Healthcare providers working for cardiovascular intensive care often face challenges and they play an essential role in palliative care and end-of-life care because of the high mortality rates in the cardiac intensive care unit. Unfortunately, there are several barriers to integrating palliative care, cardiovascular care, and intensive care. The main reasons are as follows: cardiovascular disease-specific trajectories differ from cancer, there is uncertainty associated with treatments and diagnoses, aggressive treatments are necessary for symptom relief, and there is ethical dilemma regarding withholding and withdrawal of life-sustaining therapy. Quality indicators that can iterate the minimum requirements of each medical discipline could be used to overcome these barriers and effectively practice palliative care in cardiovascular intensive care. Unfortunately, there are no specific quality indicators for palliative care in cardiovascular intensive care. A few indicators and their domains are useful for understanding current palliative care in cardiovascular intensive care. Among them, several domains, such as symptom palliation, patient- and family-centered decision-making, continuity of care, and support for health care providers that are particularly important in cardiovascular intensive care.Historically, the motivation for using quality indicators is to summarize mechanisms for external accountability and verification, and formative mechanisms for quality improvement. Practically, when using quality indicators, it is necessary to check structural indicators in each healthcare service line, screen palliative care at the first visit, and integrate palliative care teams with other professionals. Finally, we would like to state that quality indicators in cardiovascular intensive care could be useful as an educational tool for practicing palliative care, understanding the minimum requirements, and as a basic structure for future discussions.The online version contains supplementary material available at 10.1186/s40560-022-00607-6. Cardiovascular disease is one of the major causes of deaths worldwide. In the past several decades, in addition to the progress of surgical procedures and less-invasive devices, the birth of cardiac intensive care units (CICUs) has contributed to the outcome improvement in cardiovascular disease patients . The rolSeveral barriers to the integration of palliative care and critical care have long been discussed and guidelines for cardiovascular palliative care have been recently published –12. HoweThe term “palliative care” is popular; however, what “palliative care” indicates is vague . PalliatPalliative care has been developed mainly in the field of cancer patients and its coverage has expanded to many non-cancer patients . In addiConsidering these difficulties of palliative care for cardiovascular disease, the detailed components of palliative care might need to be clarified for many clinicians to implement it in cardiovascular intensive care effectively. Although some guidelines or statements described components of palliative care narratively, iterations or checklists would be better implemented , 28. QuaThere are only a limited number of studies on quality indicators for palliative care in intensive care units (not limited to cardiovascular disease). Clarke et al. summarized 53 quality indicators and seven domains: (1) patient- and family-centered decision-making, (2) communication, (3) continuity of care, (4) emotional and practical support, (5) symptom management and comfort care, (6) spiritual support, and (7) emotional and organizational support for intensive care unit clinicians . These sStudies on quality indicators of palliative care for cardiovascular intensive care are scarce. We performed an updated and a structured PubMed literature review on quality indicators for palliative care in cardiovascular disease patients, with only two articles related to cardiovascular intensive care (Additional file Symptom palliation and support decision-making processes are two major domains of quality indicators of palliative care in cardiovascular intensive care and reflect structural and process indicators in the SPO framework Fig. . The symThe support decision-making process is imperative for current palliative care in cardiovascular intensive care. As described above, decision-making in cardiovascular intensive care is more complex and time limited compared to other healthcare settings. There are two important essences of supporting the decision-making process . First, Finally, as described above, many patients and families frequently do not have any experiences about advance care planning, lack medical background knowledge, and are under time-restricted situation in intensive care unit. To support this, several decision aids and programs support surrogate decision maker have been developed –59. As tTheoretically, there are two major motivations for using quality indicators. The first is for a quality assurance system as a summative mechanism for external accountability and verification . Pay forConsidering these usage limitations in palliative care quality indicators for quality assurance, some other insights are needed to use quality indicators Fig. . First, Finally, we should acknowledge that there are several limitations in the use of quality indicators and speculations on how to use indicators effectively. As described above, quality indicators of palliative care in cardiovascular intensive care have not been fully evaluated and have not been validated with patient outcomes. The domain and subcategories could also be just hypothetical contrasts, and we could not deny arbitrariness. The following strategies could be realistically implemented to use quality indicators of palliative care for cardiovascular intensive care from a clinical perspective. First, we should check the structure indicators, including workflow, policy, and resources about palliative care in each healthcare service line, such as hospitals and departments. Second, palliative care needs and symptoms should be screened at the first encounter and then repeatedly. Finally, we should integrate multidisciplinary palliative care teams and other specialists when necessary, mainly reflected by process indicators.Although there are limited numbers and limited usage of quality indicators of palliative care for cardiovascular intensive care compared with other fields, quality indicators could be used as educational tools to implement palliative care and the fundamental structure for future discussion. To implement palliative care for cardiovascular intensive care, we should learn several basic concepts of palliative care through quality indicators and monitor indicators to see, where we stand now. With the increasing demand for palliative care for every patient, further high-quality evidence and valid quality indicators are warranted.Additional file 1. Initial search for quality indicators of palliative care in heart disease.Additional file 2: Table S1. Comparison of quality indicators for palliative care.


IPV is a significant concern among active duty (AD) military personnel or veterans, and there is a need for initiatives to address violence perpetrated by such personnel, and IPV victimisation in military and veteran-specific contexts. The aim of this paper was to provide an overview of major IPV intervention approaches and evidence in military and veteran-specific health services. A scoping review was conducted involving a systematic search of all available published studies describing IPV interventions in military and veteran-specific health services. Findings were synthesised narratively, and in relation to a conceptual framework that distinguishes across prevention, response, and recovery-oriented strategies. The search identified 19 studies, all from the U.S., and only three comprised randomised trials. Initiatives addressed both IPV perpetration and victimisation, with varied interventions targeting the latter, including training programs, case identification and risk assessment strategies, and psychosocial interventions. Most initiatives were classified as responses to IPV, with one example of indicated prevention. The findings highlight an important role for specific health services in addressing IPV among AD personnel and veterans, and signal intervention components that should be considered. The limited amount of empirical evidence indicates that benefits of interventions remain unclear, and highlights the need for targeted research. Intimate partner violence (IPV) can describe any behaviour in a current or former intimate relationship that results in physical, psychological, or sexual harm . This maIPV is a significant concern among active duty (AD) military personnel or veterans, with available studies indicating high rates of violence perpetrated by current or former personnel , and alaThe high rates of IPV among AD personnel and veterans suggests a pressing need for initiatives to address violence in military and veteran-specific contexts. Relevant initiatives may include programs that focus on preventing violent behaviour, holding perpetrators accountable, and enhancing safety among victims, and have been considered mainly in civilian contexts. However, military occupational health models highlight important features of this employment context  which mean that civilian modes of intervention can have variable effects and benefit from adaptation to account for occupational and cultural considerations in military or veteran-specific environments . In thisA scoping review was conducted  involvinEligible studies comprised any design and described an intervention targeting IPV perpetrators or victims in military or veteran-specific health services; the latter defined by provision of specific care for physical or psychiatric issues of AD personnel or veterans. These could be from any country, and examples included Veteran Affairs (VA) Medical Centres in the United States, and Operational Stress Injury Clinics in Canada. Eligible studies included pilot studies or trials of interventions, and descriptive studies or evaluations of implementation processes.Intervention studies were included if they were delivered in specific health services, or if participants were recruited entirely or substantially from these settings. Eligible studies also reported on IPV identification strategies that were considered in such services, including self-report tools or clinician-administered measures. Given the heterogeneity of studies describing IPV measures among patients recruited from relevant services, the search was restricted to studies reporting data regarding utility, performance, or implementation of measures. This included studies addressing questions regarding acceptability, accuracy, and psychometric properties of measures, as well as implementation processes. Thus, the search excluded studies that only described results regarding prevalence or correlates of IPV. Additionally excluded were papers that did not present any empirical data from patients regarding relevant interventions, with the exception of protocol papers for ongoing trials.Data were charted regarding study characteristics including authors, year of publication, intervention type, target population, setting, and key findings. No appraisal of evidence quality was conducted, consistent with the scoping review methodology .A narrative synthesis of studies was also conducted, in accordance with a proposed conceptual framework for IPV interventions. This was based on the Institute of Medicine (IOM) continuum of services , but wasThe PRISMA flowchart is displayed in The search identified two studies describing one program that was classified as an indicated prevention strategy that comprised a group intervention for couples called the Strength at Home—Couples (SAH-C) program . Given tSAH-C comprises a 10 week trauma-informed