Gliomas are the most common type of primary brain tumors. Although gliomas are relatively rare, they are among the deadliest types of cancer, with a survival rate of less than 2 years after diagnosis. Gliomas are challenging to diagnose, hard to treat and inherently resistant to conventional therapy. Years of extensive research to improve diagnosis and treatment of gliomas have decreased mortality rates across the Global North, while chances of survival among individuals in low- and middle-income countries (LMICs) remain unchanged and are significantly worse in Sub-Saharan Africa (SSA) populations. Long-term survival with glioma is associated with the identification of appropriate pathological features on brain MRI and confirmation by histopathology. Since 2012, the Brain Tumor Segmentation (BraTS) Challenge have evaluated state-of-the-art machine learning methods to detect, characterize, and classify gliomas. However, it is unclear if the state-of-the-art methods can be widely implemented in SSA given the extensive use of lower-quality MRI technology, which produces poor image contrast and resolution and more importantly, the propensity for late presentation of disease at advanced stages as well as the unique characteristics of gliomas in SSA . Thus, the BraTS-Africa Challenge provides a unique opportunity to include brain MRI glioma cases from SSA in global efforts through the BraTS Challenge to develop and evaluate computer-aided-diagnostic (CAD) methods for the detection and characterization of glioma in resource-limited settings, where the potential for CAD tools to transform healthcare are more likely. In contrast, over 90% of individuals with prostate or breast cancer are expected to survive after 5 years of diagnosis regardless of the malignant status2. Brain tumors in general are challenging to diagnose, hard to treat and inherently resistant to conventional therapy because of the challenges in delivering drugs to the brain. Years of extensive research to improve diagnosis, characterization, and treatment of glioma have decreased mortality rates in the U.S by 7% over the past 30 years3. Although modest, these research innovations have not translated to improvements in survival for adults and children in low- and middle-income countries (LMICs), particularly in African populations. The death rates from glioma in sub-Saharan Africa (SSA) are among the highest in the world and continue to rise. While glioma deaths rates dropped in the Global North by 10–30% from 1990 to 2016, the rates in SSA rose on average by ~25%3. This disparity could be due to several overlapping factors including, delayed presentation5, high incidence of infectious disease comorbidities such as HIV6, severe shortage of healthcare infrastructure including therapeutic options5, and lack of skilled expertise in diagnosis (neuroradiologists and neuropathologists) and treatment 7 of glioma. As standard treatment options for glioma  increasingly become available in SSA, the novel use of machine learning to advance early detection, identify precise treatment targets, and predict progression and treatment response will further widen survival disparities, if SSA populations are not included in innovative solutions that collectively benefit all patients.Brain tumors are among the deadliest types of cancer. Approximately 80% of individuals with glioma - the predominant and the most malignant form of primary brain tumor - die within two years of diagnosis9. Detection and analysis to measure glioma volume and classify glioma is currently dependent on identifying appropriate pathological features on brain magnetic resonance imaging (MRI) and confirmation by histopathology evaluation of biopsied tissue11. Computer-aided diagnosis using machine learning (ML) to segment brain tumors holds promise in increasing accuracy of tumor diagnosis, early detection, classification and in predicting tumor recurrence and patient survival13. ML algorithms for assessment of tumor burden and treatment response based on tumor segmentation on brain MRI were recently shown to outperform human readers in a large multi-center study of glioma patients13. More importantly ML can close survival disparity gaps by overcoming challenges in low-resourced setting, where time consuming manual evaluations are limited to the rare centers in urban areas that can afford highly skilled expert personnel to perform tumor analysis.Long-term survival (>3years) with glioma is not only associated with socioeconomic, environmental, and occupational factors, rather, patient survival is largely influenced by molecular, genetic, and clinical factors including tumor volume, tumor grade, age at diagnosis and histologic findings16. Each year BraTS provides open and accessible multiparametric MRI training data, ground-truth annotations and quantitative metrics for benchmarking performance and clinical utility of ML methods for glioma diagnostics. However, it is unclear if the state-of-the art ML methods developed using BraTS data can be widely implemented for clinical use in SSA, particularly given the extensive use of lower quality MRI technology in the region18. Brain MRI typically acquired in SSA have poor image contrast and resolution  Challenge has exploited the powerful role of ML in glioma diagnosis, focusing on evaluation of state-of-the art methods for tumor segmentation, classification and more recently survival predictionsolution  and may 22.11 and funding from the Lacuna Fund2 in Health Equity. As part of the BraTS 2023 cluster of challenges, this Challenge in SSA populations is a Medical Image and Computing and Computer Assisted Interventions (MICCAI) society registered challenge.This Challenge provides for the first time, annotated training, validation, and testing data sets in adult populations collected through a collaborative network of imaging centres in Africa with support from the Consortium for Advancement of MRI Education and Research in Africa (CAMERA)The MICCAI-CAMERA-Lacuna Fund BraTS-Africa 2023 (BraTS-Africa 2023) Challenge dataset is a publicly available retrospective collection of pre-operative glioma data comprising of multi-parametric (mpMRI) routine clinical scans acquired as part of standard clinical care from multiple institutions and different scanners using conventional brain tumor imaging protocols. The differences in imaging systems and variations in clinical imaging protocols result in a vastly heterogeneous image quality, providing real world cases for robust ML methods development. Ground truth annotations of the tumor sub-regions  in each The BraTS-Africa challenge is an extension of the BraTS 2023 continuous challenge with the specific task to create ML algorithms to automatically segment intracranial gliomas into three distinct classes using a 3-label system , as desc2.1.1The mpMRI scans for the BraTS-Africa 2023 challenge are image volumes of 1) T1-weighted (T1), 2) post gadolinium (Gd) contrast T1-weighted (T1Gd), 3) T2-weighted (T2), and 4) T2 Fluid Attenuated Inversion Recovery (T2-FLAIR). All imaging data were reviewed by a board-certified radiologist with extensive experience in the field of neuro-oncology.21. The preprocessing pipeline applied to the BraTS-Africa 2023 challenge data is identical with the pipeline applied on BraTS 2017–2022 challenges. Specifically, the applied pre-processing routines include conversion of the DICOM files to the NIfTI file format, co-registration to the same anatomical template (SRI24)22, resampling to a uniform isotropic resolution (1mm1), and finally skullstripping. The pre-processing pipeline is publicly available through the Cancer Imaging Phenomics Toolkit (CaPTk)21 and Federated Tumor Segmentation (FeTS) tool4. Conversion to NIfTI strips the accompanying metadata from the DICOM images, and essentially removes all Protected Health Information (PHI) from the DICOM headers. Furthermore, skull-stripping mitigates potential facial reconstruction/recognition of the patient26. The specific approach we have used for skull stripping is based on a novel DL approach that accounts for the brain shape prior and is agnostic to the MRI sequence input26. All imaging volumes were then segmented using the STAPLE27 fusion of previous top-ranked BraTS algorithms, namely, nnU-Net28, DeepScan29, and DeepMedic30 for generation of ground truth labels.Standardized pre-processing using the BraTS pre-processing workflow