We tried to use a small amount of radioactivity, injected around non-small cell lung cancers, to see if this technique can identify the lymph node receiving the flow  from the tumour. Our results show that it is possible to do so; this technique could be used to obtain a personalised and potentially safer approach in lung cancer surgery.Background: Intraoperative localisation of nodal disease in non-small cell lung cancer (NSCLC) can be challenging. Lymph node localisation via radiopharmaceuticals is used in many conditions; we tested the feasibility of this approach in NSCLC. Methods: NSCLC patients were prospectively recruited. Intraoperative peri-tumoral injections of [99mTc]Tc-albumin nanocolloids were performed, followed by removing the tumour and locoregional lymph nodes. These were examined ex vivo with a gamma probe and labelled sentinel lymph nodes (SLNs) if they showed any activity or non-sentinel lymph nodes (nSLNs) if they did not. Thereafter, the surgical field was scanned with the probe; any further radioactive lymph node was removed and labelled as “extra” SLNs (eSLNs). All specimens were sent to histology, and metastatic status was recorded. Results: 48 patients were enrolled, and 290 nodal stations were identified: 179 SLNs, 87 nSLNs, and 24 eSLNs. A total of 44 nodal metastases were identified in 22 patients, with 36 of them (82%) located within SLNs. Patients with nSLNs metastases had at least a co-existing positive SLN. No metastases were found in eSLNs. Conclusions: The technique shows high sensitivity for intraoperative nodal metastases identification. This information could allow selective lymphadenectomies in low-risk patients or more aggressive approaches in high-risk patients. Non-small cell lung carcinoma (NSCLC) is among the most common and lethal neoplasms, representing the leading cause of cancer-related death in Western countries . NSCLC iThe effectiveness of the surgical approach relies on the accurate identification of all disease foci and the subsequent attainability of a radical result. However, pre-operative staging based on medical imaging does not guarantee perfect sensitivity; in particular, [18F]FDG PET/CT is limited by the intrinsic spatial resolution of the technique and cannot detect micro-metastases reliably . MoreoveIt should be borne in mind that the process of nodal spread is not of random nature. Tumour cells are collected by the local lymphatic vessels, and then transported to the closest mediastinal nodes. This process can be tracked using specific radiopharmaceuticals, such as radioisotope-labelled colloids which, following peritumoral injection, quickly travel and become trapped within the local lymph nodes. By employing a radioisotope probe during surgery, these first-line nodes  can be identified .The intraoperative identification of SLNs via radiopharmaceuticals has been employed in several tumour types successfully, most commonly in breast cancer and melanoma, where this technique revolutionised the standard-of-care and surgical management ,16. HowePatients referring to IRCCS Humanitas Research Hospital for surgery in NSCLC were prospectively and consecutively recruited between May 2021 and April 2022. The enrolment requirements included a histologically confirmed diagnosis of NSCLC and the completion of the pre-operatory staging with CT and [18F]FDG PET/CT. All patients signed a study-specific informed consent module, and their enrolment was subject to approval from the local ethical committee . For all patients, data relative to demographics, clinical history, and tumour stage according to the eighth version of the American Joint Committee on Cancer TNM system and pathology, were collected from the electronic clinical medical records.®, ROTOP Pharmaka AG, Dresden, Germany) were performed. Starting from 10 min after the injection, the surgical removal of the primary tumour and locoregional lymph nodes was performed according to the best clinical practices.During surgery, immediately after the identification of the primary tumour site, four intraparenchymal peri-tumoral injections of [99mTc]Tc-Albumin Nanocolloids  ex vivo , unless otherwise specified. Predictors of metastases in SLNs, nSLNs, and eSLNs were analysed via a univariate binary logistic regression model; further multinomial logistic regression analysis was conducted on selected factors based on significance level at the univariate testing and clinical reasoning. SPSS v. 24  was used for the analyses. A A total of 48 patients were prospectively enrolled. In higher prevalence, they were males (65%), with smoking habits (77%), and a histologically confirmed diagnosis of lung adenocarcinoma (71%). Baseline patients’ characteristics and histopathological staging details are described in During surgery, a total of 290 lymph-nodal stations were dissected, including 179 SLNs, 87 nSLNs, and 24 eSLNs. A total of 44 metastatic lymph-nodal stations were identified in 22 patients. A total of 36 out of these affected stations (82%) were located within SLNs. In three patients, however, there was a co-existence of metastases within and without SLNs. Particularly, one of these patients had a single nSLN metastasis, one had a mixture of SLNs and nSLNs metastases, while the last one had a single positive SLN and evidence of diffuse neoplastic lymphangitis, which probably hindered the tracer diffusion to the proper sentinel localisations . Five, nIn typical upper lobe resections (26 procedures), only in 2 cases were metastases found in sub-carinal lymph nodes, and in both cases they were SLNs; in 6 cases, sub-carinal SLNs were pathologically negative; in 18 cases, pathologically negative sub-carinal nodes were nSLNs. In typical lower lobe resections (10 procedures), no metastases were located within higher para-tracheal lymph nodes; in 5 cases, pathologically negative high para-tracheal nodes were located within SLNs areas, and in the remaining 5 cases in nSLNs.Predictors of the presence of positive sentinel lymph nodes are depicted in Given the rarity of its occurrence, no single parameter was correlated with presence of metastases within non-sentinel lymph nodes, even if cN positivity showed some degree of association . TherefoFinally, a longer uptake time  was the sole predictor inversely correlated with the presence of eSLNs on both univariate  and multThe present study allowed for the gaining of a number of insights into the potential role of the sentinel lymph node technique in non-small-cell lung cancer. This technique resulted in safe, easily implementable, and accurate identification of nodal disease. In fact, disease localisations were found within sentinel nodes or, in rare instances, in non-sentinel lymph node stations located farther down the line of positive lymph nodes. These data support the use of the technique to identify nodal localisations reliably, or to prompt further exploration in case of positive sentinel localisations. Some guidelines advocate for lobe-specific mediastinal lymph node dissection, with the rationale being that there is an obvious correlation between the site of lymph-nodal metastasis and the location of the primary tumour . In partIn our series, retrieving “extra” sentinel nodes, i.e., those that the surgeon would not have removed if they had not had the sentinel node technique available, did not change the staging or improve the radicality of the intervention. However, such sentinel nodes were mostly present in patients with no evidence of nodal metastases. It might be interesting to further test the concept of additional lymph node identification in higher stages NSCLC, with a higher likelihood of node spread. Moreover, the current study was carried out in a high-volume referral centre; it might be speculated that using the sentinel node method to detect more lymph nodes than those identified by the surgeon might benefit operators still in the earlier phases of the learning curve. On the other hand, it must also be considered that the main factor inversely correlating to the presence of “extra” lymph nodes was the time elapsed between the tracer injection and the conclusion of the regular surgical procedure. In this sense, it could be hypothesised that a longer surgical procedure might allow the operators to perform a more complete lymphadenectomy, comprising all nodal stations reached by the radiopharmaceutical.Our results about the intraoperative detection rate are in line with those presented in the literature, even if the large majority of them analysed early-stage NSCLC ,21,22; nIn general, however, the information gathered thanks to this method could inform more selective lymphadenectomies, especially in early-stage lung cancers, reducing the surgical burden for operators and patients and driving a paradigm shift towards less invasive approaches . ConversThese results might prompt further targeted investigations. On the one hand, higher-stage tumours, which are those more prone to relapse and progression, might