group program that targets couples comprising veterans (who are men) and their partners that report relationship distress or psychological aggression, but no physical violence perpetration by men, and no ‘severe’ physical violence (that produced fear or injury) by women. SAH-C is based on a cognitive behavioural model which assumes that trauma can produce biases in social information processing that increases risk of violent behaviours. Modules focus on understanding impacts of trauma on relationships, conflict management, and communication skills training . n < 10 treatment completers) to two conditions (SAH-C versus Supportive Therapy) and provided descriptive data regarding veteran reports and partner reports of IPV across conditions. This pilot also required that personnel or veterans met criteria for PTSD, although this criterion was relaxed in the randomised trial. The latter involved random allocation of n = 69 couples to SAH-C versus Supportive Therapy, and post-treatment comparisons suggested small to moderate benefits of SAH-C in terms of reducing physical and psychological IPV [p < 0.05), and trends should be viewed as provisional given the small sample for a prevention trial, and thus low levels of statistical power.Published reports regarding SAH-C summarise findings from one pilot study  and one ical IPV  (see SupThe search identified four studies that addressed a related program classified as a response strategy for IPV perpetrators. The Strength at Home—Men program (SAH-M) for AD personnel or veterans was intended to end use of IPV in current relationships and prevent future violence, and was based on the same model underlying SAH-C ,15 that n < 10) and no control conditions. One pilot also reported findings from focus groups regarding acceptability [Published reports on SAH-M include two pilot studies ,31, one tability   session targeting physical violence, followed by 5 sessions of CBT . These aThe final intervention comprised a 13 week Batterer Intervention Program for male veterans that was administered through the VA Medical Centre Domestic Relations Clinic ,20. TherTwo studies described training for military health providers regarding IPV victimisation. The first comprised a training program for military dental practitioners termed PANDA  . The 1 hThere were five studies describing elements of case identification strategies in military and veteran-specific health services, encompassing tools and protocols for improving recognition of service users who have experienced IPV. Four studies described performance or implementation of brief IPV screening tools, including the 4-item Hurt-Insult-Threatens-Scream (HITS) ,24, and In the context of case identification, a 3-item version of the Danger Assessment scale has also been considered as a secondary IPV risk measure . This con = 20 women veterans, and n = 10 completed the IPV module [There were two studies describing psychosocial interventions in military and veteran-specific health services. The first comprised a modular computer-based intervention called Safe and Healthy Experiences (SHE) . SHE hasV module . The second program comprised a patient-centred and trauma-informed counselling intervention that was developed in veteran-specific health services called Recovering from IPV through Strength and Empowerment (RISE) . RISE isThis scoping review addressed IPV intervention approaches that have been considered in published studies of military and veteran-specific health services. This identified a predominant focus on response-oriented strategies for IPV, including significant examples of responses to both IPV perpetration and victimisation. However, the findings also highlight a broader range of initiatives addressing IPV victimisation, relative to perpetration, including training for health providers, case identification and risk assessment strategies, and select forms of psychosocial intervention. In contrast, there was a comparably narrow range of approaches to IPV perpetration, comprising group treatments and programs for men, with no comparable studies of training for service providers or case identification strategies. There was one example of an intervention for couples that reported relationship distress or psychological aggression, but no physical violence perpetrated by men, which by virtue of this focus on both partners was classified as an indicated prevention strategy. The review otherwise identified no interventions that reflected universal or selective prevention strategies, and no approaches were classified as promoting recovery from effects of IPV.The findings should be viewed in the context of few studies involving randomised designs, and thus limited evidence regarding benefits of interventions in relevant contexts. Accordingly, it cannot be assumed that approaches are associated with benefits that outweigh harms, and also justify costs, and these questions remain critical considerations. The findings should also be viewed in relation to the specific focus of the search, which targeted studies based in military and veteran-specific health services, and thus omitted evidence situated outside of such environments. For example, this would exclude the Family Advocacy Program in the U.S. ,35, whicNotwithstanding the narrow scope of the search, the absence of studies describing some intervention approaches, including varied responses to IPV perpetrators, and recovery-oriented interventions for victims, is likely to reflect meaningful gaps that suggest areas of need for investment and innovation. These may parallel areas identified in non-military settings, including via prior reviews that have acknowledged scant evidence for interventions targeting IPV perpetrators in health environments generally . ComprehThere were several other important trends that were discernible in eligible studies. While studies from any country were potentially eligible, the review indicated that all identified reports were situated in the U.S., and accordingly it highlights the absence of empirical attention to IPV interventions for AD personnel and veterans in other jurisdictions. Furthermore, there was a modest number of reports overall (k = 19), and these addressed different interventions using varied methodologies. Critically, there were only three interventions considered in randomised trials. Two were based on the SAH framework ,17, whicThe search considered studies situated in military or veteran-specific health services, generally involving service users in heterosexual relationships, and it did not identify intervention approaches or evidence considered outside of such contexts, and with heterogeneous populations. Second, the eligibility criteria were purposively broad and included diverse studies providing varying standards of evidence. Despite the broad criteria, as with all systematic searches, it is possible that studies were missed in the search. Furthermore, the review did not involve any risk of bias assessment, while the pool of eligible studies was small and identified few randomised trials. As such, the review should be viewed as indicating possible interventions that could have promise in military and veteran-specific services but require research to demonstrate that these produce beneficial effects. Finally, while the proposed framework provides a way of organising approaches to IPV that may have utility in military and veteran-specific health services, it remains likely that the model will not fully capture the heterogeneity and nuance of all possible interventions and may need to be elaborated in future research.IPV is a complex psychosocial problem, and it should be anticipated that meaningful reductions among AD personnel and veterans will require comprehensive strategies that involve prevention, response, and recovery-oriented interventions, along with cross-sector cooperation of military and veteran-specific agencies, and non-military organisations. The review focuses attention on military and veteran-specific health services, and thus highlights an important context for initiatives comprising responses to IPV. Such services may provide logical places to focus efforts within jurisdictions that are still at early stages of developing strategies for addressing IPV. Multiple interventions for IPV victimisation could be considered, including training programs for service providers on how to recognise and respond to victims, protocols for improving case identification and risk assessment, along with psychosocial support programs that provide referral targets for service users who disclose IPV. In addition, the review highlights the importance of interventions that support AD personnel and veterans who disclose IPV perpetration and wish to change their behaviour, along with the need for new resources that may include training for service providers on how to recognise and respond to IPV perpetration, as well as tailored case identification or risk assessment strategies. Although this review indicates that evidence underlying these approaches remains limited, the growing recognition of high rates of IPV among AD personnel and veterans, along with potentially lethal consequences for victims, strongly indicates that this should not preclude attempts to develop safe and sensible responses to IPV in these specific services.The limitations of available evidence signal ongoing needs for research to guide decisions about what works and how interventions can be improved in military and veteran-specific health services. This includes a specific need for intervention studies outside the U.S., and across jurisdictions including Canada, Australia, and the UK. These all have different systems for providing care for AD personnel and veterans, as well as family members, which may have implications for feasibility and effects of interventions. Second, there is also a need for studies to inform selection of interventions targeting IPV perpetration among AD personnel and veterans. These may include new and enhanced ways of supporting perpetrators to change their behaviour, evaluations of benefits of training programs for service providers, as well as studies of case identification strategies. Third, there is also a need for research on different components of intervention approaches for IPV victims. This includes sophisticated studies involving randomised designs that can demonstrate benefits of training programs  and casFinally, there is also a need for studies considering interventions comprising responses to IPV, as well as recovery-oriented interventions for victims. The former may include low-intensity counselling interventions delivered by military and veteran-specific health providers, or para-professionals, as well as intensive programs delivered by specialist ‘advocates’ embedded in relevant services, or within community-based agencies. The latter may include trauma-focused treatments  and oth


Primary Health Network (PHN) is the largest Federally Qualified Health Center (FQHC) in Pennsylvania expanding over 17 counties. Getting Pennsylvanians vaccinated is a critical step in reducing the spread and impact of COVID-19, although research suggests that the inequitable distribution of the COVID-19 vaccine may be a critical barrier. Although concerns regarding vaccine hesitancy are prevalent, experts also suggest that disparities in vaccination rates are in part due to the lack of accessible scheduling; adversely affecting underserved, such as rural communities, and minority populations. To address these obstacles, Primary Health Network is creating a COVID-19 Vaccination/Health Equity Team. Their objectives include: creating tools to provide comprehensive information on vaccine supply, identifying potential challenges and proactively planning for ways to mitigate likely disparities, identifying people who wish to be vaccinated but lack the means to do so, and connecting them in an equitable way, to vaccinations.


