Citations

AbstractBackgroundVorinostat combined with retinoids produces additive antitumor effects in preclinical studies of neuroblastoma. Higher systemic exposures of vorinostat than achieved in pediatric phase I trials with continuous daily dosing are necessary for in vivo increased histone acetylation and cytotoxic activity. We conducted a phase I trial in children with relapsed/refractory neuroblastoma to determine the maximum tolerated dose (MTD) of vorinostat on an interrupted schedule, escalating beyond the previously identified pediatric MTD.MethodsIsotretinoin (cis‐13‐retinoic acid) 80 mg/m2/dose was administered by mouth twice daily on days 1–14 in combination with escalating doses of daily vorinostat up to 430 mg/m2/dose (days 1–4; 8–11) in each 28‐day cycle using the standard 3 + 3 design. Vorinostat pharmacokinetic testing and histone acetylation assays were performed.ResultsTwenty‐nine patients with refractory or relapsed neuroblastoma were enrolled and 28 were evaluable for dose escalation decisions. Median number of cycles completed was two (range 1–15); 11 patients received four or more cycles. Three patients experienced cycle 1 dose‐limiting toxicities. A total of 18 patients experienced grade 3/4 toxicities related to study therapy. The maximum intended dose of vorinostat (430 mg/m2/day, days 1–4; 8–11) was tolerable and led to increased histone acetylation in surrogate tissues when compared to lower doses of vorinostat (P = 0.009). No objective responses were seen.ConclusionsIncreased dose vorinostat (430 mg/m2/day) on an interrupted schedule is tolerable in combination with isotretinoin. This dose led to increased vorinostat exposures and demonstrated increased histone acetylation. Prolonged stable disease in patients with minimal residual disease warrants further investigation.

Abstract Objective In recent years, electronic health record systems have been widely implemented in China, making clinical data available electronically. However, little effort has been devoted to making drug information exchangeable among these systems. This study aimed to build a Normalized Chinese Clinical Drug (NCCD) knowledge base, by applying and extending the information model of RxNorm to Chinese clinical drugs. Methods Chinese drugs were collected from 4 major resources—China Food and Drug Administration, China Health Insurance Systems, Hospital Pharmacy Systems, and China Pharmacopoeia—for integration and normalization in NCCD. Chemical drugs were normalized using the information model in RxNorm without much change. Chinese patent drugs (i.e., Chinese herbal extracts), however, were represented using an expanded RxNorm model to incorporate the unique characteristics of these drugs. A hybrid approach combining automated natural language processing technologies and manual review by domain experts was then applied to drug attribute extraction, normalization, and further generation of drug names at different specification levels. Lastly, we reported the statistics of NCCD, as well as the evaluation results using several sets of randomly selected Chinese drugs. Results The current version of NCCD contains 16 976 chemical drugs and 2663 Chinese patent medicines, resulting in 19 639 clinical drugs, 250 267 unique concepts, and 2 602 760 relations. By manual review of 1700 chemical drugs and 250 Chinese patent drugs randomly selected from NCCD (about 10%), we showed that the hybrid approach could achieve an accuracy of 98.60% for drug name extraction and normalization. Using a collection of 500 chemical drugs and 500 Chinese patent drugs from other resources, we showed that NCCD achieved coverages of 97.0% and 90.0% for chemical drugs and Chinese patent drugs, respectively. Conclusion Evaluation results demonstrated the potential to improve interoperability across various electronic drug systems in China.

AbstractIntroductionMedial temporal lobe (MTL) uptake on tau–positron emission tomography (PET) is seen not only in Alzheimer's disease (AD) dementia but also in the aging population. The relationship of these findings to the development of AD dementia needs to be better understood.MethodsTau‐PET with AV‐1451 was performed on 576 cognitively unimpaired (CU) participants aged 50–94 years. The number of CUs with and without abnormal MTL regions and those with or without extra‐MTL abnormalities was determined. Left and right regions were compared within each subject.ResultsOf CUs, 58% (334/576) had abnormal tau‐PET findings. MTL abnormalities were present in 41% (238/576) of subjects.DiscussionMTL tau‐PET signal is often associated with abnormal extra‐MTL tau‐PET signal in CU participants and may represent neurofibrillary tangle development that could identify participants most likely to develop AD dementia. Tau‐PET signal exclusively outside of the MTL is seen in 17% of CU participants and could be the initial findings in participants in different AD dementia pathways. Significant (P < .001) differences in tau–standardized uptake value ratio between sides were noted in 26 of 41 examined brain regions implicating further study of side‐specific deficits.

The purpose of this guideline is to provide information for the interpretation of clinical dihydropyrimidine dehydrogenase ( DPYD ) genotype tests so that the results can be used to guide dosing of fluoropyrimidines (5‐fluorouracil and capecitabine). Detailed guidelines for the use of fluoropyrimidines, their clinical pharmacology, as well as analyses of cost‐effectiveness are beyond the scope of this document. The Clinical Pharmacogenetics Implementation Consortium (CPIC ® ) guidelines consider the situation of patients for which genotype data are already available (updates available at https://cpicpgx.org/guidelines/guideline‐for‐fluoropyrimidines‐and‐dpyd/ ).

Abstract Existing general clinical natural language processing (NLP) systems such as MetaMap and Clinical Text Analysis and Knowledge Extraction System have been successfully applied to information extraction from clinical text. However, end users often have to customize existing systems for their individual tasks, which can require substantial NLP skills. Here we present CLAMP (Clinical Language Annotation, Modeling, and Processing), a newly developed clinical NLP toolkit that provides not only state-of-the-art NLP components, but also a user-friendly graphic user interface that can help users quickly build customized NLP pipelines for their individual applications. Our evaluation shows that the CLAMP default pipeline achieved good performance on named entity recognition and concept encoding. We also demonstrate the efficiency of the CLAMP graphic user interface in building customized, high-performance NLP pipelines with 2 use cases, extracting smoking status and lab test values. CLAMP is publicly available for research use, and we believe it is a unique asset for the clinical NLP community.