of pazopanib: Using cost-neutral PK-guided interventions to optimize exposure.
Authors: Stefanie L. Groenland, Ruben A.G. van Eerden, Stijn L.W. Koolen, Dirk Jan A.R. Moes, Alex Imholz, Sofie Wilgenhof, Winette T.A. Van Der Graaf, Hans Gelderblom, Jos H. Beijnen, Ron H.J. Mathijssen, Alwin Huitema, Neeltje Steeghs
Journal: Journal of Clinical Oncology (2020)

3598 Background: Pazopanib is an approved treatment for renal cell carcinoma (RCC) and soft tissue sarcoma (STS). At the currently registered fixed dose of 800 mg QD, 20% of patients (pts) do not attain the efficacy threshold of C min ≥ 20.5 mg/L (Suttle et al, 2014), providing a strong rationale for therapeutic drug monitoring (i.e. individualizing the dose based on measured plasma drug concentrations). Previous studies provided cost-neutral alternatives to absolute dose increments to optimize exposure (i.e. splitting intake moments or concomitant intake with food (Groenland et al, 2020; Lubberman et al, 2019)). This study aimed to investigate the feasibility, tolerability and efficacy of TDM of pazopanib, using cost-neutral interventions. Methods: Patients starting treatment with pazopanib at the standard dose of 800 mg QD in modified fasting state were included in the prospective DPOG TDM study (www.trialregister.nl, NL6695). PK sampling occurred 4, 8 and 12 weeks after start of treatment, and every 12 weeks thereafter. Pazopanib concentrations were measured with LC-MS/MS and C min was calculated. In case of C min &lt; 20.5 mg/L and acceptable toxicity, a dose intervention was recommended. As a first step, intake moments were split (i.e. 400 mg BID). Secondly, concomitant intake with food was recommended. Results: In total, 34 pts were included (19 STS, 15 RCC), of whom 158 PK samples were collected. Eleven pts (32%) were underdosed and had at least 1 PK sample below the target. In 24% of the pts a PK-guided intervention could be performed, which was successful in 6 pts (75%). Median C min increased from 15 mg/L to 32 mg/L (p = 0.027). Eventually, 3 pts went back to 800 mg QD due to toxicity, after which C min remained ≥ 20.5 mg/L in 2 pts. In pts with adequate exposure throughout the study, median C min was 32 mg/L (range 23 – 65 mg/L). In 3 pts, a PK-guided intervention could not be performed, due to progression (n = 1) or logistical issues (n = 2). Twelve pts (35%) received a dose reduction due to toxicity (lowest dose was 200 mg QAD), exposure remained adequate at this reduced dose in all pts. For STS pts, median PFS was 19.8 months in pts with C min &lt; 20.5 mg/L who did need an intervention vs. 6.4 months in pts with all C min ≥ 20.5 mg/L (not significant). For RCC pts, this was 15.5 months vs. 7.4 months, respectively (not significant). Conclusions: This prospective study shows that PK-guided dose optimization of pazopanib using cost-neutral interventions is feasible in daily practice. A PK-guided intervention was performed in 24% of the patients, which was successful in 75% of these patients. Clinical trial information: NL6695 .
Bimodal ntrk expression and correlation with activation of PI3K/AKT pathway in lung cancer.
