Model-Based Selection for Proton Therapy in Breast Cancer: Development of the National Indication Protocol for Proton Therapy and First Clinical Experiences

AimsProton therapy is a radiation technique that yields less dose in normal tissues than photon therapy. In the Netherlands, proton therapy is reimbursed if the reduced dose to normal tissues is predicted to translate into a prespecified reduction in toxicity, based on nationally approved validated models. The aim of this paper is to present the development of a national indication protocol for proton therapy (NIPP) for model-based selection of breast cancer patients and to report on first clinical experiences.Materials and methodsA national proton therapy working group for breast cancer (PWG-BC) screened the literature for prognostic models able to estimate the individual risk of specific radiation-induced side-effects. After critical appraisal and selection of suitable models, a NIPP for breast cancer was written and subjected to comments by all stakeholders. The approved NIPP was subsequently introduced to select breast cancer patients who would benefit most from proton therapy.ResultsThe model of Darby et al. (N Engl J Med 2013; 368:987–82) was the only model fulfilling the criteria prespecified by the PWG-BC. The model estimates the relative risk of an acute coronary event (ACE) based on the mean heart dose. The absolute lifetime risk of ACE <80 years was calculated by applying this model to the Dutch absolute incidence of ACE for female and male patients, between 40 and 70 years at breast cancer radiotherapy, with/without cardiovascular risk factors. The NIPP was approved for reimbursement in January 2019. Based on a threshold value of a 2% absolute lower risk on ACE for proton therapy compared with photons, 268 breast cancer patients have been treated in the Netherlands with proton therapy between February 2019 and January 2021.ConclusionThe NIPP includes a model that allows the estimation of the absolute risk on ACE <80 years based on mean heart dose. In the first 2 years, 268 breast cancer patients have been treated with proton therapy in The Netherlands.     

Pointwise probability reinforcements for robust statistical inference

Statistical inference using machine learning techniques may be difficult with small datasets because of abnormally frequent data (AFDs). AFDs are observations that are much more frequent in the training sample that they should be, with respect to their theoretical probability, and include e.g. outliers. Estimates of parameters tend to be biased towards models which support such data. This paper proposes to introduce pointwise probability reinforcements (PPRs): the probability of each observation is reinforced by a PPR and a regularisation allows controlling the amount of reinforcement which compensates for AFDs. The proposed solution is very generic, since it can be used to robustify any statistical inference method which can be formulated as a likelihood maximisation. Experiments show that PPRs can be easily used to tackle regression, classification and projection: models are freed from the influence of outliers. Moreover, outliers can be filtered manually since an abnormality degree is obtained for each observation.     

SAS统计软件的SURVEYSELECT过程在血吸虫病流行病学抽样调查中的应用

目的为了减少第三次全国血吸虫病流行病学抽样调查中人为选择样本带来的偏差。方法采用SAS统计软件的SURVEYSELECT过程在计算机上进行抽样。结果分别用计算机在江苏、江西、安徽、湖南、湖北、云南和四川随机抽取13、23、18、47、58、12和68个样本点;共抽取239个样本村,占未达到传播阻断标准乡镇的所有流行村的1.36%。结论SAS统计软件的SURVEYSELECT过程是计算机和现代统计学结合发展的结果,它极大地丰富了现场流行病学,它为流行病学的现场调查提供了简单而快速的样本选择方法,有着广泛的应用空间。     

Age,Creatinine and Ejection Fraction Score in Brazil: Comparison with InsCor and the EuroSCORE

Background

Risk scores for cardiac surgery cannot continue to be neglected.

Objective

To assess the performance of “Age, Creatinine and Ejection Fraction Score” (ACEF Score) to predict mortality in patients submitted to elective coronary artery bypass graft and/or heart valve surgery, and to compare it to other scores.

Methods

A prospective cohort study was carried out with the database of a Brazilian tertiary care center. A total of 2,565 patients submitted to elective surgeries between May 2007 and July 2009 were assessed. For a more detailed analysis, the ACEF Score performance was compared to the InsCor’s and EuroSCORE’s performance through correlation, calibration and discrimination tests.

Results

Patients were stratified into mild, moderate and severe for all models. Calibration was inadequate for ACEF Score (p = 0.046) and adequate for InsCor (p = 0.460) and EuroSCORE (p = 0.750). As for discrimination, the area under the ROC curve was questionable for the ACEF Score (0.625) and adequate for InsCor (0.744) and EuroSCORE (0.763).