benefit from the sentinel lymph node approach the most. Studying the behaviour of the nodal spread in these patients might improve our capability to offer a radical treatment, even in these aggressive forms. On the other hand, prospective investigations assessing the possibility of more limited nodal resection in early-stage NSCLC might help reduce the rate of complications and postoperative morbidity ,27. FinaFrom the feasibility point of view, we found that this technique can be implemented easily, with a very fast learning curve for the surgical team. An important advantage of this method is that it does not entail novel or hard-to-setup radiopharmaceutical: the lymphatic mapping can be prepared in minutes with minimal notice beforehand. Moreover, the carrier molecule is cheap and widely available; the dose absorbed by the patients as well as the surgical team is negligible.Our study is not without limitations. The studied population is relatively small, even if the sample size is in line with or larger than the existing literature. We recruited patients with all NSCLC stages amenable to surgery. Thus, our results might not always be representative of every single stage. Nonetheless, this study was conceived to shed light on the lymphatic pathing of all lung cancer stages; the consistency of our results with those of the existing literature suggests that the sentinel node mapping can be applied safely to higher stages as well. The role of this method in patients with a clinical N2 status could be limited, since these patients should undergo a full excision in all cases; however, performing a sentinel node mapping could be helpful in those cases were the cN2 staging is conflicting across methods or unclear.Finally, follow-up data of the studied patients are not available yet; the correlation between the sentinel node status and the long-term outcome should be assessed as soon as this information becomes available.Sentinel node mapping with radiolabelled colloids in NSCLC is a safe procedure in all stages, able to identify nodal metastases in most cases. The identification of metastasization in a sentinel lymph node should, however, prompt a radical excision of all the nearby nodal stations, especially when an obstacle in the lymphatic drainage is suspected. On the other hand, identifying sentinel lymph nodes outside of the standard operating field does not seem to bring advantages in metastases identification.


This umbrella review aimed to evaluate whether certain interventions can mitigate the negative health consequences of caregiving, which interventions are more effective than others depending on the circumstances, and how these interventions are experienced by caregivers themselves.An umbrella review of systematic reviews was conducted.Quantitative , qualitative and mixed-methods systematic reviews were included.Reviews were considered eligible if they met the following criteria: included primary studies targeting informal  caregivers of older people or persons presenting with ageing-related diseases; focused on support interventions and assessed their effectiveness (quantitative reviews) or their implementation and/or lived experience of the target population ; included physical or mental health-related outcomes of informal caregivers.A total of 47 reviews were included, covering 619 distinct primary studies. Each potentially eligible review underwent critical appraisal and citation overlap assessment. Data were extracted independently by two reviewers and cross-checked. Quantitative review results were synthesised narratively and presented in tabular format, while qualitative findings were compiled using the mega-aggregation framework synthesis method.The evidence regarding the effectiveness of interventions on physical and mental health outcomes was inconclusive. Quantitative reviews were highly discordant, whereas qualitative reviews only reported practical, emotional and relational benefits. Multicomponent and person-centred interventions seemed to yield highest effectiveness and acceptability. Heterogeneity among caregivers, care receivers and care contexts was often overlooked. Important issues related to the low quality of evidence and futile overproduction of similar reviews were identified.Lack of robust evidence calls for better intervention research and evaluation practices. It may be warranted to avoid one-size-fits-all approaches to intervention design. Primary care and other existing resources should be leveraged to support interventions, possibly with increasing contributions from the non-profit sector.CRD42021252841; BMJ Open: doi:10.1136/bmjopen-2021-053117. The umbrella review methodology enabled us to synthesise and describe the state of the evidence on the topic of interventions to mitigate the negative health consequences of informal caregiving.The review benefits from the mixed-methods approach, as we included both quantitative reviews on effectiveness and qualitative syntheses exploring complex aspects related to the experiences of caregivers.Synthesis is confined to a descriptive, narrative output due to heterogeneity of included reviews.More recent primary studies on new interventions were not captured, as they would not have been included in systematic reviews selected for this umbrella review.Informal caregivers are defined as any relative, partner, friend or neighbour who provides a broad range of assistance to an older person who lives with a chronic or disabling condition and with whom they have a significant personal relationship.5 6Informalisation of care has come with important concerns about the potential side effects of caregiving, and with growing interest from decision-makers and stakeholders in the effectiveness of existing support interventions to alleviate these negative consequences. The burden of informal care can be determined by various factors, such as the intensity of caregiving, care receivers’ dependency level, relationship with the care receiver, available social support from the community, and caregivers’ own health.15 16There has been a considerable increase in the number of empirical studies  on the topic of caregiver support interventions, followed—in recent years—by a large number of systematic reviews. Consequently, it has become challenging to keep a bird’s-eye view of this field of research. To provide decision-makers and stakeholders with synthetic and actionable evidence, a logical next step is to conduct a review of systematic reviews, that is, an ‘umbrella review’.In particular, the following research questions were addressed: (1) Are there effective interventions to prevent and reduce the negative health consequences of informal caregiving?; (2) Are certain types of interventions more effective than others?; (3) Is there evidence that the effectiveness of interventions depends on caregiver, care receiver, care context and implementation characteristics?; (4) How are the proposed interventions experienced by caregivers in terms of effectiveness and implementation outcomes?The protocol for this umbrella review was registered a priori in the PROSPERO database2410.1136/bmjopen-2022-068646.supp1Supplementary dataInclusion and exclusion criteria used to select reviews are presented in Box 1Publication type, date and languageReviews published in a peer-reviewed journal.Reviews published between 1 January 2000 and 26 March 2021.Reviews published in English, Swedish, Spanish, French, Italian or German.Study designFor quantitative reviews: reviews including a reproducible, systematic search strategy, AND clearly defined inclusion/exclusion criteria AND risk of bias assessment for all included primary studies.For qualitative reviews: reviews including a reproducible, systematic search strategy AND defined inclusion/exclusion criteria.PopulationReviews concerning informal caregivers  of older people OR of persons presenting with ageing-related disease .InterventionReviews focusing on interventions and assessing either their effectiveness (for quantitative reviews) or their implementation and/or the lived experience of the target population .OutcomeReviews including physical or mental health-related outcomes of informal caregivers, including health-related quality of life.Study quality and overlapFor quantitative reviews: reviews of ‘critically low’ quality as per AMSTAR-2 assessment tool.For qualitative reviews: reviews with two or more critical flaws as per ad hoc assessment tool.