Dual-energy CT (DECT) has emerged into clinical routine as an imaging technique with unique postprocessing utilities that improve the evaluation of different body areas. The virtual non-calcium (VNCa) reconstruction algorithm has shown beneficial effects on the depiction of bone marrow pathologies such as bone marrow edema. Its main advantage is the ability to substantially increase the image contrast of structures that are usually covered with calcium mineral, such as calcified vessels or bone marrow, and to depict a large number of traumatic, inflammatory, infiltrative, and degenerative disorders affecting either the spine or the appendicular skeleton. Therefore, VNCa imaging represents another step forward for DECT to image conditions and disorders that usually require the use of more expensive and time-consuming techniques such as magnetic resonance imaging, positron emission tomography/CT, or bone scintigraphy. The aim of this review article is to explain the technical background of VNCa imaging, showcase its applicability in the different body regions, and provide an updated outlook on the clinical impact of this technique, which goes beyond the sole improvement in image quality. Virtual non-calcium (VNCa) computed tomography (CT) imaging provides new relevant clinical information compared to standard CT.VNCa improves CT sensitivity and specificity to assess bone marrow disorders.VNCa CT may serve as an alternative to magnetic resonance imaging in case of contraindications.Since the advent of dual-energy computed tomography CT (DECT), numerous and noteworthy advantages over conventional CT have been investigated such as image optimization, artifact reduction, and the ability to provide additional information regarding tissue composition –8.Among different DECT applications, virtual non-calcium (VNCa) has become an increasingly popular technique due to its ability to subtract calcium from anatomical structures, resulting in better assessment of numerous pathological conditions that might be masked on standard CT. Firstly introduced in 2009, VNCa has found its mainstream applications in removing calcified plaques from vessels and depicting cancellous bone and bone marrow changes .Bone marrow edema (BME) or “bone bruise,” is considered the biomarker of injury of the skeletal system and is associated with a reduction of fat component in the trabecular bone, replaced by edema and hemorrhage. Magnetic resonance imaging (MRI) represents the reference standard technique for the assessment of bone marrow disorders . DECT maA large body of evidence has shown the potential of DECT for collagen-based tendon and ligament imaging or to differentiate hyperdense lesions from calcium, such as urate crystals in patients with gout –20. In tThis article discusses and summarizes the current clinical applications of VNCa imaging including different DECT platforms, their basic principles of physics, and areas of potential development.While standard single-energy CT uses a single polychromatic x-ray beam with a single peak energy of 120 kV, DECT systems allow for simultaneous image acquisition at two different voltages.E), as well as on the atomic number (Z) of the element, and it is predominant at lower energies and near the element K-edge.At the energy levels used in clinical routine, attenuation of biological tissues is dependent on two major interactions: Compton scattering and photoelectric effects. Compton scattering is proportional to electron density and has little energy dependence. On the other hand, the photoelectric effect is dependent on the energy of the x-ray beam  may have the same attenuation as the higher concentration of a lower Z material . However, since materials have unique attenuation profiles at different energy levels, DECT aims to identify different elements exploiting mathematical algorithms based on their linear attenuation coefficients in order to achieve the so-called material decomposition [On single-energy CT platforms, the measurement of attenuation using a single x-ray spectrum does not allow for the differentiation of materials, because the attenuation coefficient is not unique. In particular, it depends either on the energy of the x-ray beam or on the concentration of a material. This means that at a given energy, a lower concentration of a higher position –23.ratio). Since DECT uses two different energies for measuring attenuation, DEratio is defined as the ratio of the attenuation of a given material on a low-kV dataset to the attenuation of the same material on a high-kV dataset. The energy-dependent attenuation differences of elements within a voxel allow DECT to exploit two- and three-material decomposition. The ability to differentiate the DEratio of two materials also depends on the separation between low- and high-energy spectra and the Z of the evaluated materials.DECT’s ability to discriminate between different materials is highly proportional to the dual-energy ratio . At tube voltages used in clinical routine, it is possible to generate virtual unenhanced images by subtraction of iodine from contrast-enhanced DECT examinations or VNCa series by subtraction of calcium [However, DECT algorithms work better when materials have high atomic numbers, because these are characterized by large differences in attenuation at different photon energies  platforms, consisting of two x-ray tubes that generate two beams at different voltages installed at about 90° from each other, which have the advantage of high temporal resolution; although two x-ray sources are involved, the radiation dose administered to the patient is usually divided between the two, resulting in dose neutrality of second- and third-generation DSCT scanners compared with conventional CT [ional CT , 26;Single-source with sequential acquisition CT platforms, which consist of two scans acquired consecutively at different tube potentials followed by co-registration for post-processing, offering the advantage of a full field of view and the drawback of poor temporal resolution as the patient is scanned twice, with an increase of radiation dose;Single-source twin-beam platforms, in which a two-material filter splits the x-ray beam into high- and low-energy spectra on the z-axis before it reaches the patient;Single-source tube voltage switching CT platforms, in which the x-ray tube alternates high and low potentials several times within the same rotation, which have the advantage of a full field of view;Dual-layer detector CT platforms, which involve a superficial and a deep layer within the same detector plate that simultaneously collect low-energy data by the superficial layer, and high-energy data by the deep layer.Different vendors offer diverse DECT technologies:However, most of the current experience with VNCa algorithms published in scientific literature has been performed on second- and third-generation DSCT platforms Tables , and 4, Due to three-material decomposition, the VNCa algorithm estimates the amount of calcium on the DECT dataset and subtracts it from images to highlight the anatomical structures that can be covered with bone mineral or gross calcifications.ratio of calcium, bone mineral voxels are projected to the CT value of water (0 HU for both 100 kV and Sn140 kV) [On VNCa imaging, the bone marrow attenuation represents CT values of yellow and red marrow. In particular, using the characteristic slope of the DEn140 kV) , 28. As n140 kV) , 29–31.However, most of the cutoff values that have been suggested to differentiate BME from normal bone marrow are still quite heterogeneous, and range between -80 and 6 HU. These differences might depend either on the anatomical region evaluated or on the type of DECT platform used.ratio of 70/150 kV. However, when a wide DEratio may not be recommended because of the increase in image noise, such as scanning the abdomen and pelvis, higher radiation doses help provide optimal image quality [Image quality on VNCa datasets is also influenced by DECT scanning parameters. The use of higher spectral separation allows for a precise assessment of bone mineral content . Best re quality . Pitch aColor-coded VNCa datasets are usually automatically processed from raw data of most modern DECT platforms, with processing time lasting few minutes, and showing the potential to be used in routine clinical practice , 34. SliTechnical limitations of VNCa imaging should also be taken into account. In fact, it has been demonstrated the inability to accurately visualize minor alterations in marrow attenuation directly adjacent to cortical bone due to incomplete masking of the cortex and to spatial averaging. Incomplete subtraction of cortical or cancellous bone might also occur in the case of arthrosis, and in the presence of gas or severe osteosclerosis, which causes beam hardening artifacts that may result in a lack of visible edema even in the presence of a fracture. For this reason, any potential user of VNCa imaging should be aware of its potential pitfalls , 37.i.e., meningiomas, dermoids, craniopharyngiomas, and oligodendrogliomas) [Intracranial calcifications are common findings on head CT scans . They argliomas) .In an emergency setting, any focal source of intracranial hyperattenuation might confound diagnosis, especially if intracranial hemorrhage needs to be excluded. In a conventional CT scan of the head, any lesion with attenuation levels greater than 100 HU is classified as a calcification . HoweverCurrently, the proposed imaging techniques for differentiating hemorrhage from calcification include MRI-based techniques such as quantitative susceptibility mapping and gradient-echo imaging .VNCa has been shown to accurately differentiate between calcification and hemorrhage, even in lesions with attenuation comprised between 50 and 100 HU , using bone scintigraphy as a reference standard. In case of suspected or subtle fractures, MRI is considered the best advanced imaging option after conventional radiography, as it finely depicts bone marrow and adjacent soft tissues. On the other hand, MRI alone may not depict fracture lines in case of intense BME, and conventional radiographs or CT may be needed for diagnosis [A recent meta-analysis  comparediagnosis . Additioiagnosis , 78. Howiagnosis .An increasing number of studies have shown the feasibility of DECT to detect traumatic BME in small bones of appendicular skeleton exploiting VNCa imaging Table , with imDECT can complement the information provided by standard CT imaging and enhance the diagnostic capabilities of VNCa for the evaluation of acute