Authors: Wanlong Ma, Ivan De Dios, Spiraggelos Antzoulatos, Jeffrey Estella, Maher Albitar
Journal: Journal of Clinical Oncology (2020)

e21535 Background: N TRK (NTRK1, NTRK2 or NTRK3) fusions are oncogenic drivers of various types of cancer and lead to activation of the PI3K/AKT pathway. Treatment of patients with NTRK fusion using TRK inhibitors, such as larotrectinib or entrectinib, is associated with high response rates ( &gt; 75%). However these fusions are very rare in most common cancers, such as lung and colorectal cancers. We examined the expression levels of NTRK1, NTRK2, and NTRk3 in non-small cell lung cancer using targeted RNA sequencing. We also examined the effects of NTRK overexpression on PI3K/AKT pathway in non-small cell lung cancer. Methods: RNA was extracted from 160 FFPE samples of non-small cell lung cancers and sequenced using targeted next generation sequencing (NGS). The RNA sequencing was based on hybrid capture using a targeted panel of 1408 genes. The number of reads ranged from 5 to 10 million. The RNA levels were measured using Cufflinks as FPKM. Results: NTRK2 fusion was detected in one sample (0.04%). However, overexpression of NTRK 1-3 mRNA was more common and showed bimodal expression pattern. Most of the samples (75%) had low levels (median 0.6, 6,79, and 3.17 FPKM for NTR2, NTRK2, and NTRK3, respectively) while the upper 25% of samples had significantly (P &lt; 0.0001) higher levels (Median 2.7, 280, and 17.7 KPFM for NTRK1, NTRK2, and NTRK3, respectively). There was significant difference in expression between the three genes (P &lt; 0.0001). The highest levels were detected in NTRK2 and lowest in NTRK1. In addition, significant variation in alternative splicing was noted in NTRK2. All cases with high expression levels (above the upper quartile) showed significant variation in alternative splicing involving almost all exons. To explore, if high expression correlates with activation of the PI3K/AKT1 pathway, we examined the correlation between high levels (above upper quartile) of NTRK2 with various genes in PI3K/AKT pathway. High levels of NTRK2 mRNA (above the upper quartile) correlated with significantly higher levels of PIK3CA (P &lt; 0.0001) and MDM2 (P = 0.0001). There was no correlation between high expression of NTRK1 or NTRK3 and PIK3CA or MDM2 mRNA. Conclusions: Although fusions involving NTRK 1-3 genes in lung cancer are rare, significantly high expression levels can be seen almost 25% of lung cancers. Furthermore, high expression in NTRK2 correlates with activation in the PI3K/AKT pathway. This data suggests that therapy targeting NTRK2 overexpression and/or activation of PI3K/AKT pathway in patients with high NTRK2 mRNA should be explored.
Comparison of circulating tumor cells and cell-free DNA in the molecular characterization of patients with head and neck cancer.
Authors: Santiago Cabezas-Camarero, Vanesa García-Barberán, Virginia De la Orden-García, Beatriz Mediero-Valeros, Isabel Díaz-Millán, Cristina Saiz-Ladera, Mariona Baliu Piqué, Irene Gonzalo, Igor López-Cade, Alberto Ocana, Eduardo Díaz-Rubio, Pedro Pérez-Segura
Journal: Journal of Clinical Oncology (2020)

e18521 Background: The role of liquid biopsy in diagnosis and therapy monitoring in patients with head and neck cancer has been much less studied compared to other cancers. Our aim was to evaluate the perfomance in the isolation and recovery for molecular characterization of circulating tumour cells (CTC) of a new immunoafinity-based method and to compare it with the molecular diagnostic yield of plasma cell-free DNA. Methods: Patients with recurrent/metastatic (RM) head and neck cancer (HNC) were enrolled prospectively. Forty mililiters (ml) of plasma were collected at one or several time-points. First blood draw was always collected before starting a new therapeutic intervention or at the time of radiologic progression. For CTC detection and isolation, either anti-EpCAM or both anti-EpCAM + anti-EGFR antibodies were used. Digital PCR and castPCR were used to study KRAS and PI3KCA mutations in non-squamous HNC. A 15-gene customized NGS panel was used to characterized both CTC and cfDNA in patients with squamous HNC. Results: Between February 2016 and October 2018, 14 patients with R/M HNC were