*Review pairs with very high or high overlap (as per Corrected Covered Area method) were examined, and older, less relevant or lower-quality reviews were excluded.Additional exclusion criteriaexclusively on care receivers as the target population.Reviews of interventions focusing exclusively on interventions for caregivers of young populations.Reviews focusing exclusively non-health-related outcomes, such as caregiver burden, stress/strain, work or financial status, family relations, breakdown of informal care.Reviews measuring exclusively on end-of-life care interventions.Reviews focusing *See the published protocol (doi:10.1136/bmjopen-2021-053117) for the ad hoc assessment tool for qualitative reviews.Did the review authors report on the sources of funding for the studies included in the review?) from ‘critical’ to ‘non-critical’ since this information was only available in Cochrane reviews  was estimated using the Corrected Covered Area methodologyData from included reviews were extracted by two team members in structured spreadsheets designed and validated a priori by all the investigators involved in this umbrella review. The quality and validity of the extracted data were assessed through regular cross-checks. For quantitative reviews, we extracted the following information: review objectives, methodological aspects , target population and disease, characteristics of the interventions of interest, sociodemographic background of caregivers, health outcomes, degree of effectiveness of interventions , implications for practice and research, as well as the full list of primary studies included in the review. The latter was extracted for the purpose of overlap assessment. Qualitative reviews were characterised in terms of methodology, and we extracted all the verbatim text related to the reported caregivers’ experiences of interventions.et al’sFor quantitative reviews, we conducted a narrative synthesis and provided findings in a tabular format, organised by intervention type. To provide a data-driven list of intervention types, we adapted Gaugler et al’s framework.For qualitative reviews, we followed the ‘mega-aggregation framework’ synthesis method.As a complementary output, we used parallel convergence approach  to update our initial conceptual framework that was based exclusively on expert opinion and/or existing literature  and resulting pyramids are available in 10.1136/bmjopen-2022-068646.supp2Supplementary data10.1136/bmjopen-2022-068646.supp3Supplementary dataFinally, 47 reviews covering 619 primary studies were included in the umbrella review. Of these, 10 contributed to qualitative data only, 8 were included as both qualitative and quantitative data sources, while 29 reviews contributed exclusively to quantitative synthesis.All included reviews were published in English. Publication dates spanned from 2009 to 2021. Most primary studies were conducted in North America or Western Europe. Reviews set various inclusion and exclusion criteria regarding the design of primary studies, with some reviews focusing on randomised controlled trials, while others casted a wider net including quasi-experimental and qualitative studies. Among quantitative reviews, 18 undertook a meta-analysis while 19 undertook a data synthesis without meta-analysis. In qualitative reviews , the most common synthesis approach was narrative (14 reviews), but four reviews reported a qualitative meta-synthesis. Characteristics of all included reviews, such as search dates, number of studies, demographics of included populations, and types of interventions examined are summarised and presented in =6), health-related quality of life (n=6), anxiety (n=2), general health (n=1) and self-rated health (n=1). Three reviews included a meta-analysis.et al40Eight reviews reported quantitative findings related to the effectiveness of the interventions involving case management .33–40 Se=12) and stroke (n=4) to cancer (n=4) and other chronic illnesses (n=3). Most reviews included multiple interventions , even though the label ‘multicomponent’ was used differently across reviews. Meta-analysis was performed in 14 reviews. Of these, seven reviews reported insignificant effect estimates or little to no effects following psychosocial and/or educational interventions,et alet al,et alet alet alet alet alA total of 23 reviews reported quantitative findings related to effectiveness of interventions involving psychosocial support, education and skills-building for caregivers . Of theset alet alSome reviews explored findings from primary studies depending on the caregiver, care receiver and care context characteristics as well as implementation-related aspects. Successful interventions were reported to be more individualised,=4), anxiety (n=2) and general health (n=1). The largest review in this category—and the only one including a meta-analysis—reported no significant effects on caregivers’ mental health outcomes.et alet alet alet alet alFour reviews explored the effectiveness of respite care services .60–63 Th=3), neurological diseases (n=1) and various chronic illnesses (n=2). Health-related outcomes varied and included: depression (n=4), health-related quality of life (n=4), anxiety (n=4), physical health (n=3), and blood pressure and weight (n=1). Two reviews included a meta-analysis.et alet al37A total of six reviews were grouped under this category ,35 37 64et al,et alMost of the reviews in this category did not consider heterogeneity associated with caregiving factors or implementation characteristics. According to Doyle =3), anxiety (n=3), and cognition and biomarkers for stress (n=1). Two reviews included meta-analysis.et alet alFour reviews included interventions using mindfulness-based stress reduction techniques .67 69–71et alet alet alThree reviews compared the effect sizes across different types of interventions.For the qualitative part of our umbrella review, we extracted and analysed data from 18 reviews. This theme described the potential benefits and/or harmful effects to caregivers from participating in the interventions , and was informed by 13 reviews.et alPractical outcomes were explored in nine reviewset alet alet alParticipation in the interventions also brought about emotional outcomes, which were described by nine reviews.et alFinally, four reviews investigated the relational outcomes of support interventions, namely how these interventions modified the caregivers’ relationships with their care receiver or peers.et alA total of 17 included reviews examined to what extent the adoption of effective interventions was determined by implementation-related barriers and facilitators that could render them ineffective in certain circumstances.person-centeredness, flexibility and personalisation of the interventions promoted higher acceptability as expressed by caregivers.et alAlthough the included reviews covered studies with varying designs and heterogeneous interventions, we found similarities in the description of the determinants of perceived caregiver acceptability. First, seven reviews spanning almost all intervention types demonstrated that the et al also explained that ‘receiving counselling in the native language was also shown to contribute to building trust’. Additionally, having multicultural staff facilitated the acceptability of the interventions because better relationships could be built with the families, and the needs of the different communities could be better understood.60Second, three reviews documented the importance of cultural and linguistic aspects in explaining the success of support interventions,et alThird, six reviews examined how the physical, social and structural characteristics of interventions promoted or hindered their acceptability by informal caregivers and care receivers.Finally, five reviews built on qualitative findings to address the role of trust, dignity and ethical values in the degree of acceptability of support interventions.66et alIntervention feasibility is defined by Proctor recruitment were mentioned in four reviews.et al60First, challenges to accessibility by six reviews,52Second, the feasibility of interventions was questioned in terms of their service availability—that is, the coverage of support interventions in terms of time schedules and availability of staff—was broached in six reviews.52Third, adoption and retention, that is, what factors affect the initiation and the continued use of the services provided as part of an intervention.et al60 75Fourth, we found five reviews that looked at aspects related to systemic factors .33Finally, four reviews investigated et alet al66 76This category, which was documented in nine reviews,et alThis category grouped those factors associated with a sustained, long-term use of the interventionThis category was linked to the financial costs associated with implementing or using the intervention60 75The literature search was updated by the university librarians to capture reviews published between 26 March 2021  and 31 January 2023. This search yielded 1920 additional entries. A single reviewer completed title/abstract screening, leading to 57 potentially relevant reviews. After a thorough assessment of the full-text articles, a total of 26 reviews were found to meet all eligibility criteria. Finally, we excluded 14 reviews of critically low quality. The 12 remaining reviews are listed and summarised in Addressing the negative health outcomes of informal caregiving is a major challenge. In this umbrella