Biomarkers for radiation-induced small bowel epithelial damage:An emerging role for plasma Citrulline

Reduction of cancer treatment-induced mucosal injury has been recognized as an important target for improving the therapeutic ratio as well as reducing the economic burden associated with these treatment related sequellae. Clinical studies addressing this issue are hampered by the fact that specif ic objective parameters, which enable monitoring of damage in routine clinical practice, are lacking. This review summarizes pros and cons of currently available endpoints for intestinal injury. The metabolic background and characteristics of plasma citrulline, a recently investigated biomarker specifically for small intestinal injury, are discussed in more detail.

Experimental Studies on the Irradiation of Facial Bones in Animals:A Review

Introduction: Radiotherapy is often used to treat head and neck malignancies, with inevitable effects on the surrounding healthy tissues. We have reviewed the literature concerning the experimental irradiation of facial bones in animals. Materials and Methods: A PubMed search was performed to retrieve animal experiments on the irradiation of facial bones that were published between January 1992 and January 2012. The search terms were “irradiation facial bone” and “irradiation osteoradionecrosis”. Results: Thirty-six publications were included. The irradiation sources were Cobalt60, orthovoltage, 4 - 6 megavolt photons, and brachytherapy. The total dose varied between 8 - 60 Gy in single or multiple fractions. The literature presents a broad range of animal studies that differ in terms of the in vivo model, irradiation, observation period, and evaluation of results. Discussion: The different animal models used leave many questions unanswered. A detailed and standardized description of the methodology and results would facilitate the comparability of future studies.

Quality assurance and safety of hippocampal avoidance prophylactic cranial irradiation in the multicenter randomized phase III trial(NCT01780675)

Objective:NCT01780675,a multicenter randomized phase III trial of prophylactic cranial irradiation(PCI)versus PCI with hippocampal sparing in small cell lung cancer(SCLC)investigated neurocognitive decline and safety.As part of quality assurance,we evaluated if hippocampal avoidance(HA)-PCI was performed according to the NCT01780675 trial protocol instructions,and performed a safety analysis to study the incidence and location of brain metastases for patients treated with HA-PCI.Methods:This retrospective analysis evaluated the quality of the irradiation given in the randomized controlled trial(RCT)comparing SCLC patients receiving PCI with or without hippocampal avoidance,using intensity mod-ulated radiotherapy(IMRT)or volumetric modulated arc therapy(VMAT).The dose distribution for each patient receiving HA-PCI was retrieved and analyzed to evaluate if the treatment dose constraints were met.A ques-tionnaire was sent out to all participating sites,and data on radiotherapy technique,pre-treatment dummy runs,phantom measurements and treatment electronic portal imaging device(EPID)dosimetry were collected and analyzed.As part of the safety analysis,the follow-up magnetic resonance imaging(MRI)or computerized to-mography(CT)scans on which cranial disease progression was first diagnosed were collected and matched to the radiotherapy planning dose distribution.The matched scans were reviewed to analyze the location of the brain metastases in relation to the prescribed dose.Results:A total of 168 patients were randomized in the NCT01780675 trial in 10 centers in the Netherlands and Belgium from April 2013 until March 2018.Eighty two patients receiving HA-PCI without evidence of brain metastases were analyzed.All patients were treated with 25 Gy in 10 fractions.Dummy runs and phantom measurements were performed in all institutions prior to enrolling patients into the study.The radiotherapy(RT)plans showed a median mean bilateral hippocampal dose of 8.0 Gy,range 5.4-11.4(constraint≤8.5 Gy).In six patients(7.3%)there was a protocol violation of the mean dose in one or both hippocampi.In four of these six patients(4.9%)the mean dose to both hippocampi exceeded the constraint,in 1 patient(1.2%)only the left and in 1 patient(1.2%)only the right hippocampal mean dose was violated(average median dose left and right 8.9 Gy).All patients met the trial dose constraint of V 115%PTV≤1%;however the D max PTV constraint of≤28.75 Gy was violated in 22.0%of the patients.The safety analysis showed that 14 patients(17.1%)developed cranial progression.No solitary brain metastases in the underdosed region were found.Two out of 11 patients with multiple brain metastasis developed metastasis in the underdosed region(s).Conclusions:The radiotherapy quality within the HA-PCI trial is performed according to the protocol guidelines.The dose constraints to the hippocampi are met in the vast majority of cases.In all patients,the volume of the brain for which a higher dose was accepted,is according to the trial.However,within this volume there are small areas with higher doses than advised.