knee fractures Fig. . In a stSeveral authors have investigated the performance of VNCa reconstructions to detect traumatic BME in small bones of distal joints, such as the scaphoid , 84–88. VNCa imaging performs well on small bones also to depict inflammatory BME, related to rheumatoid arthritis, in either large or small joints Fig. , showingSufficient removal of calcified plaques from vessels represents a current challenge for CT angiography (CTA) studies. Calcified plaques commonly cause overestimation of vascular stenosis assessment, especially in small vessels, and may lead to unnecessary invasive procedures .Usually, a fixed HU value is used as a threshold to remove calcifications in conventional CTA, despite this method often failing due to calcium blooming. Alternatively, unenhanced CT acquisition can serve as a mask for subtraction of calcified plaques. However, misregistration artifacts may occur due to patient’s movements or arterial pulsations between the two scans , 91. DECIn this context, VNCa imaging has been shown to improve the quantification of carotid artery stenoses caused by hard plaques compared to conventional CTA, using digital subtraction angiography as reference . MoreoveEnergy-integrating detectors used in modern DECT platforms are based on an indirect process of x-ray conversion into an electrical signal, which passes by photodiodes and conversion into light photons . On the However, we are still at the doorstep of this new era of CT technology and further investigation needs to be performed prior to introduction of photon-counting detector CT platforms into clinical routine.In the last ten years, DECT-based VNCa imaging has been shown to provide additional clinically relevant information compared to standard CT in several neuroradiology, vascular, and musculoskeletal applications. The greatest experience in using VNCa reconstructions exists in bone marrow imaging to date, particularly for trauma, but also for inflammatory and oncologic bone marrow pathologies. Several studies have demonstrated its potential also for the differentiation of hyperdense lesions as well as for intervertebral disc assessment. In addition, inflammatory or infiltrative bone marrow disorders that are conventionally assessed by means of MRI or bone scintigraphy can be assessed in more detail with DECT in comparison to standard CT. Subjective as well as objective analysis of VNCa images has shown high diagnostic accuracy and demonstrated its potential to serve as a viable imaging alternative to MRI, bone scintigraphy, or PET/CT in case of contraindications or limited availability. Especially in emergency/trauma settings, patients can substantially benefit from this technique due to time savings, early accurate diagnosis, and prompt therapy initiation. However, despite multiple studies having shown the potential of DECT-based VNCa imaging, this technique still has not gained ground in clinical routine, probably because of its limited availability considering that most of available studies have been performed on second- and third-generation DSCT platforms. This might have limited inter-vendor correlation studies and hampered the integration of VNCa imaging into clinical routine.It is crucial to be aware of VNCa technical limitations and differences related to acquisition protocols and reconstruction software, which may differ across vendors, and generate different cutoff values for quantitative assessment. Further investigation of VNCa imaging algorithms is needed to gain a more comprehensive understanding of its potential.


The close interplay between systemic autoimmune diseases and reproductive health has long been known: gestations in women with rheumatic disease are at higher risk of maternal and fetal complications. In addition, the physiologic hormonal changes that characterize the different phases of pregnancy modulate disease activity, in some diseases exacerbating the disease activity, while in others improving the disease severity. The impact of disease activity on reproductive issues in rheumatology is crucial: in many different conditions, disease activity before and during pregnancy is the main predictor of gestational outcome. This observation implies the compelling relevance of tight disease control throughout gestational course, which in turn translates into the necessity to ameliorate the pharmacological approach to rheumatic pregnant patients.Bongenaar et al. investigated the potential role in RA-associated female subfertility of interleukin (IL)-6 and tumour necrosis factor (TNF)-α, two pro-inflammatory mediators exerting a key pathogenic role. In a cohort of 61 RA women seeking a pregnancy, preconceptional IL-6 but not TNF-α levels predicted prolonged time to pregnancy, an association that held significance even after correction for confounders as disease activity.If the impact of rheumatologic conditions on pregnancy progression had been ascertained in the early days, the scientific community could not yet reach a unanimous consensus whether rheumatic conditions can affect female fertility. As a matter of fact, women with rheumatoid arthritis (RA), the most common rheumatologic inflammatory disease, take a longer time to conceive and have decreased family size compared to healthy controls. Again, active disease is the main determinant of these difficulties in achieving conception, but the exact mechanisms underlying such subfertility are still uncharacterized. Larosa et al., SLE disease activity score (SLE-DAS), a score composed by 17 items that has been recently proposed in SLE .The pivotal importance of optimal disease control reflects on the requirement of valid tools to evaluate disease activity even during pregnancy. Unfortunately, the reliability of conventional measures of disease activity in pregnant women is to be assessed: gestation may induce symptoms evaluated by these instruments and the physiological changes that occur in pregnancy may affect laboratory parameters used to assess disease activity, such as serum complement levels and C reactive protein . Accordid in SLE , is a reMarzano et al. The pharmacological approach to pregnant women with pemphigus and pemphigoid gestationis is challenging, and the therapeutic armamentarium includes systemic and topical corticosteroids, topical calcineurin inhibitors, dapsone, intravenous immunoglobulins, plasmapheresis/plasma exchange and biological agents.Similarly to SLE, autoimmune bullous diseases can manifest or exacerbate during pregnancy, as elegantly reviewed by the group of Beltagy et al., inhibitors of TNF-α  are considered safe during gestational course. Carnovale et al. focused on agents targeting IL-1, together with colchicine, estimating maternal and fetal adverse events in a nested case-control study on data from the United States Food and Drug Administration Adverse Event Reporting System database. Reassuringly, the rates of pregnancy loss, fetal disorders, congenital defects, neonatal adverse events and delivery complications were not increased in women receiving inflammasome-targeted therapy .The introduction of biologics has revolutionized the management of rheumatic diseases over the last decades; moreover, insights are being progressively gained on their use in pregnant women. Given their immunoglobulinic structure, biologics can cross the placenta from the 17th gestational week, when the Fc receptor becomes expressed. As outlined by Giani et al.). Three out of the four children had positive anti-ß2GPI and aCL IgG, which disappeared within 2 years of life and could be due to transplacental autoantibody transfer. One baby presented anti-ß2GPI IgM, while her mother tested negative for all aPL subtypes suggesting neonatal de novo production of aPL. The exact pathogenetic role of transmitted or de novo aPL in neonatal ischemic stroke is still unclear and may be linked with other genetic and acquired thrombophilic factors. Surely pharmacological treatment of rheumatic conditions in pregnant women allows a tighter disease control and, in turn, better obstetric and fetal outcomes. However, concerns have arisen about the potential long-term effects of in utero exposure to anti-rheumatic medications. A multi-disciplinary team of rheumatologists and child neuropsychiatrists investigated the impact of treatment during gestation in 18 school-age children born to 16 women with inflammatory arthritis. Neurodevelopmental issues were found to be more frequent in the offspring of patients with longer disease duration and those who were breastfed for less than 6 months . Lazzaroni et al. focused on the neuropsychiatric impact of exposure to azathioprine during fetal life in children born to women with SLE. In this prospective study, offspring of lupus patients had a similar neuropsychiatric outcome compared to the general pediatric population, and no difference emerged stratifying upon in utero exposure to azathioprine .In women with rheumatic diseases, the above-cited Fc receptor mediates even the active transportation of maternal autoantibodies, some of which can induce a passively acquired autoimmune disease. This is the case of neonatal anti-phospholipid syndrome, an exceedingly rare condition in newborns. Paediatric rheumatologists describe four cases of stroke in neonates born to women with anti-phospholipid antibodies . Interestingly, not only gut microbiome undergoes several modifications during pregnancy and lactation, but also several pharmacological compounds commonly used in the treatment of inflammatory arthritis affect gut microbiome. Thus, as proposed by a Chinese group, the modulation of gut microbiome might affect disease activity in pregnant women with RA: prebiotics and probiotics, antibiotics, fecal microbiota transplantation and dietotherapy are among the potential strategies .These data are reassuring, further supporting the importance of appropriate prescription of available anti-rheumatic drugs to obtain disease control in pregnant patients. However, research efforts are still pursued to identify novel pharmacological targets. As a whole, the manuscripts enclosed in the present research topic clearly highlight how rapidly the field is emerging: the times in which women with rheumatic diseases were discouraged from embarking in a pregnancy are luckily far away. Nevertheless, despite the much recent advancement, there are still many issues that should be unraveled to further improve the clinical management and the therapeutic approach to mothers-to-be as well as new mothers with rheumatologic conditions and their offspring.