review on support interventions for people providing informal care to older adults, we synthesised data from 47 systematic reviews covering 619 distinct primary studies. This is, to date, the most comprehensive map of the available evidence. Four main conclusions stem from our analysis.First, whether existing interventions are effective at reducing the negative impact of caregiving on the physical and mental health of caregivers remains uncertain. Quantitative reviews provided largely discordant findings, with reviews rated as being at low risk of bias reporting trivial or no benefits.71 73Second, we found that multicomponent interventions showed more consistent positive effects on health outcomes across reviews, despite a large heterogeneity in what these interventions actually entailed.18 20The third conclusion is that the available evidence on support interventions relies on the simplistic assumption that informal caregivers represent a homogeneous target population, with little attention being paid to the variability in caregiver, care receiver, care context and implementation characteristics. Hence, while a number of reviews reported valuable information about the characteristics of the interventions being evaluated,et alfidelity of the interventions, that is, the degree to which an intervention was implemented as it was intended, was not reported.Finally, our overview casts new light onto how support interventions are experienced by informal caregivers. By synthesising the qualitative findings of 18 distinct reviews, we showed that caregivers mention a myriad of social benefits, for instance, improved relationships with care receivers, better organised routine and less stress/burden associated with caregiving.The extensive set of qualitative findings incorporated in this umbrella review shows that support interventions targeting informal caregivers seem to improve a wide range of practical, emotional and relational outcomes. It is likely that these benefits translate indirectly into positive changes in caregivers’ mental and physical health, even though high-quality evidence for this connection was lacking from quantitative reviews. To better visualise this pathway, we organised the findings from our umbrella review into a framework, SIICO, as presented in et al,85Beyond its initial goals, our umbrella review identified several important knowledge gaps in caregiver intervention research that, we believe, could serve as a roadmap for future studies in this field. Hence, there was a clear over-representation of certain types of interventions , care receiver diseases  and outcomes . Our umbrella review also highlights the overproduction of systematic reviews and meta-analyses on the effectiveness of support interventions for informal caregivers: more than 145 reviews have been published in the last two decades and, as expected, the overlap between them is substantial. This overproduction has become even more evident upon updating our search: between March 2021 and January 2023, a total of 57 additional reviews (compared with 303 for 2000–2021) were published. This raises questions about the potential waste of valuable research resources, especially since the overall quality of published reviews was poor. Approximately two-thirds of the reviews that we identified were rated as being of ‘critically low’ quality. However, one should keep in mind that some of these reviews were carried out before current guidelines and risk-of-bias appraisal tools became mainstream; in fact, more recent reviews demonstrated higher adherence to such guidelines. Qualitative synthesis and reporting practices were often subpar, with important contextual and methodological items missing from an unexpectedly large share of included reviews. The lack of consensus regarding the classification of support interventions was yet another struggle: much like Gaugler Against the backdrop of staff shortages and budget restrictions worldwide (exacerbated by the ongoing COVID-19 pandemic), certain public health services will need to be prioritised over others. Four main implications for public health and practice emerged from our review. First, better intervention research and evaluation practices are warranted to create an evidence base for resource allocation: we would not know what works best in different contexts if we keep relying on low-quality studies. Second, time has come for a more targeted approach to intervention design. While caregiver interventions may not work for the ‘average caregiver’, targeting high-risk groups—for example, caregivers with pre-existing conditions, multimorbidity or frailty—might deliver more convincing and cost-effective results. Third, since our healthcare systems are already under considerable pressure, support interventions should build on existing resources rather than entirely new services. To our surprise, very few of the interventions included in the systematic reviews and meta-analyses that we synthesised mustered primary care professionals to support informal caregivers. Yet, family physicians and home care nurses (among others) have frequent contacts with caregivers, with whom they often share a long-lasting relationship. They should have the means to remain vigilant, identify high-risk subgroups of caregivers and enlist them in relevant support programmes. Fourth, our umbrella review also highlights the potential for non-profit organisations: trained volunteers could, for instance, take a larger role in delivering social care services to alleviate the burden of caregivers.Our findings may be useful for decision-makers trying to untangle the state of the evidence on this complex topic, but also for those interested in more specific intervention types, given the broadness of our review. There are moreover several implications for future research stemming from our umbrella review. First, the enforcement of a priori protocol registration could avoid the wasteful production of reviews. Second, the consistent application of systematic review guidelines  is warranted to ensure higher quality of evidence synthesis. Third, at the primary study level, a better definition of intervention components and a clear harmonisation of intervention types are needed to ensure comparability of the generated evidence. Last, future interventions should identify and report results across subgroups defined by caregiver, care receiver and care context characteristics, and consider including not only social and relational outcomes, but also objective mental and physical health outcomes, measured comprehensively and over an extended period of time. This will be essential to better understand the potential pathways connecting social to physical/mental health outcomes, although the latter will require a mixed-methods evaluation approach.The primary strength of this umbrella review is the rigorous study selection process, initiating from a generous search strategy identifying over 6000 abstracts. Such process was completed in duplicate and included quality and overlap assessment. Further, we included both quantitative and qualitative evidence to better understand the complex phenomenon of caregiver support interventions and their impact on health. In addition, data synthesis and framework elaboration were guided by existing theory and expertise within the group, adding to the rigour of the review. However, umbrella reviews are limited in terms of drawing conclusive statements, given that they do not assess primary studies, nor retest meta-analyses provided by single systematic reviews. Thus, the interpretability of our findings is limited by the quality and conclusions of included reviews, which are considerably heterogeneous across reviews. In addition, recent primary studies on new interventions may not be captured, as they may not yet have been included in systematic reviews. Finally, our umbrella review focused on caregiver-centred interventions and, thus, could not shed light on the potentially positive spillover effect of formal care services delivered to patients on informal caregivers’ health. Yet, the importance of well-organised and sufficiently staffed professional services for household chores and personal care should not be underestimated, and the expansion of support services for informal caregivers cannot come to the detriment of formal care.Despite an abundance of systematic reviews, whether certain support interventions are effective at improving informal caregivers’ physical and/or mental health is uncertain due to a lack of high-quality evidence. It seems that multicomponent and flexible interventions are more likely to address the complex needs of caregivers, making them more acceptable and thus leading to more tangible effects on objective health outcomes. To confirm this, we do not need more reviews: we need more carefully designed intervention studies that look at both subjective and objective health outcomes, and account for heterogeneity in caregiving.