were used to generate the training, validation, and testing dataset2.1.228 model trained on the BraTS 2021 dataset16. All these segmentation methods and the exact pipeline used to generate the fused automated segmentation has been made publicly available through the Federated Tumor Segmentation (FeTS) platform31. The segmented images were refined manually by volunteer trained radiology experts of varying rank and experience, following consistently the BraTS annotation protocol. The volunteer radiology expert annotators were provided with the four processed mpMRI scans  along with the fused automated segmentation volume to initiate the manual refinements. The ITK-SNAP32 software was used for making these refinements. Once the automated segmentations were refined by the annotators, two senior attending board-certified radiologists with 5 or more years of experience, reviewed the segmentations. Depending upon correctness, these segmentations were either approved or returned to the individual annotator for further refinements. This process was followed iteratively until the approvers found the refined tumor sub-region segmentations acceptable for public release and the challenge conduction. The manually refined annotations were finally approved by experienced board-certified attending neuro-radiologists, with more than 5 or more years of experience interpreting glioma brain MRI.For each case, the BraTS tumor annotation protocol was used to generate the ground truth labels, to ensure consistency in the ground truth delineations across various annotators. To facilitate the annotation process for BraTS 2021, initial automated segmentations were generated from an nnU-NetWe note that radiologic definition of tumor boundaries, especially in such infiltrative tumors as gliomas, is a well-known problem. In an attempt to offer a standardized approach to assess and evaluate various tumor sub-regions, the BraTS initiative, after consultation with internationally recognized expert neuroradiologists, defined three tumor sub-regions. However, we note that other criteria for delineation could be set, resulting in slightly different tumor sub-regions. For the BraTS-Africa 2023 challenge the sub-regions considered are:The enhancing tumor (ET): includes all portions of the tumor that have noticeable increase in T1 signal on postcontrast images relative to pre-contrast images. This does not include adjacent blood vessels, even if abnormally enlarged. Intrinsic T1 hyperintensity is also NOT included in this label.Non-enhancing tumor core (NETC): includes all portions of the tumor core  that do NOT enhance. This includes necrosis, cystic change, calcification, and even exophytic hyperostosis extending into the tumor. This also includes intrinsic T1 hyperintensity such as intratumoral hemorrhage and fat.Surrounding non-enhancing flair hyperintensity (SNFH): is the entire extent of FLAIR signal abnormality surrounding the tumor that is not part of the tumor core. For meningiomas, this is often described as “vasogenic edema”. This does NOT include non-tumor related FLAIR signal abnormality such as prior infarcts or microvascular ischemic white matter changes.The BraTS tumor sub-regions  are image-based and do not reflect strict biologic entities. For example, the ET regions may be defined as hyper-intense signal on T1Gd images. However, in high grade tumors, non-necrotic, non-cystic regions are present that do not enhance and can be separable from the surrounding vasogenic edema, representing non-enhancing infiltrative tumor. Another issue is defining the tumor center in low grade gliomas as it is difficult to differentiate tumor from vasogenic edema, particularly in the absence of enhancement.2.1.3Building upon observations during all previous BraTS instances, we note some common errors in the automated segmentations. The most typical such errors observed are:Extension of ET into vessels and choroid plexusUnder and over segmented areas of SNFHIncorrect segmentation of areas of hemorrhage as ET2.1.433 maintained by the MLCommons organization6. GaNDLF offers some network architectures, but also allows the user to leverage the functionality of other libraries, such as PILLOW and MONAI. The participants can decide to use GaNDLF to develop their approach or use their own custom source code. For submission, participants are required to package their developed approach in an MLCube container following instructions provided in the Synapse platform. Cube containers are automatically generated by GaNDLF and will be used to evaluate all submissions through the MedPerf platform34 on each contributing site’s data.A baseline approach implemented in a modular open-source framework, namely the Generally Nuanced Deep Learning Framework (GaNDLF)The evaluation metrics, used in this challenge are the same metrics from previous BraTS challenges:the Dice Similarity Coefficient (DSC), which is commonly used in the assessment of segmentation.the 95% Hausdorff distance (HD) as opposed to standard HD, in order to avoid outliers having too much weight, sensitivity and Specificity to determine whether an algorithm has the tendency to over- or under segment.precision to complement the metric of Sensitivity .35. Missing results on test cases or if an algorithm fails to produce a result metric for a specific test case, the metric will be set to its worst possible value . The ranking scheme from previous challenges will be used and in keeping with discussions with the biostatistician involved in the design of The BraTS challenge (Dr Shinohara), and also while considering transparency and fairness to participants. Similar to BraTS 2017–2022, uncertainties in rankings will be assessed using permutational analyses36. Performance for the segmentation task will be assessed based on relative performance of each team on each tumor tissue class and for each segmentation measure. These will be combined by averaging ranks for the measures, and statistical significance will be evaluated only for the segmentation performance measures and will be quantified by permuting the relative ranks for each segmentation measure and tissue class per subject of the testing data. This permutation testing would reflect differences in performance that exceeded those that might be expected by chance.Participants submitted algorithms will be ranked based on the generated metric results on the test cases by computing the summation of their ranks across the average of the metrics described above as a univariate overall summary measure. This measure will decide the overall ranking for each specific team’s submission. To visualize the results in an intuitive fashion, the outcome will be plotted via an augmented version of radar plotThe challenge will commence with the release of the training dataset, which will consist of imaging data and the corresponding ground-truth labels. Participants can start designing and training their methods using this training dataset. The validation data will then be released within three weeks after the training data is released. This will allow participants to obtain preliminary results in unseen data and also report these in their submitted short MICCAI LNCS papers, in addition to their cross-validated results on the training data. The ground truth of the validation data will not be provided to the participants, but multiple submissions to the online evaluation platforms will be allowed. The top-ranked participating teams in the validation phase will be invited to prepare their slides for a short oral presentation of their method during the BraTS challenge at MICCAI 2023.Finally, all participants will be evaluated and ranked on the same unseen testing data, which will not be made available to the participants, after uploading their containerized method in the evaluation platforms. The final top-ranked participating teams will be announced at the 2023 MICCAI Annual Meeting. The top-ranked participating teams of both the tasks will receive monetary prizes. To improve inclusion and participation of teams from underrepresented communities in imaging grand challenges, specifically teams from Africa, where data for the BraTS-Africa challenge was acquired, participating African teams with the best rank will receive Lacuna Equity & Health Prizes. This prize, as subjected to funding, will be limited to teams who completed the BraTS-Africa BrainHack 2023 workshop.