With rapid advances in modern imaging, minimally invasive ablative procedures have emerged as popular alternatives to surgical removal of tumors. Tumor ablation modalities currently offered in clinical practice include microwave ablation, radiofrequency ablation, cryoablation, high-intensity focused ultrasound, and irreversible electroporation. Cryoablation, a non-heat-based method of ablation, is increasingly being used for treating various solid tumors. Accumulated comparative data of cryoablation versus heat-based ablation techniques  shows superior tumor response and quicker recovery time. Evolving research has demonstrated that nanocarriers may serves as excellent catalysts for the cryoablation therapy, imaging guidance, and the co-delivery of therapeutics for minimally invasive, precise, and complete treatment of cancer with immune modulation. This review article focuses on the current status of cryoablation in clinical practice, considers opportunities for enhancing therapeutic outcomes from cryoablation, and discusses new research in the field, including theranostic nanoparticles-mediated cryotherapy and combinational cryo-based immunotherapies. Since the rapid advancement of ablation-based technology in the 1990s, energy-based ablation has been used for the treatment of many tumor types, including liver, kidney, lung, breast, and prostate cancers, and soft tissue sarcomas. Being minimally invasive, they are now primarily used for the treatment of small, unresectable tumors or for patients who are poor surgical candidates. Cryoablation has distinct advantages over other modes of ablation  in that it can be monitored with imaging during the procedure, have greater control of the shape of the ablation zone, and mitigate pain. Among cancer therapies, cryoablation is well-positioned for precision image-guided surgery, which has shown to reduce complications, costs, and recovery time th century Although the application of cold temperatures to treat fractures and wounds have been traced back to 3000 B.C., the first application of cryotherapy in tumor was carried out by Dr. James Arnott in the mid-19Figure 1) Cellular death by cryoablation is accomplished through multiple mechanisms, including physical damage of cellular membrane by ice formation, initiation of cellular stress responses (kill switch activation) and necrosis and apoptosis cascade, vascular stasis during thawing process, and likely activation of immune responses  on the temperature distribution during cryosurgery have shown that the convective heat transfer from bifurcated vessels can limit ice ball formation, cause irregular ice ball shape near the arterial bifurcation and prevent the blood vessels from being frozen Table 1 and discussed below in detail.Cryoablation is currently used to treat benign and malignant tumors of the liver, prostate, kidney, lung, breast, and bone, as well as non-tumor diseases relating to the heart. Advantages and disadvantages of cryoablation in three major organs, liver, prostate, and kidneys, are included in 2; p = 0.003) In certain carcinomas such as liver 1b renal cell carcinomas showed a 2.5-fold increase in 5-year cancer specific mortality  when cryoablation was performed compared to partial nephrectomy 1b renal cell carcinoma patients who underwent partial nephrectomy also had a lower rate of local cancer recurrence than patients with cryoablation (laparoscopic or percutaneous) 1b renal cell carcinomas caused frequent complications (grade II or worse) Renal cryoablation is a minimally invasive alternative to surgery for poor operative candidates or those with multiple renal tumors, with comparable efficacy to nephrectomy Cryoablation of the prostate, although still investigational, has recently emerged as a focal tool for the treatment of localized prostate cancer. Compared with conventional surgical removal, cryoablation allows for decreased hospitalization time, reduced postoperative morbidity, decreased interval for return to daily activities, and reduced overall treatment cost Various skin lesions, including non-melanoma basal and squamous cell carcinomas and Kaposi sarcoma have been routinely treated with cryotherapy. Direct application of liquid nitrogen to the site using cotton tips or spray is used most often to treat superficial masses on the surface of the skin. A large-scale study with 2932 patients afflicted by basal or squamous cell carcinomas less than 2 cm in size saw a 98.6% cure rate over a 30-year period with only 5 cases of recurrence Cryoablation has been increasingly used to treat breast cancer over the last two decades, ranging from early to late stage disease. Preference for a good cosmetic outcome has led to breast-conserving, minimally invasive procedures such as radiotherapy and ablation therapies in lieu of surgery. Multiple cases have demonstrated the safety and effectiveness of cryoablation for singular, small-sized tumors Figure ). Drug or radiation-induced DNA damage can induce stromal secretion of factors that promote survival, proliferation, resistance, invasion, and metastasis of cancer cells. It can also cause non-activated CAFs to convert to a CAF-like phenotype. In addition, the stromal ECM or fibroblasts can modulate the immune cell population in the tumor microenvironment by preventing the infiltration of effector cells and expressing PD-L1 Figure ). In addition, the hypoxic tumor microenvironment can lower the efficacy of radiotherapy or chemotherapy and contribute to the development of resistance. However, low pH or oxygen environment sensitizes tumor and endothelial cells to freezing Figure ). Clinical benefits of those cryo-based combination therapies are highlighted in Table 2.Refinements in technology and procedural techniques optimizes the capacity of cryoablation in treating small-sized tumors. However, it is often not sufficient to completely eradicate larger tumors. Combining cryoablation with other cancer therapies may create a synergistic anticancer effect greater than either monotherapy alone. Cryoablation, for instance, can target cancer stem-like cells and create an unfavorable environment for tumor regrowth and vascularization. In the more distal zones of cryoablation, hypoxia and ATP deprivation can promote local acidosis and death of cancer-associated fibroblasts, stifling the exchange of essential growth factors for tumor proliferation and revascularization Since Jerrel W. Benson reported the pilot work of the combination therapy of cryoablation and chemotherapy for treating advanced oral carcinomas in 1975 Conventional systemic chemotherapy is similarly able to improve therapeutical efficacy when combined with cryoablation. Using a xenogenic mouse model, Le Pivert et al. were able to enhance growth inhibition of human prostrate tumors with the addition of 5-fluorouracil to cryoablation. The combination therapy overcame one of the limitations of cryoablation monotherapy - low efficacy due to partial freezing of tissue, usually occurring at the edge of the ice ball generated during cryoablation Radiotherapy causes irreversible damage to the DNA of tumor cells in the irradiation field and promotes the release of tumor-related antigens, increases the production of cytokines, alters the tumor microenvironment, and activates the body's immune system to initiate an anti-tumor immune response. Further, ionizing radiation can penetrate deeply into the body and provide a complete, uniform eradication of tumor mass. Hence, by combining radiotherapy with cryoablation, the general disadvantage of ablative therapies in producing heterogeneous tumor destruction can be addressed. Radiotherapy can be categorized into two types: external or internal radiation. Typically, the external radiotherapy involves a beam of ionizing radiation delivered from outside the body to a localized area around the tumor for destruction. Five cases of advanced-stage hepatic malignancies treated from 2017-2018 indicated that cryoablation combined with external intensity-modulated radiotherapy can be implemented safely. No complications above grade II occurred in the five patients, and their quality of life was significantly improved. Four patients experienced no disease progression and longer survival, with three of them still alive at the time of the study Aside from direct first-line therapies, cryoablation is also used as a second-line therapy after radiotherapy to treat the tumor recurrence. Biochemical recurrence (rise in prostate-specific antigen level in blood) of prostate cancer after a form of radiotherapy occurs in approximately 26%-52% of patients. In cases of tumor recurrence following the biochemical failure, cryoablation may be applied to patients as a second-line, salvage therapy Although cryoablation is usually a preferred option in patients with unresectable cancer, it can be combined with surgery in certain cases where