Although vegan diets have been reported to be associated with a reduced risk of cardiovascular disease, it was not known whether this might be partly due to vegan diets’ effects on plasma triglyceride metabolism. This study aimed to investigate if there are differences in the activity of lipoprotein lipase (LPL), an enzyme that functions at the vascular endothelium and is responsible for triglyceride breakdown, in sera obtained from vegans and omnivores. LPL activity was assessed using isothermal titration calorimetry, which allows measurements in undiluted serum samples, mimicking physiological conditions. Fasted sera from 31 healthy participants  were analyzed. The results indicated no significant differences in average LPL activity between the vegan and omnivore groups. Interestingly, despite similar triglyceride levels, there were considerable variations in LPL activity and total very-low-density lipoprotein triglyceride breakdowns between individuals within both groups. Biomarker analysis showed that vegans had lower total cholesterol and LDL-C levels compared to omnivores. These findings suggest that the lipid-related benefits of a vegan diet, in terms of atherogenic risk, may primarily stem from cholesterol reduction rather than affecting serum as a medium for LPL-mediated triglyceride breakdown. In healthy individuals, lipid-related changes in serum composition in response to a vegan diet are likely overshadowed by genetic or other lifestyle factors. Vegan diets are defined as diets that exclude all animal foods. Many studies show that a vegan diet reduces the risk of cardiovascular disease (CVD). This health benefit is generally thought to be related to the fact that vegans tend to have lower levels of plasma cholesterol, LDL-C and inflammatory biomarkers compared to people on omnivorous diets . Less reOne crucial factor in regulating TG levels in blood is the hydrolytic degradation of TGs in triglyceride-rich lipoproteins (TRL) by the catalytic action of endothelial-bound lipoprotein lipase (LPL). LPL also facilitates the cellular uptake of lipoprotein particles and cholesteryl esters . LPL actn-6) PUFA, (n-9) PUFA, and α-linolenic acid (ALA) and lower levels of trans-fatty acids, saturated fatty acids (SFA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) oleate was investigated. Although our results are largely in accordance with Vinagre et al.’s results, it is important to point out the necessity of our study. This is primarily related to the questionability of using artificial synthetic substrate emulsions. As previously shown, exchangeable apolipoproteins can attach to synthetic emulsion particles ,31,32,33Higher LPL activities were measured in participants whose daily fat consumption consisted mainly of saturated fats. However, several in vitro studies ,17 have As in several previous studies ,20,43, wIn summary, our results show that there was no significant difference in LPL activity measured in the fasted blood serum of vegans and omnivores. Interestingly, there were individuals in both groups that had similar TG levels but considerably different measured LPL activities and total VLDL TG hydrolysis. These results show that the vegan diet has no effect on blood sera as an environment for TRL hydrolysis by LPL; rather, there are other factors to consider besides dietary restrictions. Thus, following a vegan diet does not play a role in the context of vascular lipolysis in healthy individuals as compared to omnivores. Future research is warranted with individuals with similar TG levels but vastly different LPL activities through investigating such parameters as the physical properties of lipoproteins, HDL-C levels, and fatty acids in the composition of lipoprotein lipids.


Blood culture-negative infective endocarditis (BCNE) is a challenging condition associated with significant morbidity and mortality. This review discusses the epidemiology, microbiology, diagnosis, and treatment of BCNE considering advancements in molecular diagnostics and increased access to cardiac surgery. BCNE can be categorized into bacterial endocarditis with sterilized blood cultures due to previous antibiotic treatment, endocarditis caused by fastidious microorganisms, and true BCNE caused by intracellular organisms that cannot be cultured using traditional techniques. Non-infectious causes such as nonbacterial thrombotic endocarditis should also be considered. Diagnostic approaches involve thorough patient history; blood and serum testing, including appropriate handling of blood cultures; serological testing; and molecular techniques such as targeted and shotgun metagenomic sequencing. Where available, evaluation of explanted cardiac tissue through histopathology and molecular techniques is crucial. The therapy for BCNE depends on the likely causative agent and the presence of prosthetic material, with surgical intervention often required. Despite advances in antimicrobial diagnostics and therapeutics in the 20th century, mortality from infective endocarditis (IE) remains high. Over one-third of patients affected die within one year of diagnosis . Blood cThe advent of non-culture-based diagnostics and increased access to cardiac surgery over the past two decades have allowed for the identification of culprit organisms in cases of IE that would previously have been considered culture-negative. This has led to changes in our understanding of the epidemiology, microbiology, treatment, and prognosis of BCNE. Accounting for contemporary advances, in this review we outline an updated approach to the diagnosis and treatment of BCNE.Bacterial endocarditis with sterilized blood cultures from previous antibiotic treatment, which accounts for the majority of cases;Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella) group, nutritionally variant Streptococci, Pasteurella spp., mycobacteria, and fungal organisms;Endocarditis due to fastidious microorganisms, which have historically included the HACEK  or polymerase chain reaction (PCR) of valvular tissue .