Flexible strain sensors for multi-directional strain detection are crucial in complicated hman–computer interaction (HCI) applications. However, enhancing the anisotropy and sensitivity of the sensors for multi-directional detection in a simple and effective method remains a significant issue. Therefore, this study proposes a flexible strain sensor with anisotropy and high sensitivity based on a high-aspect-ratio V-groove array and a hybrid conductive network of iron nanowires and carbon nanotubes (Fe NWs/CNTs). The sensor exhibits significant anisotropy, with a difference in strain detection sensitivity of up to 35.92 times between two mutually perpendicular directions. Furthermore, the dynamic performance of the sensor shows a good response rate, ranging from 223 ms to 333 ms. The sensor maintains stability and consistent performance even after undergoing 1000 testing cycles. Additionally, the constructed flexible strain sensor is tested using the remote control application of a trolley, demonstrating its high potential for usage in practical HCI systems. This research offers a significant competitive advantage in the development of flexible strain sensors in the field of HCI. In recent years, the rapid development of wearable, flexible devices has attracted the attention of many researchers ,2,3,4. IHeretofore, much effort has been made to improve the performance of flexible strain sensors. Flexible strain sensors achieve the detection of mechanical strain by relying on changes in the conductive network formed by the sensitive material, which in turn is caused by the deformation of the flexible substrate. Two key aspects of sensor performance are optimized, primarily in terms of sensitive material selection and structural design ,21,22,23To enhance the anisotropy of flexible strain sensors for strain detection in different directions, numerous researchers have introduced surface micromorphologies with orientation ,43,44,45In this work, the researchers introduce a direct transfer method to prepare a flexible strain sensor substrate with a high-aspect-ratio V-groove array, and they spray Fe NWs and CNTs to form a hybrid conductive network, producing an anisotropic and highly sensitive flexible strain sensor. The PDMS substrate prepared via die transfer, instead of the conventional pre-stretching method, has a high-aspect-ratio V-shaped groove. On the one hand, it increases the sensitivity of the flexible strain sensor to the initial strain. The sensor exhibits a gauge factor (GF) of 2058.25. On the other hand, high-aspect-ratio V-groove arrays enable the sensor to exhibit exceptional anisotropy. In addition, the sensor demonstrates good stability through the ongoing 1000-cycle test. This highly sensitive anisotropic flexible strain sensor can be used as an input control device for HCI systems, enabling the remote control of vehicles. It also has the potential to be used as a wearable device for various applications in the field of HCI, guiding the design of other flexible strain sensors.The surface morphology changes during the preparation of the sensor are tracked by SEM. The PDMS flexible sensor substrate with a high-aspect-ratio V-groove array configuration is obtained from the resin printed mold a,b. AddiThe conductive network of Fe NWs is formed on the surface of the high-aspect-ratio V-groove array by spraying the Fe NWs solution with a mass fraction of 2% on the PDMS flexible substrate e,f. AddiThe high and wide diameter of the sprayed sensitive material is more likely to accumulate at the bottom of the gully than the V-groove g. HoweveThe results above demonstrate that the PDMS flexible substrate prepared using a mold-transferred high-aspect-ratio V-groove array structure and then sprayed with a solution of Fe NWs and CNTs forms a hybrid conductive network with good conductivity. At the same time, the high-aspect-ratio V-grooves, with more sensitive material aggregating at the bottom, expand the strain detection range while maintaining high sensor sensitivity.Flexible strain sensors with high-aspect-ratio V-groove arrays are characterized by high sensitivity, sensing anisotropy, and good reliability and can be easily packaged for use. The high-aspect-ratio V-groove array on the sensor surface achieves sensing anisotropy. There is a significant difference in sensitivity in different directions for the same strain. This feature effectively differentiates strains from different directions in practical applications. The Fe NWs/CNTs sensitive material coated on the surface of the high-aspect-ratio V-groove array forms a hybrid conductive network that changes during mechanical deformation of the sensor, causing a change in the resistance value. Since Fe NWs and CNTs have different mechanical properties, the use of Fe NWs/CNTs to build interleaved conductive networks effectively improves the sensitivity and operating range of the sensor ,39.The researchers had designed a series of tensile strain experiments to investigate the electromechanical properties of the sensor. The tensile strain experiments used sensors sprayed with 10 mL of Fe NWs solution with 2% Fe NWs by mass and 10 mL of CNTs solution with 1% CNTs by mass in a 10 m × 20 mm microstructure section. The effective area was 10 mm × 20 mm for the direction T stretching experiment a and 10 In addition to the high sensitivity and anisotropic sensing characteristics, the sensor also had good stability and response speed. When the tensile strain in the direction T occurs in the flexible strain sensor with a high-aspect-ratio V-groove array, it can be divided into three stages to analyze the strain process sensor characteristics: smaller stretch degree b, mediumFlexible strain sensors with high-aspect-ratio V-groove arrays experience tensile strain in the direction L with a significant difference from the direction T f,g. TherIn summary, the V-shaped trench array structure with a high aspect ratio brings remarkable anisotropy and high sensitivity to the sensor, and the conductive network composed of Fe NWs/CNTs fillers optimizes the sensitivity and stability of the sensor. Furthermore, the sensor’s simple preparation considerably boosts its economic benefits and has great competitive potential in the field of HCI.A flexible sensor with high sensitivity in multiple directions can be prepared based on a single anisotropic high-sensitivity sensor, effectively detecting complex and weak human motions. This characteristic is used to prove the effectiveness of the sensor as an input device in HCI systems. It is worth noting that despite the successful realization of human motion detection using a single anisotropic sensor . Morphological observation and elemental analysis of the active part of the sensor after coating with Fe NWs and CNTs sensitive materials are conducted using a field emission scanning electron microscope (OXFORD ULTIM Max65). A tensile tester  performs a cyclic tensile test, using a jig to hold both sensor ends and a resistive flexible strain transducer with an effective area of 10 mm × 20 mm. The maximum stretch is 10%, and the stretching speed is 1 mm/s or 5 mm/s. The resistance measuring instrument used in the tensile test is the source meter (34465A) from Keysight Technologies, Inc. .In conclusion, we have prepared a flexible V-groove array anisotropic strain sensor with a high aspect ratio. A conductive network with excellent conductivity has been formed by spraying Fe NWs and CNTs solutions. The sensor preparation process has been simple, effective, and cost-effective. The sensors have been reasonably assembled into mutually orthogonal double-layer structures, and the anisotropy and high sensitivity of the sensors have been utilized to realize remote wireless operation of the trolley motion, which has proven the effectiveness of the sensors as an input device in complex HCI systems, as described below.(1)The high-aspect-ratio V-groove has been designed to increase the sensor’s sensitivity and realize its anisotropy. This high-aspect-ratio V-groove design has enabled the sensor to achieve a 35.92-times-higher sensitivity variability in the mutually perpendicular directions L and T. Furthermore, the sensor has consistently maintained a high sensitivity in direction L across the entire operating range. It has exhibited a value of GF = 268.21 for stretching below 8% and a value of GF = 2058.25 for stretching between 8% and 10%. The sprayed Fe NWs solution and CNTs solution have formed a conductive network with excellent electrical conductivity, making the sensor preparation simple, with less-sensitive materials, and more economical.(2)The double-layer structure sensors are assembled in a mutually orthogonal way as the input devices of HCI system to realize the remote control of the motion of a trolley, and this has effectively proven that the sensor preparation method proposed in this paper can be applied in the complex HCI field.While our current sensors have been successfully applied to complex human–computer interaction systems, they lack the ultra-high-pressure force-pixel detection sensitivity and fast sensor response demonstrated by VATJ sensors . Additio