included (n = 1 local-only disease, n = 10 local and distant disease, n = 3 distant-only disease). Squamous histology (S): n = 9. Non-squamous (NS): n = 5 (1 naso-ethmoidal intestinal-type adenocarcinoma, 1 parotid gland exadenoma pleomorfic carcinoma, 2 parotid-gland salivary duct carcinomas (SDC), 1 parotid-gland high-grade neuroendocrine carcinoma). Twenty-five CTC determinations were performed. In 5 patients serial CTC determinations were performed. Median CTC was 4 (min-max: 0-49). Median CTC among 11 CTC determinations in S-HNC was 4 (min-max: 0-49). Median CTC was 3 CTC (min-max: 0-26) among the 14 determinations performed in NS-HNC. Digital PCR unveiled mutations in CTC and in cfDNA in 2 of 4 patients tested with NS histology (KRAS, PIK3CA), with one of them being concordant for the specific mutation. NGS unveiled mutations in CTC in 7/9 patients and in cfDNA in 6/9 patients, with only one loci-concordant case between CTC and plasma. Conclusions: IsoFlux detected CTC in the majority of patients with R/M HNC, regardless of the histologic type, and allowed for molecular characterization of CTC using different techniques for mutational analysis. Both NGS and digital PCR allowed for the detection in cell-free DNA of commonly mutated genes in HNC. Liquid biopsy should be more actively studied in this disease in order to better define its role in diagnosis and therapeutic monitoring.
Integrated genomic and functional analysis of patient-derived sarcoma cell lines validates their use for candidate treatment discovery including knockdown of a novel BCOR fusion gene.
Authors: Sabina Swierczek, Deep Pandya, Jean-Noel Billaud, Irma Vigil Dominguez, Sara Farisello, Steven Sieber, Ying Chen, Linus T. Chuang, Vaagn Andikyan, John Martignetti
Journal: Journal of Clinical Oncology (2020)

e23572 Background: Malignant peripheral nerve sheath tumors (MPNST) are rare, biologically-aggressive soft tissue sarcomas of neural origin, characterized by high risk of recurrence, metastases, treatment resistance and lethality. Preclinical models accurately reflecting underlying genetics are needed for exploring the tumor’s biology and developing novel therapeutic approaches. Using genomic, biochemical and bioinformatic approaches we generated and deeply characterized a patient-derived MPNST cell-line model (PDCL) and functionally validated identified therapeutic targets including a novel BCOR fusion gene. Methods: Under IRB consent, two geographically distinct metastatic tumor samples were obtained from a right peritoneal nodule (PN) and the pelvis (P) of a 63-year-old woman, with recurrent uterine MPNST to generate PDCL. Whole exome (WES) and RNA sequencing was performed on all samples. Data and bioinformatic analysis was performed using the QIAGEN software suite (CLC Genomic Workbench, Ingenuity Variant and Pathway Analysis, OmicSoft-ArrayStudio). Results: To define the degree of shared genomic diversity, WES and RNAseq of tumors and PDCL was performed. WES of metastatic samples identified both shared (n = 39) and novel (98 and 116, respectively) cancer driver variants, which were also present in the paired PDCL (38% and 39%, respectively). Furthermore, somatic copy number alterations (SCNAs) were also shared between tissue and paired PDCL. These SCNAs are present in the MPNST TCGA dataset suggesting broad biologic significance. Finally, a novel and expressed BCOR-CREBRF fusion was present in all samples. With the potential to identify and validate candidate therapies, bioinformatic analysis was used to identify shared canonical signaling pathways (Ephrin receptor signaling) and upstream regulators (HBEGF, VEGFA, and ERBB2) between tumors and PDCL. Based upon this analysis, the inhibitory effects of a targeted list of candidate drugs was performed: Dasatinib, Pazopanib, PD153035, and Lapatinib all selectively resulted in tumor cell death. Moreover, siRNA-mediated BCOR-CREBRF knockdown significantly inhibited PDCL growth. Conclusions: We demonstrate that MPNST PDCL capture the genomic diversity inherent in their founder tumor tissues and potentially other MPNST. Moreover, using a bioinformatic approach for therapeutic discovery, demonstrate the use of these PDCL for testing treatment candidates for possible use in MPNST patients.