“True” BCNE due to infection with intra-cellular organisms that cannot be cultured in blood using traditional techniques but may be diagnosed with serology , should also be included in the differential diagnosis of BCNE in the right clinical context. NBTE is associated with hypercoagulable states, e.g., malignancy or autoimmune disease, which may result in the deposition of sterile thrombi on cardiac valves.A systematic review of 142 studies reporting IE microbiology over five decades from 1960–2010 found a decrease in the incidence of BCNE over that time period from 23.1% to 14.2% . AccountSepsis is a common clinical presentation of IE, and as a result antibiotics are often administered prior to obtaining blood cultures. In retrospective studies, the prevalence of BCNE attributed to antibiotic administration prior to culture has varied from 35% to 74% ,11. The Granulicatella spp., Abiotrophia defectiva) have traditionally been cited as common causes of BCNE due to the difficulty associated with culturing in standard media. However, modern automated culture systems can identify these organisms within 5 days of incubation in the vast majority of cases [The HACEK group of organisms and nutritionally variant streptococci  and IE associated with endemic fungi, e.g., Histoplasma capsulatum, do not traditionally grow on routine blood cultures, and close attention to risk factors in the history  antibody titer ≥ 1:800 and indirect immunofluorescence assays (IFA) for the detection of IgM and IgG antibodies to Bartonella henselae or Bartonella quintana with IgG titer ≥ 1:800 are major microbiologic criteria for the diagnosis of IE in the 2023 modified Duke criteria [Bartonella spp. and Coxiella burnetii, although antibody titers against the true infecting agent tend to be higher [Brucella is endemic, or where the patient has specific risk factors , rheumatoid factor (RF), and anti-double-stranded DNA.When the medical history or clinical presentation is suggestive of a zoonotic etiology, or when blood cultures are negative at 48 h, serological testing should be performed. e higher . In regi factors , serologSpecific molecular methods that may aid in the diagnosis of IE include organism-specific PCR testing; broad-range PCR for the amplification of bacterial genetic material from 16S rRNA, also referred to as targeted metagenomic sequencing (tMGS); and shotgun metagenomic sequencing (sMGS), where all sequences of genomic DNA from a blood or tissue specimen are sampled. Although the sensitivity and specificity of these techniques are higher in explanted tissue over blood or plasma , cardiacC. burnetii, Bartonella spp., and T. whipplei, among others. In the case of C. burnetii and Bartonella spp., PCR testing from plasma or whole blood is unlikely to add additional diagnostic benefit beyond that obtained by serologic testing [T. whipplei PCR from peripheral blood was found to be positive in only 5 of 16 (31.2%) patients with Whipple’s endocarditis confirmed on a histology or PCR of valve tissue in one cases series [Organism-specific PCR testing has been developed for  testing . T. whips series  but shouCandida albicans. Two small studies have evaluated sMGS using plasma microbial cell-free DNA (mcfDNA) testing [To date, one prospective cohort study has evaluated tMGS on plasma and whole blood . In this testing ,42. AlthSurgical intervention is performed in approximately 22.5–51.2% ,44 of paValve tissue has historically been sent for Gram staining and culture: Positive culture from a cardiac vegetation is considered a major pathological diagnostic criterion in the modified Duke criteria . DespiteBartonella spp.), and Periodic acid–Schiff (T. whipplei) can be used to detect specific organisms in the appropriate clinical setting [Conventional hematoxylin and eosin (H&E) stains confirm the presence of inflammation and necrosis and can provide insight into the acuity of the infectious process. Specialized stains such as methenamine silver (fungi), acid-fast , Warthin–Starry silver  should be determined based on the timing of the infection. Where onset of IE is within one year of surgery, antimicrobial therapy should provide coverage for staphylococci, enterococci, and aerobic Gram-negative bacilli. An empiric regimen with vancomycin, gentamicin, cefepime, and delayed addition of rifampin (after three to five days of therapy) is appropriate. Rifampin has historically been recommended specifically in cases of staphylococcal prosthetic valve endocarditis, although recent data have called this into question . For casC. burnetii endocarditis bears mention given the inclusion of hydroxychloroquine along with doxycycline as part of the suggested treatment regimen. As C. burnetii replicates within macrophages and monocytes where the acidified phagosomal compartment decreases the bactericidal efficacy of antibiotics, it has been proposed and subsequently validated in retrospective case series that an alkalizing agent such as hydroxychloroquine may improve outcomes [If there is a reasonable chance of infection due to a zoonotic agent, empiric therapy versus the suspected agents can be started. Directed therapy for zoonotic agents and fastidious organisms is outlined in outcomes ,57. If houtcomes .Kong et al. conducted the largest study to date comparing outcomes of culture-positive and culture-negative endocarditis using a large European registry to obtain 1-year follow-up data on 3113 patients . One-yeaBlood culture-negative endocarditis remains a clinical challenge and is associated with worse outcomes than culture-positive endocarditis. The diagnostic landscape has evolved with the emergence of non-culture-based methodologies, including serological assays, targeted metagenomic sequencing, and shotgun metagenomic sequencing. These approaches have enabled the identification of pathogens that were historically challenging to detect through conventional blood cultures, and their role is likely to assume greater prominence as these technologies are validated and become more widely available outside of reference laboratories. The diagnostic algorithm outlined in this review provides a comprehensive and rational approach to the evaluation of BCNE cases, emphasizing the importance of thorough clinical history, appropriate blood culture techniques, serological testing, and the judicious use of molecular methods on both blood specimens and explanted cardiac tissue.