This study aimed to investigate the feasibility and efficacy of high-intensity interval training (HIIT) compared with moderate-intensity continuous training (MICT) in pulmonary rehabilitation (PR) for people with interstitial lung disease (ILD).Single-centre, randomised controlled feasibility, pilot trial.Patients were recruited from the chest clinic of a tertiary ILD centre and attended circuit-based PR in the hospital’s gym, followed by a personalised 6-month community programme.58 patients, stratified per ILD type, were randomised into two groups: 33 to HIIT  (mean age (SD): 70.2 (11.4) years) and 25 to the MICT exercise mode  (mean age (SD): 69.8 (10.8) years).8-week, twice weekly, circuit-based PR programme of exercise and education, followed by a personalised 6-month community exercise programme.Feasibility outcomes included staff-to-patient ratio and dropout rates per group. Primary outcome was the 6 min walk distance (6MWD). Secondary outcomes included the sniff nasal pressure, mouth inspiratory and expiratory pressures, handgrip and quadriceps strength and health status. Random-effects models were used to evaluate average variation in outcomes through time across the two groups.The 6MWD peaked earlier with HIIT compared with MICT (at 4 months vs 5 months) but values were lower at peak (mean (95% CI): 26.3 m (3.5 to 49.1) vs 51.6 m (29.2 to 73.9)) and declined faster at 6 months post-PR. Secondary outcomes showed similar faster but smaller improvements with HIIT over MICT and more consistent maintenance 6 months post-PR with MICT than HIIT.HIIT is feasible in circuit-based ILD PR programmes and provides quick improvements but requires closer supervision of training and resources than MICT and benefits may be less well sustained. This would make it a less attractive option for clinical PR programmes. A definitive, multicentre randomised controlled trial is required to address the role of HIIT in ILD.ISRCTN55846300. This randomised controlled feasibility, pilot study, showed that high-intensity interval training (HIIT) is feasible in circuit-based pulmonary rehabilitation (PR) programmes.Our results identify the point at which exercise reinforcement may be needed after completion of a HIIT programme.Although it was possible to recruit enough patients with interstitial lung disease from a single site, not enough patients with idiopathic pulmonary fibrosis could be recruited to evaluate the effect of HIIT on this particular group.We did not use supplementary oxygen during PR for patients other than those already on long-term oxygen therapy.This study adds valuable information for the design of larger, definitive studies, on the peak and subsequent deterioration of outcomes over time depending on exercise mode.Interstitial lung disease (ILD) is a broad term used to describe a diverse group of pulmonary conditions that cause fibrotic changes in the lung interstitium with subsequent reduction in lung compliance and oxygen diffusion capacity.7 8Pulmonary rehabilitation (PR) is a non-pharmacological strategy that improves physical function and quality of life2peak),High-intensity interval training (HIIT) is a modality characterised by intervals of high-intensity exercise followed by intervals of low intensity or rest.The aim of this pilot study was therefore to evaluate: (1) the feasibility of using HIIT in an ILD-PR programme; (2) determine the short-term and medium-term effects of HIIT on exercise capacity, respiratory and peripheral muscle strength, breathlessness and health status; and (3) explore responses in different types of ILD.Some of the results of this study have been reported previously in abstract form.23Single-blind, randomised-controlled feasibility, pilot trial.Symptomatic patients over 18 years old, of all types and severity, apart from sarcoidosis, and with a respiratory-physician diagnosis of ILD from a tertiary referral hospital, were invited to participate. This included patients with IPF  and approved by the South East Coast-Surrey Ethics committee (14/LO/0149).People with ILD were involved in the original design of this research and determined acceptability of the proposed interventions and likelihood of adherence to this programme. During the study, all participants were involved in the conduct of the research by giving regular feedback in the education-discussion part of the PR programme and via interviews. On completion of this study, some participants formed a local ILD- Support Group and viewed the final results for dissemination.Following baseline assessments, participants were randomised into two groups: exercise using MICT (MICT group) or exercise using HIIT (HIIT group). Participants were stratified by ILD type to ensure a balanced distribution of types between groups. They were placed into three subgroups: (1) idiopathic group ; (2) autoimmune group ) and (3) chronic hypersensitivity pneumonitis/Extrinsic Allergic Alveolitis group (CHP/EAA). The investigator performing all assessments and the statistician were blinded throughout the study.This was a circuit-based 8-week, twice weekly, outpatient programme, including only people with ILD and consisting of an hour of exercise and an hour of education. Exercise was set, supervised and progressed by two experienced physiotherapists, according to a standardised protocol for each group allocation. Supplementary oxygen was not used during the sessions. Participants already on LTOT continued to exercise with oxygen as recommended but were not given additional oxygen. Aerobic exercises included treadmill walking, brisk walking between two cones, cycle ergometer, trampette and step ups. Strength training exercises, upper and lower limb, were conducted using ‘Thera-bands’ and functional movements such as sit-to-stand and ball raises.A minimum of 30 min were dedicated to aerobic training. Aerobic training intensity at the MICT group was set at 60% maximum heart rate (HRmax) and progressed each week. In the HIIT group, intensity was set at 80% HRmax and patients were instructed to exercise in dynamic intervals followed by low-intensity exercise or rest. The aim in this group was to increase the amount of time on the ‘high-intensity’ phase each week.In the first week, the average time on HIIT (at 80% HRmax) for each aerobic exercise was 2.5 min, therefore HIIT was 12.5 min of the total 30 min session, and this time increased each week. Progression of training was determined by reducing time in the low-intensity phase of HIIT and/or increasing time in the target HR. Each participant’s individualised programme was recorded on exercise logs during the sessions.Heart rate and oxygen saturation were monitored using pulse oximeters and perceived exertion and breathlessness were recorded at set intervals using the modified 10-point Borg Scale and the Rate of Perceived Exertion Scale, respectively.25 26The education session, on the second hour of the programme, was common for all participants and included presentations and discussion on topics important to patients with ILD, such as topics about breathing and breathlessness , topics about ILD  and topics about managing the condition .On the first day of the programme all participants were given an ‘ILD-Pulmonary rehabilitation booklet’ designed by our team, which contained information and pictures of all exercises, an exercise diary and summary of the education topics see . All par10.1136/bmjopen-2022-066609.supp1Supplementary dataFollowing completion of the PR programme, participants were given a personalised exercise programme, starting at the level achieved at the end of PR, and were asked to continue to exercise three times per week as well as do daily walking. The plan was recorded in their personal booklet. The 6-month programme included outdoor walking in HIIT or MICT mode, as well as stretching and strength training exercises. Some participants joined their local gym or organised exercise classes to ensure participation in group exercise at least once per week and followed a home programme the remaining time. Others opted for home-based exercise only. Regardless of the choice, during the 6-month period, participants were self-monitoring and had regular phone calls (once per month) and at least one home visit by the research physiotherapists on the third month. The physiotherapists guided participants on filling-in the exercise diaries and progressing training depending on mode of exercise. The ILD-PR booklet was used as a resource for the home exercises and as a reminder of the educational topics.All assessments were performed by the same investigator (DN), using identical instructions and methods, at three time points; at baseline, at 8 weeks (post-PR) and at 6 months (post-community programme). The investigator was blinded throughout the study.Feasibility outcomes included the proportion of eligible patients who consented to the study, attrition in each group, staff-to-patient ratio and supervision requirements, reasons for discontinuing the programme and adverse events.The primary efficacy outcome was functional exercise capacity and was measured using the 6 min walk distance (6MWD) test as recommended by the American Thoracic Society (ATS) guidelinesSecondary outcomes were:Respiratory muscle function—sniff nasal pressure (SNIP) and the maximal inspiratory and expiratory pressures (PImax and PEmax) were recorded using a handheld portable respiratory muscle testing device . A minimum of 10 attempts were made