Conclusion

Although simple to use and practical, the ACEF Score, unlike InsCor and EuroSCORE, was not accurate for predicting mortality in patients submitted to elective coronary artery bypass graft and/or heart valve surgery in a Brazilian tertiary care center.     

临床常规生化项目室内质控方法的设计

目的：探讨保证临床质量要求的常规生化项目室内质控规则的设计。方法收集2012年7—12月碱性磷酸酶(ALKP)、钾、钙的质控数据,以室内质控的累积变异系数(CV)作为项目的不精密度,应用卫生部临床检验中心室间质评结果计算偏倚,选择美国临床实验室改进修正法规88能力比对检验评价限为总允许误差,借助操作过程规范图设计符合本实验室切实可行的室内质控方法,从而提高误差检出概率( Ped),降低假失控概率( Pfr)。结果ALKP、钾每天测定质控品个数为2,选择1-3 s单质控规则即可满足Ped>90%,Pfr<5%;钙每天测定质控品个数为4,选择1-3 s/2-2 s/R-4 s/4-1 s/12-X作为质控规则,满足Ped>90%,Pfr<5%。结论不同生化分析项目应根据分析方法性能特征的不同,选择满足临床质量要求的控制方法。     

Patient’s Preferences for Adjuvant Postoperative Chemoradiation Therapy in Rectal Cancer

PURPOSE This study was designed to elicit patient’s preferences with regard to adjuvant postoperative chemoradiation therapy in rectal cancer. METHODS Forty-seven previously treated colorectal cancer patients underwent a structured interview and were presented with two scenarios involving surgery for rectal cancer: surgery alone, or surgery followed by postoperative chemoradiation therapy. Acute and long-term health states for each options were described. Their willingness to trade-off side-effects for treatment efficacy was evaluated by using the probability trade-off method. RESULTS The age and gender distribution of the cohort were comparable with the general colon cancer population. Rectal cancer had been diagnosed in 20 individuals. The majority of patients valued their disease-free status in light of the anticipated long-term effects on their quality of life. The median point at which patients switched their preference was 5 percent, a value reflecting the critical local recurrence rate acceptable. The important items that influenced decisions were the effects on bowel function and fear of recurrence. CONCLUSIONS This small study demonstrates a substantial variation in patient’s preferences with regard to postoperative chemoradiation for rectal cancer. Further studies in the preoperative setting are warranted.     

Probability of passing dissolution acceptance criteria for an immediate release tablet

During development of solid dosage products, a pharmaceutical manufacturer is typically required to propose dissolution acceptance criteria unless the product falls into Biopharmaceutics Classification System (BCS) class I, in which case a disintegration test may be used. At the time of filing the new drug application (NDA) or common technical document (CTD), the manufacturer has already met with regulatory agencies to discuss and refine dissolution strategy. The dissolution acceptance criteria are based on stability and batch history data and are often arrived at by considering the percentage of batches that pass United States Pharmacopeia (USP) criteria at Stage 1 (S(1)), when in fact, the product is deemed unacceptable only when a batch fails USP criteria at Stage 3 (S(3)) [H. Saranadasa, Disso. Technol. 7 (2000) 6-7, 18 [1]]. Calculating the probability of passing (or failing) dissolution criteria at S(1), S(2), or S(3) can assist a manufacturer in determining appropriate acceptance criteria. This article discusses a general statistical method that was developed to assess the probability of passing the multistage USP test for dissolution and how it was applied to an immediate release tablet formulation. In this case, acceptance criteria were set and the analysis was conducted to assess the probabilities of passing or failing based on this acceptance criterion. Whether the acceptance criteria were relevant to the product was also considered. This mathematical approach uses a Monte Carlo simulation and considers a range of values for standard deviation and mean of historical data.     

Probability effects in the stop-signal paradigm: the insula and the significance of failed inhibition

In the present randomized, mixed-trial event-related fMRI study, we examined the neural mechanisms underlying inhibitory control using a stop-signal paradigm in which stop-signal frequency was manipulated parametrically across blocks. As hypothesized, presenting stop signals less frequently was accompanied by a stronger set to respond to the go stimuli as subjects were faster in responding to go stimuli on no stop-signal trials and made more commission errors (i.e., were less successful in inhibiting the go response) on stop-signal trials. When response inhibition was successful, having to inhibit responses more frequently compared to less frequently was associated with greater activation in occipital areas. This presumably reflects enhanced visual attention to the stop signal. When response inhibition failed, greater activity was observed in bilateral insula when stop signals were presented less compared to more frequently. The insula may thus play a role in processing the significance of inhibitory failure.