there is a need to achieve a complete response. In a pilot experiment, twenty participants with breast cancer (<15 mm) underwent ultrasound-guided cryoablation before subsequent surgical resection. Here, cryoablation was used to combine with traditional surgical excision to assess the diagnosis effectiveness of contrast-enhanced MRI and improve therapy outcome by eradicating residual cancer post cryoablation Transcatheter arterial chemoembolization (TACE), local treatment of HCC, is considered to have fewer side effects compared with systemic chemotherapy + T cells and decrease in CD4+ T cells near cryo-ablated tissues compared to non-ablated tissues + and CD4+/CD8+ T cells It is conjectured that cryoablation itself elicits immune response. Cryoablation-mediated necrosis results in immune response via recognition of the released intracellular contents by activated T cells. This immune response is not shown in apoptotic cell death, which resolves into smaller apoptotic bodies without breaking the cell membrane and thus exposing the signaling molecules that involve immune response Figure 3) reg). Normally, T cell activation requires costimulatory signals from antigen presenting cells (APCs) aside from antigen-specific T cell receptor engagement. CTLA-4 on effector T cells binds to CD80/86 on APCs, suppressing T cell activation and causing clonal anergy. Further, CTLA-4 is constitutively expressed on Treg cells (unlike effector T cells) and aid in immunosuppressive functions of Treg cells on dendritic cells. CTLA-4 blockers prevent these inhibitions and allow cytotoxic T cells to kill cancer cells. Despite early clinical success in ICIs, they alone are often not enough to sufficiently clear cancer cells. Recent studies have explored ICI treatments combined with other forms of cancer therapy including ablative options. Clinical work by Zhu et al. showed a significant reduction of metastatic lesions in patients with cervical carcinosarcoma when treated with a PD-1 blocker, pembrolizumab, following cryoablation To enhance the innate immunogenicity of the cryoablation, several immunotherapies involving adoptive cell transfer, immune checkpoint inhibitors, and immunostimulants can be combined synergistically with the ablative therapy Figure  3, 118. Next to T and B lymphocytes, natural killer (NK) cells are important components of the innate immune system and play a critical role in the early host defense against cancer. With progress in the NK cell biology field and in understanding NK function, adoptive NK cell transfer has developed to be a powerful cancer immunotherapy tool in various cancers treatment In situ administration of CpG-ODN 12 h after DC injection might be considered the optimum application Aside from immune checkpoint inhibitors, there are other class of immunostimulants that can activate the immune system. Certain immunostimulants bind to pattern recognition receptors such as toll-like receptors (TLR), C-type lectin receptors, NOD-like receptors, and RIG-I-like receptors, which then trigger pro-inflammatory pathways and initiate adaptive immune response with antigen-presenting dendritic cells. For instance, toll-like receptor 9 (TLR9) can recognize viral or bacterial DNA and can induce pro-inflammatory cytokines. Unmethylated single-strand DNA called cytidyl guanosyl oligodeoxynucleotide (CpG-ODN) is one such molecule recognized by TLR9 on B cells and plasmacytoid dendritic cells. Therapeutic efficacy was closely associated with immune-adjuvant CpG-ODN administration in the combined therapeutic protocol of cryoablation, dendritic cells (DCs), and CpG-ODN. Table 3.Accurate preoperative staging including computed tomography (CT) scan and magnetic resonance imaging (MRI) with a paramagnetic contrast agent  is essential to define the extent and location of an internal disease and the involvement of major vessels and bile ducts. In this section, image-guided cryoprobe positioning and ice ball formation, as well as post-operative assessment, will be discussed. Three major imaging modalities, CT, MRI, and ultrasound (US) are compared in Image-guided cryoablation via multiple imaging modalities such as MRI Figure ). Among main imaging modalities, MRI, CT, PET, and ultrasound (US), only MRI, CT, and US can be used to position the cryoprobes.Pre-operative imaging is necessary for planning accurate placement of cryoprobes. Typically, the probe will be inserted through or parallel to the long axis of the tumor mass for the ice ball to form around the extent of the mass (A diagnostic ultrasound scan uses high-frequency sound waves emitted from a transducer which travel through the body and reflect back when they strike interfaces between regions of different densities. These echoes create images of the inside of the body. The cryoprobes are readily identified by their hyperechoic pattern with posterior acoustic shadow Computed tomography (CT) scanning, also known as computerized axial tomography scanning, is a diagnostic imaging procedure that uses x-rays to build cross-sectional images of the body. Cross-sections are reconstructed by calculating attenuation coefficients, or how easily the x-ray beams penetrate the volume of the object studied. Unlike ultrasound, CT offers a much better image with higher sensitivity, specificity, and accuracy, and it can be directed precisely at a target area, including but not limited to prostate cancer, pancreatic adenocarcinoma, and renal tumors In the 1990s, magnetic resonance imaging (MRI)-guided percutaneous procedures were initially performed in open-bore MRI units Figure 4). It is important for physicians to monitor the real-time formation of the ice ball so that the edge of the ice ball does not overextend into healthy tissues. This ability is a significant factor in giving cryoablation an advantage over other ablation therapies, because it allows for the killing of tumor cells while sparing surrounding tissues. Thus, early visualization of ice ball formation on ultrasound or CT is crucial since the necrotic isotherm tends to lag several millimeters behind the actual edge of the visible ice ball. In an in vivo porcine model, a triple-freeze protocol not only increased the area of cryolesion but also expanded the region of necrotic isotherm compared to a double-freeze protocol Figure ) In general, a cryoablation procedure is deemed complete when imaging reveals ice-ball formation covering the entire tumor with a suitable margin  fluorescence imaging and NIR thermography have been explored in preclinical studies. Near infrared fluorescence imaging offers high spatial resolution, quick response rate, low cost, and portability. However, NIR fluorescence imaging suffers from limitations such as limited tissue penetration, tissue autofluorescence, and photobleaching in vivo applications.Conventional temperature monitoring methods require the placement of thermocouples next to cryoprobes. However, they are invasive and can only measure the temperature of the cryoprobes and immediate vicinity, but not peripheral tissue temperatures. MR thermography opens opportunities for a non-invasive way to measure tissue temperature with high spatial and temporal resolution. It can be used to map the temperature gradient and track the progress of the cold front approaching the boundary between tumor margins and healthy tissues. Real-time temperature monitoring with thermography should be coupled with other imaging modalities to guide cryoablation. Multifunctional MR imaging, for example, can provide detailed anatomical information before and after cryoablation, but also accurate temperature monitoring and thus on-the-fly thermal regulation 99mTc-MDP) within the prostate bed was enhanced after cryoablation of prostate carcinoma 99mTc-MDP uptake. Whereas 99mTc-MDP is now used mostly for single photon emission computed tomography (SPECT) of bone, one of the most common radiopharmaceuticals used today for tumor contrast is fluorodeoxyglucose (18F-FDG). In CT guided cryoablation of hepatic tumors, follow-up 18F-FDG PET/CT achieved 100% technical success and efficacy at 3 months post-cryoablation, superior to CT or MR imaging 18F-FDG PET-CT for the follow-up of small renal mass and adrenal metastasis cryoablation showed that 18F-FDG PET-CT imaging could be used to characterize cryoablative tissue injury at different times after cryoablation 18F-FDG, other radionuclides may be used in PET. A report of one patient with clinical diagnosis of tumor-induced osteomalacia visualized with Ga-68 DOTATOC PET/CT and MRI showed successful application of PET/CT to locate and perform image-guided biopsy and cryoablation of a radiographically occult phosphaturic mesenchymal tumor mixed connective tissue Use of radiotracers in cryoablation dates back more than 20 years, when it was observed that soft tissue uptake of technetium-99m-methylene diphosphonate . The nanoparticles