for each test, on at least one session. PImax was recorded from functional residual capacity and PEmax from total lung capacityPeripheral muscle function—handgrip strength, assessed in the dominant hand, with the elbow at 90° angle, using a hydraulic hand dynamometer . Quadriceps strength (QUADS-DOM) and hip flexion (HIP-DOM) were assessed in sitting position, with the knee at 90° angle and back upright and supported using a handheld dynamometer .Health status, using the St George’s Respiratory Questionnaire for IPF (SGRQ-I)Data were collected and managed using REDCap electronic data capture tools hosted at the NHS Trust.30This was a pilot study to test feasibility of the HIIT exercise mode and inform the design and power of a larger, next phase, randomised controlled trial. Intention-to-treat analyses are presented, that is, all participants who were randomised were considered in the analysis, not only those who completed the programme together with estimates’ uncertainties as 95% CIs. This is not a hypothesis testing setting, hence the numbers followed instructions from the literature.Exploratory analyses used random effects (mixed) models to estimate average values in outcomes across the follow-up time for the four continuous longitudinal outcomes of interest, that is, 6MWD, SNIP, SGRQ-I and Quads strength which were relatively normally distributed on each occasion. Average estimates of these measurements were derived following fitting a series of a non-linear, quadratic mixed models over time allowing for a three-way interaction between time, intervention (HIIT vs MICT) and clinical group (ILD type) as well as between age, intervention and clinical group. For each of the four key exploratory outcomes of interest, a series of nested models of increasing complexity were developed and tested for their statistical improvement against the next less complex model. The complete data analysis (using missing data jargon) using mixed modelling on the four continuous longitudinal outcomes accounted for all participants and their complete observations  and operated under ‘missing at random’ assumption for the attrition at the follow-up assumption which is not testable from the data in hand.10.1136/bmjopen-2022-066609.supp2Supplementary dataThe average variations of outcomes through time, within and between groups, are presented as means (95% CI) and descriptive statistics as mean (SD). All analyses were conducted on STATA software (V.11).Sixty participants consented to the study but two participants withdrew prior to commencement of the PR programme. A total of 58 participants started the PR programme. Baseline characteristics are shown in HIIT was well tolerated in a circuit-based clinical PR programme but required closer supervision to monitor participants’ target heart rate and avoid desaturation below 85%. There were no adverse events from HIIT during or after the PR programme; although attrition in the HIIT group was higher (42% compared with 28% in the MICT group) this did not appear to be due to a specific factor that could be directly attributed to the type of programme .The change in outcomes from baseline at all assessment points are shown in The quadratic term was significant for all secondary outcomes  .SNIP values peaked earlier than 6MWD values in both groups by approximately 2 weeks . QUADS-DThere was no evidence for a difference between treatment groups for the SGRQ-I values. The time to reaching the greatest improvement in SGRQ-I score was shorter in the HIIT group, but the changes in the HIIT group were of smaller magnitude at all time-points .10.1136/bmjopen-2022-066609.supp8Supplementary data10.1136/bmjopen-2022-066609.supp9Supplementary dataOur models included three-way interactions between time, intervention (HIIT or MICT) and clinical group, to predict changes from baseline in the combined fibrosis (IPF and CHP group) and CTD-ILD groups. The patterns of change are consistent with the primary analysis, that is, while the HIIT group peaked faster than the MICT group, the level of improvement was less .10.1136/bmjopen-2022-066609.supp4Supplementary data10.1136/bmjopen-2022-066609.supp5Supplementary data10.1136/bmjopen-2022-066609.supp6Supplementary data10.1136/bmjopen-2022-066609.supp7Supplementary dataDespite stratified randomisation, DLCO seemed to differ between intervention groups . We ther10.1136/bmjopen-2022-066609.supp3Supplementary dataTo our knowledge, this is the first study to investigate the feasibility and potential efficacy of HIIT in the context of a circuit-based clinical PR programme for ILD and compare it with MICT. It demonstrated the feasibility of HIIT, in PR for patients with ILD and provided preliminary data on the exercise mode more likely to maintain benefits 6 months after programme completion. In addition, we identified the time of peak benefit and time course of subsequent deterioration.HIIT proved to be feasible and well tolerated but required closer supervision and careful instructions for patients to continue this mode of training than MICT. The attrition rate was higher in the HIIT group compared with the MICT group and more contact was needed in the 6-month period to ensure that the HIIT mode of training met the protocol requirements.The preliminary efficacy of HIIT over MICT was tested using random effects models. Their aim was to understand the average variation of the four key outcomes through time across groups to answer five main questions: (1) How do these measurements change over time? (2) Does the benefit differ between groups? (3) How sustainable is the benefit? (4) Does the attrition rate differ between groups? and (5) What is the influence of age? The study was primarily designed to compare the two treatment groups, but an exploratory analysis was performed to look for differences between clinical groups, although this resulted in small numbers in the subgroups.Contrary to our initial hypothesis, our data showed no evidence of greater benefit with HIIT compared with that achieved with MICT in exercise capacity, respiratory and peripheral muscle function or health status in the medium term. The study was designed as a pilot to test the potential for a trial of HIIT in a larger, definitive study, but we are forced to conclude that a study of the same design may not be worthwhile.At 2 months, both groups improved >34 m in the 6MWD, which is the reported minimal clinical important difference in patients with IPF,In addition to functional exercise capacity, patients improved quadriceps muscle strength post-PR but similarly, there was no difference between treatment groups. Age-adjusted results for quadriceps force were less variable than for 6MWD and benefits were well maintained above baseline in both groups. The modelling suggested that quadriceps force peaked a little later than other outcomes at 5.5 months in the MICT group and at 5 months at the HIIT group. Our results support the inclusion of strength training in ILD-PR programmes and suggest that it may explain why some studies showed greater improvement and maintenance in functional capacity2O in both groups) as previously describedRespiratory muscle strength was preserved at baseline . We combined the IPF and CHP subgroups into the combined ‘Fibrosis’ clinical group. This was due to smaller numbers of IPF participants at the end of the study which did not allow for independent evaluation of this subgroup.The effects of HIIT on ILD of different aetiology were consistent with our primary analysis, that is, that HIIT peaked faster and the level of improvement was less. This result seemed to be largely attributable to the fibrosis group, which peaked fastest but showed the lowest improvement from baseline compared with the CTD-ILD group. Similar findings were observed for the other outcomes, again showing lack of preferential benefit from HIIT in any subgroup. While the CTD-ILD subgroup improved in most variables, the HIIT mode was not superior to MICT.The study has limitations. First, although our retrospective analysis showed no evidence that baseline DLCO had an effect on outcomes following our training programme , the effSecond, we did not use supplementary oxygen during PR for participants other than for those already on LTOT. Although promising benefits have been reported with acute oxygen supplementation during exercise in patients with IPF,Finally, the number of IPF participants who remained in the study was small and did not allow us to investigate the effect of HIIT over time in this particular group.This pilot, enabled us to explore the effect of mode of training on an ILD-PR programme of 8 weeks duration followed by community-based training for 6 months. Our programme duration reflects current UK-based clinical programmes and showed improvements that were maintained at 8 months and were similar to a recent study of a much longer PR programme duration.In the current study, HIIT was found to be feasible and improved exercise capacity in an ILD-PR programme, but this exercise modality showed no evidence of superiority over MICT. Indeed, our findings suggest that it may be less effective and may require closer monitoring to avoid exercise-induced desaturation so, until further evidence becomes available, MICT appears to be more appropriate in the general clinical setting.