Psychosomatic diseases are widely regarded as a result of the complex interplay between both psychological factors and physiological conditions. As such, in the field of healthcare the diagnosis and treatment of such disorders have become a significant challenge, which would necessitate collaborations among multiple disciplines and professions , breast cancer, orofacial pain, and infertility; two studies evaluated treatment efficacy for bipolar disorder (BD) and Psychosomatic diseases; and one study explored psychotherapy for chronic pelvic pain. Among the three studies on the neuroimaging mechanism, two studies examined major depressive disorder (MDD); and one study investigated generalized anxiety disorder (GAD).Huang G. et al. employed neuroimaging techniques along with Natural History Interview (NHI) and Barratt Impulsiveness Scale (BIS-11) to study the cognitive performance and neurofunctional impairments related to psychiatric conditions in methamphetamine (MA) abusers. Their research revealed a correlation between attentional bias in MA addicts and the N200 component, which can be used to detect psychiatric factors in abstinent MA abusers. Li et al. utilized the Somatic Symptom Disorder B Criteria Scale (SSD-12), Whiteley Index-8 (WI-8), and other measures to quantitatively assess patients' perceptions and coping strategies related to bodily discomfort, as well as the distress level of somatic symptoms. They also employed the Fear of Cancer Recurrence-4 (FCR-4) and Functional Assessment of Cancer Therapy-Breast (FACT-B) scales to evaluate the magnitude of fear of cancer recurrence and the quality of life in breast cancer patients. These assessments can help breast cancer patients understand their psychological factors and improve their quality of life.Psychological assessment involves the collection of psychological information from individuals using various measurement tools and techniques to understand their cognitive abilities, emotional states, and behavioral manifestations , which demonstrated good psychometric quality and can be used to assess functional limitations and psychosocial distress in patients with orofacial pain in China. Mubashir et al. developed the Social Comparison Scale (SCS) and Submissive Behavior Scale (SBS), which exhibited acceptable psychometric properties in Pakistani women with primary infertility, as confirmed by confirmatory factor analysis with good model fit indices.Additionally, international standardized psychological assessment scales need to be culturally adapted to be more scientifically applicable to the local population (Phillips et al., Huang J. et al. reported a case of chronic pelvic pain syndrome in which the patient achieved effective relief through a combination of medication and psychological therapy.Psychological therapy, by modulating the bio-psycho-social factors, offers a new perspective on appropriate treatment for mind-body disorders (Hilbert et al., Meng et al. found that abnormal connectivity patterns were observed in the left middle temporal gyrus in GAD, underscoring the significance of GAD pathophysiology. Zhou et al. found that adolescent MDD with a history of suicidal attempts exhibited reductions in the amplitude of low-frequency fluctuations in the bilateral medial superior frontal gyrus and bilateral precuneus, potentially serving as indicators of MDD and suicidal attempts. Additionally, Wang et al. discovered that decreased regional homogeneity in the salience network may contribute to cognitive impairments in patients with MDD.Neuroimaging techniques combined with psychological scales, have been extensively employed in investigating structural and functional brain disorders (Gao et al., Psychological scale assessment involves expertise from various fields, including medicine, psychology, and sociology. These assessment scales can be combined with multiple research techniques to study psychosomatic disorders. The treatment of psychosomatic disorders requires the integration of knowledge from medicine, psychology, and sociology, among other disciplines. We advocate for enhanced interdisciplinary collaboration among experts in the medical, psychological, and sociological fields to collectively address the challenges posed by psychosomatic disorders and provide patients with improved assessment, treatment, and management approaches. Interdisciplinary collaboration can also facilitate prevention and early intervention of psychosomatic disorders, thereby reducing incidence rates and minimizing long-term negative impacts.YG and HY reviewed all articles, summarized individual studies' findings, and drafted the manuscript. All other editors participated in editing articles and reviewed and had access to the manuscript. All authors contributed to the article and approved the submitted version.


Ischemia with no obstructive coronary arteries (INOCA) is a relatively newly discovered ischemic phenotype that affects patients similarly to obstructive coronary artery disease (CAD) but has a unique pathophysiology and epidemiology. Patients with INOCA present with ischemic signs and symptoms but no obstructive CAD seen on coronary CTA or invasive coronary angiography, which can assess epicardial vessels. The mechanisms of INOCA can be grouped into three endotypes: coronary microvascular dysfunction, epicardial coronary vasospasm, or a combination of both. Accurate and comprehensive assessment of both epicardial and microvascular disease in suspected cases of INOCA is crucial for providing targeted therapy and improving outcomes in this underrepresented population. This review aims to clarify the complex pathophysiology of INOCA, present an overview of invasive and non-invasive diagnostic methods, and examine contemporary approaches for coronary perfusion assessment using cardiac magnetic resonance (CMR). We also explore how recent advancements in quantitative CMR can potentially revolutionize the evaluation of suspected INOCA by offering a rapid, accurate, and non-invasive diagnostic approach, thereby reducing the alarming number of cases that go undetected. First discovered in 1973 by Harvey Kemp . The mecThis review discusses the endotypes of INOCA, explores its underlying pathophysiology, offers a concise overview of the existing evaluation methods for INOCA, and emphasizes contemporary approaches for myocardial perfusion analysis utilizing cardiac magnetic resonance (CMR).INOCA is a relatively common condition, affecting 3 to 4 million individuals in the United States alone . Among pSeveral studies have highlighted the significant morbidity and mortality associated with INOCA, including an increased risk of major adverse cardiac events (MACE), heart failure with preserved ejection fraction (HFpEF), stroke, and coronary microvascular dysfunction (CMD) ,10. INOCUnfortunately, INOCA is often under-detected and undertreated in both men and women due to limitations in our current diagnostic tools, inadequate awareness, and bias . Early iThe coronary microvasculature  provides a significant component of the overall coronary vascular resistance and is thereby a pivotal regulator of myocardial blood flow . DisturbThe two endotypes of INOCA include microvascular dysfunction (MVD) and vasospastic angina (VSA). They represent distinct but frequently coexistent mechanisms . A meta-Physiologically, endothelium-independent and endothelium-dependent vasodilator responses regulate the coronary vasculature . AdenosiAberrancies in the above pathway can lead to INOCA . Just asThe MVD endotype is characterized by coronary microvascular disease due to structural remodeling and/or microvascular vasospasm. Structural remodeling in the microvasculature leads to an increased wall-to-lumen ratio and a loss of myocardial capillary density (capillary rarefaction) . This inThe current criteria for diagnosing MVD include the clinical presence of myocardial ischemia , the absence of obstructive CAD on coronary CTA or invasive angiography, and evidence of microvascular dysfunction on invasive or non-invasive coronary reactivity testing . The finAs opposed to the microvascular disease found in MVD, VSA is characterized by epicardial dysfunction without evidence of obstruction. Though functional dysregulation may lead to enhanced vasoconstriction in either epicardial and/or microvascular vessels , VSA is According to the COVADIS criteria, definitive vasospastic angina is diagnosed when nitrate-responsive angina  is accompanied by either transient ischemic electrocardiographic changes  or coronary artery spasm  .CRT, the current gold standard for diagnosing INOCA, measures coronary blood flow (CBF), coronary flow reserve (CFR), thrombolysis in myocardial infarction (TIMI) flow count, and index