useful in cryoablation can be divided into four general categories: metal, organic , liquid metal, and hybrid of the three previous materials. Table 4 briefly summarizes the nanoparticles discussed below.Although many examples of beneficial nanoparticle use in thermal ablation therapies have been discussed in the literature, not much have been seen in cryoablation therapies. The role of nanoparticles in cryoablation will be discussed in detail in this review. Briefly, nanoparticles can help cryoablation in the following possible manners: faster ice formation, inducing cellular damage by altering properties of cell membranes, controlled drug release in thaw-freeze cycles, enhanced imaging, controlling ice shape, and protecting surrounding healthy tissues from cryoinjury  suppresses ice formation, while those larger than the critical ice nucleus (>11 nm) promotes ice growth 3O4 nanoparticles increase the rate of ice growth and intracellular ice formation by acting as nuclei for ice crystallization 3O4 nanoparticles increases the probability of intracellular ice formation and cellular dehydration after the freezing and thawing cycle  Figure ). Meanwhile, Au nanoparticles result in faster ice ball growth, but not earlier intracellular ice formation than Fe3O4 nanoparticles, suggesting that there are variances between metal nanoparticles , likely due to differences in the rate of nanoparticle cellular uptake Figure ) and CS-TPP nanoparticles improve cellular penetration and raise the efficiency of trehalose. Preserving important immune cells in the surrounding the health tissues may benefit immune response post-cryoablation of the tumor.In terms of heat transfer, metal nanoparticles generally have higher thermal conductivity than polymeric or lipid-based nanoparticles and can therefore exchange heat more efficiently. They can permeate throughout the tumor and allow more uniform temperature gradient during cryoablation. Further, when the nanoparticles accumulate around the tumor tissues due to EPR effect and enter cells, they can enhance intracellular ice formation. MgO, gold, and silver nanoparticles have shown high thermal conductivity. Biodegradable MgO nanoparticles increases the rate of intracellular ice formation and can be used as an adjuvant to cryoablation without added risk of toxicity Figure ). The effect is likely due to increased hydrogen bonding between water molecules and the carboxyl groups of cellulose at a specific surface of the nanorods. Therefore, surface modification and shape of nanoparticles are facets to examine for cryo-cytotoxic or cryoprotective effects. However, there needs to be more studies done to evaluate the damaging effect of ice crystal morphology, as it is not clear how much of cryotoxicity is credited to the geometry of the ice crystals. Further, these nanoparticles must be studied under a variety of animal models to prove their efficacy in a physiological environment which contains many solutes and biological molecules that can affect therapeutic outcomes.Surface functional groups of the nanomaterials are important in altering the shape of ice crystals and crystallization growth. Hydrophobic interactions and hydrogen bonding between the surface functional groups and water molecules have been regarded as main attributes for preferential binding of synthetic nanomaterials or natural antifreeze proteins to ice crystals to depress crystallization Another mechanism of cryoinjury is osmotic stress. As ice accumulates in the extracellular space, concentration of solutes will increase, thus prompting water to rush out of cells. The resulting cellular dehydration can be potentially lethal. When there are intracellular ice crystals, the osmotic gradient across the cell membrane is maintained and dehydration is less severe. Whether the formation of intracellular ice crystals or dehydration that dominates cellular death is still elusive. Regardless, membrane fluidity and permeability are crucial to cell viability during the freeze-thaw process Physical binding of the cell membrane by nanoparticles can also change its fluidity and permeability and sensitize the cells to cryo-shock. Nanoparticles of certain sizes and charge can adsorb onto the cell membranes and perturb their mechanical properties. Citrate-capped anionic gold nanoparticles of 13 nm in diameter were able to adsorb onto the lipid bilayer of liposomes and induce lipid gelation Figure ). Because nanoparticles tend to remain in the tumor regions via EPR effect, they have a longer half-life over small molecule contrast agents. During cryoablation, the delineation of tumor edges is highly important in ensuring that the ice ball does not extend into healthy tissues. Thus, cryoablation can only be used for tumors that can be seen by imaging. In tumors that do not show clearly defined edges on images, it may be beneficial to use targeting nanoparticles to accumulate near the tumor edges. Typically, certain classes of metal nanoparticles can act as intrinsic imaging contrasts, while other types of organic nanoparticles may instead carry contrast agents such as gadolinium for MR or Lipiodol for CT. Currently, metal nanoparticles that do not need molecular probes or dyes avoid the problem of additional toxicity. Gold nanoparticles have been extensively used as CT contrast agent in preclinical and clinical settings Figure ). Depending on a diagnostic biopsy, these imaging nanoparticles can be utilized to actively target tumors. Active targeting of tumor cells involves ligand-receptor interactions for specific homing. Nanoparticles may be decorated with ligands to target tumor receptors  for increased affinity and specificity over passive targeting. Gold nanoparticles loaded with anti-epidermal growth factor receptor (anti-EGFR) have shown clear contrast in the tumor regions over passive targeted gold nanoparticles coated with nonspecific immunoglobin G antibodies Figure ).Various types of nanoparticles have been tested in the recent years for high imaging contrast during therapeutic procedures . These types of multimodal imaging nanoparticles provide advantages of each imaging modality. MR imaging using gadolinium is suitable for assessing drug release from nanoparticles, since it relies on the movement of water molecules. Temperature-sensitive liposomes co-encapsulating gadolinium and doxorubicin demonstrated correlated release between doxorubicin and gadolinium Figure 8). Aside from MR, CT, or US imaging, non-conventional methods of imaging for cryoablation such as near infrared (NIR) fluorescence imaging with probe-conjugated nanoparticles or surface-enhanced Raman scattering with gold nanoparticles may be feasible to use with cryoablation. Optical imaging such as NIR and Raman imaging have some advantages over the non-optical imaging modalities, including better spatiotemporal resolution, sensitivity, and signal specificity. Nanoparticles loaded with image probe-conjugated drug can reveal tumor structures unhindered by the ice ball and characterize drug distribution in the tissues like the MRI-based theranostic nanoparticle discussed above. Combined with cryotherapy, these intraoperative imaging modalities using nanoparticles offer more accurate ablation of the tumor margins, lower chance of residual tumor, decreased rate of recurrence, and prolonged survival of patients.Bimetallic nanoparticles such as iron oxide-gold nanoparticles can provide both MR and CT contrast in vivo fluorescence imaging and to locally generate heat upon near-infrared radiation (NIR). When the temperature dropped below 10 °C, the PNIPAM-B polymer became hydrophilic, turning the water-in-oil-in-water (W/O/W) emulsion to water-in-water-in-water (W/W/W) emulsion. The nanoparticles disassembled to release irinotecan. They could also generate heat upon NIR for a photothermal effect. Importantly, in vivo fluorescence could be detected on IR images to confirm the co-localization of nanoparticles and ice formation.Alongside the imaging properties, nanoparticles can carry therapeutic drugs for local delivery and minimize systemic toxicity. A spatiotemporal release of chemotherapeutic drugs complementing cryoablation can achieve a homogenous destruction of cancer cells and be used for tumors of larger sizes. Further, special care should be taken to allow drugs to be released from nanomaterials at the right time using thermosensitive polymers or degradable materials. Localized burst release of chemotherapy or immunotherapy on demand by applying cryoshock can concentrate drugs within tumor cells due to the formation of ice and increase cytotoxic effect in situ cancer vaccination. Therefore, there have been efforts to combine immunotherapy with cryoablation. Nanoparticle-based immunotherapy delivery systems have been explored for reducing the side effects of immunotherapeutic drugs as well as modulating the immunosuppressive