We describe our initial experience using a multipolar pulsed-field ablation catheter for the treatment of left atrial (LA) reentry tachycardia.We included all patients with LA reentry tachycardia treated with PFA at our institution between September 2021 and March 2022. The tachycardia mechanism was identified using 3D electro-anatomical mapping (3D-EAM). Subsequently, a roof line, anterior line, or mitral isthmus line was ablated as appropriate. Roof line ablation was always combined with LA posterior wall (LAPW) ablation. Positioning of the PFA catheter was guided by a 3D-EAM system and by fluoroscopy. Bidirectional block across lines was verified using standard criteria. Additional radiofrequency ablation (RFA) was used to achieve bidirectional block as necessary.Among 22 patients (median age 70 (59–75) years; 9 females), we identified 27 LA reentry tachycardia: seven roof dependent macro-reentries, one posterior-wall micro-reentry, twelve peri-mitral macro-reentries, and seven anterior-wall micro-reentries. We ablated a total of 20 roof lines, 13 anterior lines, and 6 mitral isthmus lines. Additional RFA was necessary for two anterior lines (15%) and three mitral isthmus lines (50%). Bidirectional block was achieved across all roof lines, 92% of anterior lines, and 83% of mitral isthmus lines. We observed no acute procedural complications.Ablation of a roof line and of the LAPW is feasible, effective, and safe using this multipolar PFA catheter. However, the catheter is less suited for ablation of the mitral isthmus and the anterior line. A focal pulsed-field ablation catheter may be more effective for ablation of these lines.This study shows the feasibility to ablate linear lesions with a multipolar pulsed-field ablation catheter. 27 left atrial reentry tachycardia were treated in 22 patients.The online version contains supplementary material available at 10.1007/s10840-022-01436-1. Reentrant left atrial (LA) tachycardia may develop following LA ablation of atrial fibrillation or occur spontaneously in diseased LA. The main mechanisms of reentrant LA tachycardia are roof-dependent- or mitral isthmus-dependent macro-reentry, or micro-reentry involving scar tissue.The ablation strategy for LA tachycardia involves ablation of a line across the roof, the mitral isthmus or anterior wall, or focal ablation of scar tissue. However, in 20–30% of LA linear ablations, bidirectional block cannot be achieved acutely. Even if bidirectional block can be achieved, it may recover in up to 40% of cases. Both scenarios can facilitate new arrhythmias –3. Most Pulsed field ablation (PFA) is a novel, non-thermal ablation modality in which cardiac tissue is exposed to repetitive short and intense electrical fields . PFA resConsecutive patients with documented LA reentry tachycardia undergoing ablation by PFA at our institution were prospectively enrolled into an institutional registry. The registry was approved by the local ethics committee , and the study was carried out in accordance with the principles of the Declaration of Helsinki. The authors had full access to and take full responsibility for the integrity of the data.Our workflow has been described previously . In brieThe PFA platform, called the FARAPULSE PFA System , includes a generator (Farastar), which produces the therapeutic electrical field, a 12F over-the-wire multipolar ablation catheter (Farawave), available in two sizes (31 mm and 35 mm), and a 13-F steerable sheath (Faradrive). The platform has been described in detail previously and is CE Marked with an indication for PVI in patients with paroxysmal atrial fibrillation . The mulFor 3D-EAM, we used both the Carto  and Rhythmia system . Visualization of the PFA catheter in the Carto system was realized by defining a custom 6F circular catheter with six 2-mm electrodes and 17-mm center-to-center inter-electrode spacing. Since the catheter only has five splines, we split the signal of the first electrode and routed it to the additional sixth pin, consequently displaying the curved shape always as a closed loop. Catheter position was verified on 3D-EAM and fluoroscopy before ablation .Patient and procedural characteristics are summarized in Table An overview of the mapping findings and the ablation lesion sets is presented in Tables Of the seven roof-dependent macro-reentries and one micro-reentry involving the posterior wall, five 63%) terminated during ablation of the roof line. For all patients receiving roof line ablation, LAPW isolation was also performed. Furthermore, a supplementary roof line and LAPW isolation was applied in 12 patients to avoid future occurrence of roof-dependent arrhythmia  and an anterior line in the remaining six  terminated during PFA of the area of origin within an anterior scar region Fig. . Two patIn this cohort of 22 patients, we report our initial experience using a commercially available PFA catheter for the treatment of LA reentry tachycardia. Of the 39 lines attempted, a roof line and LAPW isolation was the target in 20 patients, an anterior line in 13, and a standard mitral isthmus line in 6. Bidirectional block could be achieved across 37 (95%) of the targeted lines, with supplementary RF ablation in 5 (14%) cases.Due to the combination of procedural efficacy, procedural safety, and lesion durability, the non-thermal PFA technology has the potential to become the preferred technology for atrial fibrillation ablation. Most of the PFA work to date has focused on PVI , 14, 15.The multipolar PFA catheter is particularly well suited for the application of a roof line and for LAPW isolation. In comparison, ablation of a roof line or LAPW isolation by RF ablation is challenging. In a meta-analysis, the success rate for LAPW isolation with RF ablation was 71%  . Pak et In a pre-market trial, the same PFA device that was used in our study was successful in LAPW isolation in 25/25 patients , 14. WitAblation of a standard mitral isthmus line with RF ablation is successful in achieving bidirectional block in only 64% of patients . The mitUsing PFA, we were able to achieve acute bidirectional block across the mitral isthmus line in 83% of cases, including three cases in which additional RF ablation within the great cardiac vein was needed. Since the successful ablation of standard mitral isthmus line might still request additional ablation from within the great cardiac vein, a focal PFA catheter may be better suited. In a pre-clinical study, a different PFA system was used to deliver a combination of pulsed field and RF lesions from a single lattice-tip catheter both endo- and epicardially and achieved acute mitral isthmus block in 13/14 patients .It remains to be demonstrated, whether the necessary lesion depth for durable block of the standard mitral isthmus line can be achieved by PFA. Gunawardene et al. reported successful mitral isthmus ablation using PFA in two patients without the need for additional RFA. However, in one case, coronary artery spasm occurred after eight PFA applications and resolved upon administration of nitroglycerin . AlthougIn our study, for the ablation of the mitral isthmus line, PFA lesions were applied in both the flower and basket configuration. The flower configuration can be used to target a larger area. The basket configuration might be used to optimize tissue contact of some splines of the PFA catheter at sites with residual gaps identified by 3D-EAM subsequent to PFA applications in the flower configuration.Increased tissue thickness and epicardial connections may be obstacles to the application of an anterior line from the RSPV to the anterior mitral annulus. Ablation of an anterior line usually is not the first choice for the treatment of peri-mitral macro-reentry. However, this line might be the preferred approach in the presence of an extensive scar on the anterior wall, forming the substrate for both peri-mitral macro-reentry and anterior micro-reentry tachycardia. Using RF ablation, a report on a large cohort of 398 patients observed an acute success rate for block across an anterior line of 64% . DespiteThe multipolar PFA catheter can be used with simple fluoroscopic guidance and without the need for a 3D-EAM system. However, for planning and delivery of more complex lesion sets than PVI, real-time visualization using a 3D-EAM system allows for verification of appropriate catheter position before ablation. To identify the tachycardia mechanism of LA reentry tachycardia, 3D-EAM is used either way, and integration of the PFA catheter is an obvious option. Despite the current lack of magnetic tracking, impedance-based visualization of the multipolar PFA catheter in two established mapping systems was remarkably accurate. Overlap between lesions