Trends in treatment and overall survival among patients with proximal esophageal cancer

BACKGROUND The management of proximal esophageal cancer differs from that of tumors located in the mid and lower part of the esophagus due to the close vicinity of vital structures.Non-surgical treatment options like radiotherapy and definitive chemoradiation(CRT)have been implemented.The trends in(non-)surgical treatment and its impact on overall survival(OS)in patients with proximal esophageal cancer are unclear,related to its rare disease status.To optimize treatment strategies and counseling of patients with proximal esophageal cancer,it is therefore essential to gain more insight through real-life studies.AIM To establish trends in treatment and OS in patients with proximal esophageal cancer.METHODS In this population-based study,patients with proximal esophageal cancer diagnosed between 1989 and 2014 were identified in the Netherlands Cancer Registry.The proximal esophagus consists of the cervical esophagus and the upper thoracic section,extending to 24 cm from the incisors.Trends in radiotherapy,chemotherapy,and surgery,and OS were assessed.Analyses were stratified by presence of distant metastasis.Multivariable Cox proportional hazards regression analyses was performed to assess the effect of period of diagnosis on OS,adjusted for patient,tumor,and treatment characteristics.RESULTS In total,2783 patients were included.Over the study period,the use of radiotherapy,resection,and CRT in non-metastatic disease changed from 53%,23%,and 1%in 1989-1994 to 21%,9%,and 49%in 2010-2014,respectively.In metastatic disease,the use of chemotherapy and radiotherapy increased over time.Median OS of the total population increased from 7.3 mo[95%confidence interval(CI):6.4-8.1]in 1989-1994 to 9.5 mo(95%CI:8.1-10.8)in 2010-2014(logrank P<0.001).In non-metastatic disease,5-year OS rates improved from 5%(95%CI:3%-7%)in 1989-1994 to 13%(95%CI:9%-17%)in 2010-2014(logrank P<0.001).Multivariable regression analysis demonstrated a significant treatment effect over time on survival.In metastatic disease,median OS was 3.8 mo(95%CI:2.5-5.1)in 1989-1994,and 5.1 mo(95%CI:4.3-5.9)in 2010-2014(logrank P=0.26).CONCLUSION OS significantly improved in non-metastatic proximal esophageal cancer,likely to be associated with an increased use of CRT.Patterns in metastatic disease did not change significantly over time.

Radiotherapy for small cell lung cancer in current clinical practice guidelines

Several guidelines including radiotherapy recommendations exist worldwide for the treatment of small cell lung cancer(SCLC).To evaluate the differences in radiotherapy recommendations we conducted a systematic review.PubMed and the sites of medical societies were searched for SCLC guidelines published in either English,Chi-nese,or Dutch.This was limited to January 2018 till February 2021 to only include up-to-date recommendations.Data was extracted and compared regarding the guideline’s development method and radiotherapy recommenda-tions.Eleven guidelines were identified(PubMed n=4,societies n=7)from Spain(n=1),Canada(n=1),America(n=3),United Kingdom(n=1),the Netherlands(n=1),and China(n=3),respectively.Nine guidelines assessed the strength of evidence(SOE)and specified the strength of recommendation(SOR),although methods were dif-ferent.The major radiotherapy recommendations are similar although differences exist in thoracic radiotherapy(TRT)dose,time,and volume.Controversial areas are TRT in resected stage I-IIA(pN1),prophylactic cranial irradiation(PCI)in resected as well as unresected stage I-IIA,stereotactic body radiation therapy(SBRT)in un-resected stage I-IIA,PCI time,and PCI versus magnetic resonance imaging(MRI)surveillance in stage IV.The existence of several overlapping guidelines for SCLC treatment indicates that guideline development is(unnec-essarily)repeated by different organizations or societies.Improvement could be made by better international collaboration to avoid duplicating unnecessary work,which would spare a lot of time and resources.Efforts should be made to work together on controversial or unknown fields.