强直性脊柱炎致主动脉瓣脱垂、关闭不全一例
Authors: 吕荣, 王维中, 陈群娟
Journal: BMJ (2007)

患者男,34岁.因间歇性腰骶、四肢关节酸痛13年,水肿3个月,气促10 d入院.患者21岁起反复腰骶处、四肢大关节酸痛,服止痛片类药物能缓解.2005年4月曾在苏州大学附属第一医院查腰骶关节X线片示双侧骶髂关节炎3级,血聚合酶联免疫吸附试验法(PCR-SSP)人类白细胞抗原(HLA-B27)阳性,诊断为强直性脊柱炎(AS),此后患者外购药物治疗(不详),症状能好转.住院前3个月患者出现双下肢水肿,腹胀纳减,夜尿2～3次,上三四层楼感气促.10 d前出现咳嗽、气促,夜间阵发性呼吸困难,咳黏痰.心电图示:窦性心动过速,左房负荷过重,胸导联V2的R波大于胸导联V3的R波;胸片示左心扩大、心功能不全、肺淤血.否认既往游走性关节痛史。
First-in-human study of palcitoclax (APG-1252), a novel dual Bcl-2/Bcl-xL inhibitor, demonstrated advantages in platelet safety while maintaining anticancer effect in U.S. patients with metastatic solid tumors.
Authors: Nehal J. Lakhani, Drew W. Rasco, Qi Zeng, Yuefen Tang, ZHIYAN LIANG, Hengbang Wang, Ming Lu, Jason Chen, Lei Fu, Cunlin Wang, Dajun Yang, Yifan Zhai
Journal: Journal of Clinical Oncology (2020)

3509 Background: Targeting Bcl-2/Bcl-xL proteins is considered as an important approach for anticancer drug development. Palcitoclax (APG-1252) was being developed to reduce on-target platelet toxicity without diminishing antitumor potency. Methods: The phase 1 study was to evaluate the safety/tolerability, pharmacokinetics (PK), and preliminary efficacy (assessed per RECIST 1.1) of palcitoclax in US patients with metastatic small-cell lung cancer (SCLC) or other solid tumors (NCT03080311). A standard “3+3” design was applied to the dose-escalation stage. Palcitoclax was administered IV infusion for 30 minutes, twice a week (BIW) or once a week (QW) for 3 weeks in a 28-day cycle. Once the maximum tolerated dose / recommended phase 2 dose (MTD/RP2D) was determined, additional patients were treated in a dose-expansion stage. Results: The dose-escalation phase has been completed with 42 patients (31 on BIW and 11 on QW) who received palcitoclax at 8 dose cohorts ranging 10 mg - 400 mg. Most adverse events (AEs) were grade 1 or 2 (G1 or G2), and 26.2% patients had ≥ G3 TRAEs. The most common TRAEs were platelet count decreased (14.3%), aspartate aminotransferase increased (9.5%), and alanine aminotransferase increased (7.1%). Rapid platelet drop was observed in patients treated at 320 mg and 400 mg, which was transient and resolved rapidly within 2-6 days. Palcitoclax at 240 mg once weekly was determined to be MTD/RP2D. Of 36 efficacy-evaluable patients, 3 patients with SCLC, neuroendocrine prostate cancer, and ovarian cancer respectively achieved partial response (PR) and 8 patients had stable disease (SD) as their best overall response. One patient with SCLC had a PR that lasted over 21 cycles. Preliminary PK analyses showed that C max and AUC were approximately dose proportional over the range of 10 mg to 320 mg following the IV infusion on Day 1, with a mean T 1/2 of 3.0-13.0 hours. Conclusions: Palcitoclax is safe and well tolerated, with a favorable platelet toxicity profile. Its promising antitumor effect supports its further development in combination therapies for treatment of patients with SCLC and other solid tumors. Clinical trial information: NCT03080311 .