as well as proximity to the LA tissue can easily be verified and the catheter position adjusted as needed Fig. . In addiPulsed-field ablation can result in local myocardial capture, thereby terminating the tachycardia by the mechanism of overdrive pacing. Therefore, termination by PFA should not be interpreted as proof of the tachycardia’s mechanism nor as proof for an effective lesion application. Extensive use of PFA for linear ablation and LAPW isolation may impair left atrial pump function. Nakatani et al. compared the effect of PFA with radiofrequency ablation on left atrial mechanical and structural characteristics after pulmonary vein isolation . They foPotential limitations of the presented study merit consideration. First, this is a small cohort and represents a single-center experience at an early stage of the implementation of a new technology. Therefore, conclusions on the efficacy and safety of linear PFA should be drawn cautiously. Our results need external validation, ideally by the contribution of multiple centers. Second, the PFA system utilized in this study is labeled and designed for PVI. Dedicated PFA catheters for linear ablation have been developed, are undergoing pre-clinical testing, and will further improve results. Third, we report the acute results to achieve block across ablation lines. Despite favorable evidence accumulating on the durability of PFA lesions in PVI, the durability of linear PFA lesions is currently not known. Fourth, our experience is limited to a specific PFA system. Our results cannot be applied to other PFA platforms as they incorporate different ablation parameters and catheter designs.Ablation of a roof line and LAPW isolation is feasible, effective, and safe with this multipolar PFA catheter. However, the catheter is less suited for ablation of the mitral isthmus and the anterior line, for which complementary RF ablation may be needed to achieve bidirectional block. A focal pulsed-field ablation catheter may be more effective for ablation of these lines.Supplementary file1 (JPG 4582 KB)Below is the link to the electronic supplementary material.


Radiation therapy combined with immune checkpoint inhibitors (ICIs) has recently turned into an appealing and promising approach to enhance the anti-tumor immunity and efficacy of immunological drugs in many tumors. Abscopal effect induced by radiation is a phenomenon that often leads to an efficient immunity response. In this study, we investigated whether the combination of the immunogenic effects derived from radiotherapy sequential ICIs-based therapy could increase the incidence of abscopal effects, and improve the survival rates.We described a clinical case regarding a 35-year-old male patient who was admitted to our hospital with a diagnosis of adenocarcinoma of the sigmoid colon and synchronous multiple liver metastases following a surgical resection. The molecular pathological examination showed immune-desert phenotype and proficient mismatch repair (pMMR). The patient was treated with adjuvant chemotherapy after surgery, however, after 7 months, multiple metastasis in the pelvic lymph nodes were diagnosed. Unfortunately, the tumor progressed despite multiple cycles of chemotherapy combined with cetuximab or bevacizumab. Within the follow-up treatment, the patient was administered with only 50Gy/25F of radiation dose to treat the anastomotic lesions. Subsequently, mono-sindilizumab was used as systemic therapy, leading to a rapid reduction of all pelvic lesions and complete clinical remission. So far, the patient survived for more than 20 months under continuous mono-sindilizumab treatment and is still in complete remission.A localized radiotherapy combined with a sindilizumab-based systemic therapy may overcome the immune resistance of pMMR metastatic colorectal cancer (mCRC), thus obtaining greater efficacy of the therapy. Its mechanism may be related to the abscopal effect obtained by the synergistic use of radiation and sindilizumab, which should be further investigated in the future. ICIs have been extensively used to treat many cancers, leading to significant improvements in the survival rates for some patients . PatientA 35-year-old man with a diagnosis of primary sigmoid colorectal cancer was admitted to the Second Affiliated Hospital of Army Military Medical University in August 2019. Computed tomography (CT) and high-resolution magnetic resonance imaging (MRI) revealed a tumor mass in the sigmoid colorectal region accompanied by perforation and multiple liver metastases. The patient was in bad condition (karnofsky performance status (KPS) = 70) and complained of moderate abdominal pain with weight loss. He has concomitant anemia (grade 1) and a history of tobacco use for 10 years; no history of alcohol or drug abuse; no family history of colorectal cancer, polyps, inflammatory bowel disease, or other malignancies. Later, the radical resection of rectal cancer (Dixon) was performed in laparoscopy with a simultaneous resection of liver metastasis. Pathological examination confirmed a poor differentiated tubular adenocarcinoma classified as stage IV based on the TNM staging of T4N0M1 (the American Joint Committee on Cancer (AJCC) staging manual, version 8). Immunohistochemistry testing performed on a tumor biopsy sample revealed a pMMR, a negative programmed death ligand-1 (PD-L1) result, combined positive score (CPS)<1, and a Ki67 proliferative index of 80-90%. Additionally, next generation sequencing (NGS) analysis was used to demonstrate that the tumor was KRAS/BRAF/NRAS wild type. After surgery, he was treated with six cycles of the adjuvant chemotherapy drug, XELOX . In March 2020, metastasis in multiple pelvic lymph nodes were diagnosed, including the mesenteric (18×18 mm) and anastomotic (19×13 mm) ones. Afterwards, a treatment with the chemotherapeutic drug, FOLFIRI (5-fluorouracil+irinotecan+leucovorin), in combination with cetuximab was performed for six cycles. In August of the same year, the patient showed lower abdomen pain and the CT exam revealed a further progression of the disease up to the enlargement of two other big lymph nodes . Consequently, the patient was treated with XELOX  combined with bevacizumab for 4 cycles. However, the patient’s lower abdominal pain persisted and the efficacy assessment test suggested a further progression in October 2020 Figure 2The standard application of RT was influenced by the recent therapeutic breakthroughs in the field of cancer immunotherapy , 8.To thDespite the abscopal effect is a rare phenomenon, it was found that RT combined with ICIs may improve the effectiveness of the antitumor immunity increasing the frequency of the abscopal effect, especially when RT is followed by ICIs treatment after a week . HoweverIn this case, the lesion outside the radiotherapy area (non-radiotherapy mesenteric lymph nodes) is we want to emphasize, where the abscopal effect might occur. Meanwhile, its pathological type (pMMR) is primary resistant to PD-1 antibody, so PD-1 antibody alone will not have effect. However, when the anti-PD-1 antibody was later used as a systemic treatment, not only the lesions in the radiotherapy area, but also the lesions outside the radiotherapy area (the mesenteric lymph nodes) were significantly subsided. For the lesions in the radiotherapy area, its regression can be interpreted as a synergism of direct killing effect of radiotherapy and immune enhancement effect of pd-1 antibody. However, for the lesions outside the radiotherapy area (non-radiotherapy mesenteric lymph nodes), its regression may be caused by the abscopal effect promoted by PD-1 antibody. According to the immunological mechanism, radiation acts on tumor cells in the radiotherapy field, inducing tumor cell death and tumor associated antigen release. These tumor-related antigens activate cytotoxic T cells that target tumor cells through the mediation and presentation of dendritic cells. Then, the subsequent application of PD-1 antibody can relieve the immune tolerance of tumor cells to T cells and promote the anti-tumor effect of T cells.In conclusion, we presented a case of pMMR mCRC with long-term clinical benefits deriving from the use of new approaches based on a simultaneous use of immunotherapy and RT, which induced the abscopal effect. We conclude that the understanding of the potential benefits of combined therapies is essential to design optimized treatment strategies targeting severe cancers, like pMMR mCRC.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.WZ developed the study design. PZ, YW, and YH contributed to Patient management and follow-up. YY, LZ, and QZ performed analyze. All authors contributed to the article and approved the submitted version.