tumor microenvironment for a robust activation of the immune system. Recent findings of “sticky” nanoparticles with many functional groups like carboxyl, hydroxyl and amine that capture tumor-associated antigens and DAMPs from ablated tumor cells show an efficient method of capture-and-delivery of the tumor lysates to antigen-presenting cells such as dendritic cells, which in turn travel to lymph nodes to activate T cells Figure 8 summarizes the translational applications of nanoparticles from imaging to therapy in cryoablation.Cryoablation itself triggers an immune response via tumor lysates and can be considered a weak form of Figure 9).Ideally, when designing multifunctional nanomaterials for use in a combination cryotherapy, fundamental parameters to look for are size, surface area, and surface functionalization. Nanoparticles with high surface area, as mentioned previously, can enhance heat transfer but also can increase more drug payload, which allows for lower number of nanoparticles and smaller drug dose. Functional groups decorated on the surface may also induce morphological change in ice crystals and affect affinity to the cell membranes. These factors should be based on what function of cryoablation or of nanomaterials to incorporate with cryoablation is desired. For instance, surface functionalization of a nanoparticle with imaging probes may confer high visualization of tumor but also affects drug loading efficiency or thermal conductivity, as well as nanoparticle-biomembrane interactions. Hence, it is important to consider what aspect of nanoparticles to utilize to enhance cryoablation. Their applications can be divided into diagnostic and therapeutic strategies. Diagnostic nanomaterials should be selected for their specificity and detection in cancer tissue. For types of cancers that are difficult to detect on traditional imaging platforms such as MRI, CT, or US, nanoparticles conjugated with contrast agents and molecular probes can be delivered into the tumor for precise ablation, as well as targeted therapy if adjuvants are additionally loaded onto the nanoparticles. Further, conditions of the cancers, such as size and shape of the tumor, and biomarkers for detecting expression of aquaporin and unsaturated fatty acids, low oxygen and pH levels, and immunosuppressive tumor microenvironment should be gathered from patients by imaging and liquid or tissue biopsy. Therapeutic nanoparticles can then be chosen based on the diagnostic result based on the discussions made in prior sections of this paper  Figure ). The liquid metals-paste hybrid exhibited high thermal conductivity that increased during the cryoablation phase due to its phase transition from liquid to solid. Finally, although not strictly nanosized, gallium microparticles (~200 µm) exhibited sharp protrusions that pierced tumor cells upon freezing  Finally, new types of materials and their intrinsic properties should be continuously explored for application in cryotherapy. A relatively new type of nanoparticle that has been garnering attention is liquid metal. Liquid metals such as gallium-based alloys have attracted considerable interest in the biomedical field due to their stability, high electrical and thermal conductivity, and non-toxicity Minimally invasive tumor ablations are commonly used in the treatment of a broad range of tumors. Ablation therapies are one of many primary options for the patients who have failed chemotherapy or radiotherapy or are not surgical candidates. They have the potential to be first-line treatments for these patients at various stages of cancer. Thus, multiple ablative tools have been developed for a precise, minimally invasive removal of tumors or as an adjuvant tool to surgery. Radiofrequency (RF), microwave (MW), laser, and high-intensity focused ultrasound (HIFU) systems utilizing heat energy are well-established for the ablation of many types of tumors. However, tumor recurrence after the ablation and additional heat-related side effects continues to be an obstacle to better therapeutic outcomes. Compared to heat-based ablations, non-thermal ablation such as IRE and non-heat-based thermal ablation such as cryoablation have a better chance of minimizing damage to vascular structures and nearby organs. Further, cryoablation can be monitored real-time unlike all other ablation therapies, readily accomplishing high precision removal of tumor while preserving normal tissues. Moreover, it has accumulated years of clinical data and been deemed to be safe and easy to use. However, despite these benefits, cryoablation suffers from heterogenous tumor ablation, especially incomplete killing of tumor cells around the margins of the ice ball. Further, in cases where tumor is not readily visible by imaging, there is a risk of freezing healthy tissues. In addition, while cryoablation can induce anti-tumor immune response, this phenomenon by itself is insufficient for effective tumor regression and therefore must be supplemented with other forms of immunotherapy.As immunotherapy becomes the main pillar of cancer therapy, the ablation therapies which can induce immunogenic cell death and antigen presenting cells or immune modulation will become paramount in achieving complete tumor response jointly with immunotherapy. Recent reports of cryoablation-mediated immune modulation strongly support the combination of cryoablation with various immunotherapies. Considering rapidly evolving essential imaging guidance and interventional oncology techniques, cryoablation and cryoablation-mediated combination therapy will be an exciting area in cancer therapy. For complete success of the treatment, image-guided approach can help clearly visualize ablation zone and assess complete tumor eradication. Real-time monitoring of both the ice and immunotherapeutic agents will be important in limiting systemic exposure, and post-ablation images can be assessed for signs of tumor progression or pseudoprogression occurring in less than 10% of the patients treated with immunotherapy One promising platform to increase therapeutic efficacy and reduce side effects of cryoablation is multifunctional nanoparticles. Presently, nanoparticles are capable of loading of therapeutic chemicals and image contrasts due to their high surface area-to-volume ratio, while nanoparticles are image contrasts themselves. Nanocarriers have shown extensive potential as a catalyst of the ablation therapies, for supporting imaging guidance for minimally invasive procedure and precise ablation, and for further co-delivery of therapeutics that can allow various combination therapies, especially immunotherapies. As cryoablation is a local therapy, drug-eluting nanoparticles offer the benefit of localized chemo- or immunotherapy and can prevent systemic side effects, overcome drug resistance, and create synergy with cryotherapy. In addition, their high contrast imaging properties can provide accurate treatment and be used to track the biodistribution of drugs or nanoparticles. Recent studies demonstrated that nanoparticles could control different properties of ice ball formation, including rate of crystallization, probability of intracellular ice formation, and crystal morphology within tumor tissues for precise ablation targeting. Lipid-based nanoparticles, for example, can lower the freezing point and hamper ice growth while metallic nanoparticles can accelerate ice growth. Intravenously injected nanomaterials may additionally affect heat convection between vessels and the ablation zone. In summary, although there are currently very little clinical studies investigating nanoparticle-delivered therapeutics with cryoablation, cryoablation is a promising ablation technology that can achieve an innovative synergistic combination with other therapies. In conjunction with nanoparticles, image-guided combination cryotherapy has the possibility of eradicating cancer completely while preserving neighboring organs and tissues. Utilizing well-developed nanomedicine that supports hypothermic effects, image guidance and synergistic combinational immuno-therapeutics will play a critical role in extending cryoablation-based cancer therapies. Current clinical advances of cryoablation demonstrating precise ablation, strong immunogenicity and positive therapeutic outcomes are providing great potential to be one of the main ablation techniques that also can allow various combinational cancer therapies. Utilizing well-established nanomedicine and theranostic nanoparticles that can be used for cancer ablation techniques would be the best option to achieve an innovative therapeutic outcome by enhancing the tumor specificity and inducing anti-tumor immunogenicity. Further investigation of the nano-cryoablation therapies that have been relatively less studied is required for extending the therapeutic options of various types of tumors.