Development and validation of multicentre study on novel Artificial Intelligence-based Cardiovascular Risk Score(AICVD)

Objective Cardiovascular diseases(CVD)are one of the most prevalent diseases in India amounting for nearly 30%of total deaths.A dearth of research on CVD risk scores in Indian population,limited performance of conventional risk scores and inability to reproduce the initial accuracies in randomised clinical trials has led to this study on large-scale patient data.The objective is to develop an Artificial Intelligence-based Risk Score(AICVD)to predict CVD event(eg,acute myocardial infarction/acute coronary syndrome)in the next 10 years and compare the model with the Framingham Heart Risk Score(FHRS)and QRisk3.Methods Our study included 31599 participants aged 18–91 years from 2009 to 2018 in six Apollo Hospitals in India.A multistep risk factors selection process using Spearman correlation coefficient and propensity score matching yielded 21 risk factors.A deep learning hazards model was built on risk factors to predict event occurrence(classification)and time to event(hazards model)using multilayered neural network.Further,the model was validated with independent retrospective cohorts of participants from India and the Netherlands and compared with FHRS and QRisk3.Results The deep learning hazards model had a good performance(area under the curve(AUC)0.853).Validation and comparative results showed AUCs between 0.84 and 0.92 with better positive likelihood ratio(AICVD−6.16 to FHRS−2.24 and QRisk3−1.16)and accuracy(AICVD−80.15%to FHRS 59.71%and QRisk351.57%).In the Netherlands cohort,AICVD also outperformed the Framingham Heart Risk Model(AUC−0.737 vs 0.707).Conclusions This study concludes that the novel AI-based CVD Risk Score has a higher predictive performance for cardiac events than conventional risk scores in Indian population.

Distributed Analytics on Sensitive Medical Data:The Personal Health Train

In recent years,as newer technologies have evolved around the healthcare ecosystem,more and more data have been generated.Advanced analytics could power the data collected from numerous sources,both from healthcare institutions,or generated by individuals themselves via apps and devices,and lead to innovations in treatment and diagnosis of diseases;improve the care given to the patient;and empower citizens to participate in the decision-making process regarding their own health and well-being.However,the sensitive nature of the health data prohibits healthcare organizations from sharing the data.The Personal Health Train(PHT)is a novel approach,aiming to establish a distributed data analytics infrastructure enabling the(re)use of distributed healthcare data,while data owners stay in control of their own data.The main principle of the PHT is that data remain in their original location,and analytical tasks visit data sources and execute the tasks.The PHT provides a distributed,flexible approach to use data in a network of participants,incorporating the FAIR principles.It facilitates the responsible use of sensitive and/or personal data by adopting international principles and regulations.This paper presents the concepts and main components of the PHT and demonstrates how it complies with FAIR principles.

Evaluation of Optical Localization in the Visible Band for Ultrasound Guidance in Radiotherapy Using A Robotic Arm

In many medical fields,spatial localization of devices is of paramount importance to e.g.deliver treatments correctly or to perform accurate diagnostic evaluations.Among the different technologies available,optical localization in the visible band of the spectrum offers many advantages:minimum interference with other instruments,flexibility in position of the devices used and extra features such as patient/operator surface tracking or vital signs monitoring.Its application in the domain of radiotherapy is novel,and potentially very beneficial.In this work we introduced a workflow to test the reliability of one of these systems,developed in house,to localize an ultrasound transducer for ultrasound guided radiation therapy(USg RT).Accuracy,precision,latency,sensitive volume and sensitivity to light intensity were evaluated.The workflow we proposed allowed us to establish that,while all the clinically relevant parameters of the system are acceptable,accuracy in locating the transducer could be as intended purpose of the system.