To better understand how the COVID-19 pandemic impacted end-of-life care in patients with advanced cancer at a comprehensive cancer center, we compared in-hospital deaths from April through July 2019 with those from April through July 2020. After the onset of the pandemic, do-not-resuscitate orders occurred earlier, palliative care referrals occurred earlier, fewer deaths occurred in the Intensive Care Unit, and more deaths occurred in the Palliative Care Unit. These outcomes suggest an improvement in the quality of end-of-life care in response to the COVID-19 pandemic. These encouraging findings may have future implications for maintaining quality end-of-life care post-pandemic.p = 0.028), and palliative care referrals also occurred earlier . During the pandemic, 36% of inpatient deaths occurred in the Intensive Care Unit (ICU) and 36% in the Palliative Care Unit, compared to 48 and 29%, respectively, before the pandemic (p = 0.001). Earlier DNR orders, earlier palliative care referrals, and fewer ICU deaths suggest an improvement in the quality of end-of-life care in response to the COVID-19 pandemic. These encouraging findings may have future implications for maintaining quality end-of-life care post-pandemic.To evaluate how the COVID-19 pandemic impacted the quality of end-of-life care for patients with advanced cancer, we compared a random sample of 250 inpatient deaths from 1 April 2019, to 31 July 2019, with 250 consecutive inpatient deaths from 1 April 2020, to 31 July 2020, at a comprehensive cancer center. Sociodemographic and clinical characteristics, the timing of palliative care referral, timing of do-not-resuscitate (DNR) orders, location of death, and pre-admission out-of-hospital DNR documentation were included. During the COVID-19 pandemic, DNR orders occurred earlier (2.9 vs. 1.7 days before death,  The beginning of the novel coronavirus disease 2019 (COVID-19) pandemic challenged healthcare systems throughout the world to think critically about potential medical and ethical dilemmas, such as how to ration care in a resource-limited environment. Due to the high mortality associated with COVID-19, the involvement of palliative care and advance care planning discussions, such as those including values and preferences regarding cardiopulmonary resuscitation, became increasingly important at the onset of the pandemic. There were appropriate concerns that non-beneficial or unwanted cardiopulmonary resuscitation had the potential to place additional strain on essential healthcare workers, exhaust limited supplies of personal protective equipment, and increase the risk of psychological distress on patients and families . p = 0.041]. There was a significant difference in the location of death (p = 0.001), with 12% fewer deaths occurring in the ICU and 7% more deaths occurring in the palliative care unit after the onset of the COVID-19 pandemic. The overall length of stay showed a non-significant increasing trend after the onset of the COVID-19 pandemic .The clinical outcomes are summarized in This study provides a unique examination of how the delivery of end-of-life care at a comprehensive cancer center has evolved in response to the COVID-19 pandemic. We report here several interesting observations related to the terminal admission of patients with advanced cancer after the onset of the COVID-19 pandemic, including earlier DNR orders, earlier referrals to palliative care, and fewer ICU deaths. These important findings indicate an improvement in the quality of end-of-life care.Our finding that DNR orders for patients with advanced cancer occurred significantly earlier after the onset of the COVID-19 pandemic is especially encouraging as it highlights a positive shift in timely and intentional conversations between clinicians and patients, promoting optimal patient autonomy in end-of-life decision-making while capacity is more likely to be intact. As described in other studies, unfortunately, discussions around advance care planning and DNR orders frequently occur very late, within hours to days of death, for many different reasons ,24,25,26This study provides evidence that DNR orders occurred earlier after the onset of the COVID-19 pandemic; however, we did not find a concomitant increase in the overall frequency of DNR orders. This is likely due to a ceiling effect as most decedents (at least 90%) both before and after the onset of the COVID-19 pandemic had a DNR order. A substantially larger sample size would have been required to detect a difference. The high frequency of DNR orders prior to death is consistent with existing studies that have analyzed DNR trends in patients with advanced cancer . We alsoWe identified that palliative care referrals occurred significantly earlier in the terminal admission after the onset of the COVID-19 pandemic. This is an important finding considering that patients with advanced cancer generally receive very late palliative care referrals (often within days of death) and exhibit a significant level of physical and emotional suffering upon presentation ,18,19,20We report several findings related to operational changes unique to tertiary care comprehensive cancer centers that were implemented in anticipation of the potential surge at the beginning of the COVID-19 pandemic. Due to the nature of the specialized care provided at our cancer center, the characteristics of our patient population likely differ from those in the community setting. For example, the dramatic decline (10%) in inpatient deaths in patients with leukemia after the onset of the COVID-19 pandemic can be attributed to the suspension of interhospital transfers for select patients seeking specialized care. While most patients diagnosed with solid tumors are initially seen in consultation as an outpatient and generally considered for admission in the case of decompensation, many patients with hematologic malignancies initially present as an inpatient or require transfer to tertiary care centers for a higher level of care. Additionally, we observed a non-significant increase in length of stay after the onset of the COVID-19 pandemic, which may be attributed to an increase in patients with a need for ventilatory support as well as challenges in discharging patients to long-term acute care centers, skilled nursing facilities, or inpatient hospice units due to more restrictive acceptance criteria. More research is needed to further explain these results.This study has several limitations. First, this study was conducted at a single tertiary care institution. This may limit the generalizability of our study as the patient demographics seeking care at our cancer center likely differ from those in the community. Only 5% of deaths occurred in our separate and dedicated COVID-19 unit that was designated for all patients who tested positive for COVID-19. Our comprehensive cancer center includes a palliative care unit that is staffed by a well-established and continually growing interdisciplinary palliative care team . As mentDuring the COVID-19 pandemic, we observed significantly earlier referrals to palliative care, earlier DNR orders and fewer ICU deaths in patients with advanced cancer at our comprehensive cancer center. These findings indicate an improvement in the quality of end-of-life care and may have future implications for the timely integration of palliative care. Further research is needed to understand how to maintain and expand on such progress as healthcare systems transition toward an endemic model of care.