of microvascular resistance (IMR) ,24. DecrTo assess endothelial dysfunction that leads to vasospasm at the epicardial and/or microvascular level, one can perform invasive provocative testing using intracoronary acetylcholine, which induces coronary vasoconstriction and reproduces ischemic symptoms . VasospaCRT is invasive, expensive, not typically covered by insurance, and not readily available, prompting this investigation into more viable methods for diagnosis.There is growing interest in the use of non-invasive imaging techniques for evaluating INOCA, with CMR being the most promising due to its high spatial resolution and tissue characterization without radiation exposure. Other modalities such as quantitative perfusion, cardiac PET, and CT scans can also play a role. These imaging methods typically involve the administration of a “stressor” or vasodilator, such as adenosine or regadenoson. Contraindications to the use of a vasodilator include the presence of significant reactive airway disease, advanced conduction abnormalities in the absence of a pacemaker, unstable blood pressure, recent caffeine intake, or recent acute coronary syndrome ,26.Coronary CTA (CCTA) can evaluate myocardial perfusion by tracking the movement of contrast from the coronary vasculature into myocardial tissue during rest and after adenosine administration . ContrasCardiac PET is a well-validated imaging modality that can measure myocardial blood flow (MBF), myocardial perfusion reserve (MPR), and myocardial flow reserve  . PET meaCMR is a powerful, non-invasive imaging modality that provides comprehensive evaluation of myocardial structure, function, and both global and regional perfusion without the exposure to ionizing radiation . CMR is Though CMR is a relatively new modality, it has been shown to provide an unmatched breadth of qualitative and quantitative information on cardiac structure and function. Different techniques and analyzing software are emerging that each examine the heart from a unique lens. Here, we compare several applications of CMR in their ability to assess INOCA. The proposed diagnostic algorithm of INOCA, including the use of CMR, is illustrated in When using stress CMR, first-pass sequence perfusion imaging is the most common approach to evaluate coronary perfusion . VasodilSemi-quantitative methods of measuring myocardial perfusion use a parameter called the up-slope with a correction factor known as the arterial input function (AIF). The up-slope represents the signal intensity in the myocardium enhancing over time as contrast is injected. The up-slope has an approximately linear dependence on blood flow . The corQuantitative perfusion methods involve precise measurements of myocardial enhancement, requiring advanced computational power . During Rahman et al.  reportedDeveloping a fully quantitative CMR technique has the benefit of improved diagnostic accuracy but also the ability to characterize disease severity . StudiesThese quantitative methods require more complex imaging protocols and may be more time-consuming, and so they would benefit from a fully automated approach .In-line CMR uses a novel respiratory motion-corrected myocardial perfusion method with automated perfusion mapping, allowing free-breathing acquisition and pixel-wise quantification of MBF . In-linep-value = 0.001).Kotecha et al.  examinedThe scientific community has made great strides in developing the understanding of the clinical significance of INOCA and its disproportionate effect on women. The next challenge is diagnosing INOCA in a manner that is cost-effective, readily accessible, and less invasive than coronary reactivity testing. By applying creative techniques to well-established cardiac imaging modalities, we can lower the barriers for INOCA testing and reduce our high rates of underdiagnosis. CMR perfusion imaging seems to be the most promising, where novel automated software can quickly and non-invasively provide diagnostic data that rival the gold standard.Given the high burden of INOCA and the difficulties in detection, there is growing interest in optimizing our methods for diagnosis. Preliminary studies have demonstrated the potential for non-invasive cardiac imaging in characterizing INOCA, but more work is needed to confirm their accuracy and to learn how they can provide more refined data to stratify patients by disease severity and/or subtype. With more accessible and more revealing diagnostic techniques, we can reduce the number of patients with INOCA who are suffering silently and connect them to the care they need.


Postmastectomy pain syndrome (PMPS) affects nearly half of patients who undergo mastectomy to treat breast cancer. As the survival rate of breast cancer increases with advancements in treatment, the incidence of PMPS is also increasing. Patients with PMPS can experience unrelenting, chronic pain refractory to traditional management with oral pharmacotherapy in conjunction with nonpharmacologic treatment ). Neuromodulation is an emerging treatment modality for numerous chronic pain conditions. This case report highlights the tremendous success of spinal cord stimulator placement for a patient with PMPS. Breast cancer is the most common cancer diagnosed globally, according to the American Cancer Society . A corneNeuromodulation is an emerging approach over the last decade being used for more definitive treatment of chronic pain syndromes. This procedure involves targeted electrical stimulation of peripheral and central nervous system neuronal firing patterns to increase levels of pain-modulating neurotransmitters and suppress hyperexcitable pain-driving neurotransmitters. Specifically, the generation of electric fields between electrodes in the epidural space changes the electrical potentials of surrounding tissues, triggering action potentials in excitable areas and activating large dorsal column axons. Electrical charge is delivered using various waveforms differentiated between pulse amplitude, width, and frequency, which, in combination, deliver a charge to the targeted nerve area. It is not currently understood which fibers are activated to achieve maximal pain relief or how activation patterns change with chronic spinal cord stimulation (SCS). Currently, it is thought that SCS promotes the activation of gamma-aminobutyric acid (GABA) and adenosine-1 receptors, leading to pain modulation .Neuromodulation has been used scarcely, but successfully, for PMPS pain. The two types of neuromodulation that have shown efficacy in chronic pain syndromes include traditional SCS (t-SCS) and dorsal root ganglion (DRG) stimulation. Here we describe a successful trial and implantation of a dorsal column spinal cord stimulator in a patient experiencing PMPS pain that was previously refractory to oral medications, physical therapy, and targeted nerve injections.A 57-year-old female presented to the interventional pain clinic with right-sided neuropathic breast pain that started at the end of October 2019 following treatment for breast cancer. The patient was initially treated with lumpectomy for right breast ductal carcinoma in situ (DCIS); however, after one year, the patient had a 2.5cm growth at her lumpectomy site showing a human epidermal growth factor receptor 2-positive (HER2+) invasive ductal carcinoma, treated with mastectomy. The patient received a right breast reconstruction with a deep inferior epigastric perforator flap, followed by 20 sessions of breast radiation, causing severe breast pain. The pain was described as diffuse, burning pain along her right breast, axilla, and right upper extremity, with concurrent allodynia in these areas as well. She had previously tried physical therapy and desensitization without relief. Furthermore, a thoracic medial branch block was attempted once with minimal, short-term relief. Her pain was managed with Lyrica 75 mg twice daily, but her symptoms continued to limit her daily activities. She noted that the nerve pain became much more severe if she missed even one dose of Lyrica.As the pain continued to cause increased functional limitations and neuropathic medications had not been successful for more than 12 months, the decision was made to trial SCS implantation. Before trial implantation, a cervical MRI was obtained and showed no acute findings with age-appropriate changes. Her baseline pain levels before SCS implantation ranged from 6/10 to 10/10, with an Oswestry Disability Index (ODI) of 42%, which is considered a moderate disability.For trial implantation, epidural access was obtained at the T12/L1 level, and neurostimulator electrode leads were placed at the top of thoracic T2 and middle of T3 vertebral levels, as seen below in Figure Differential target multiplexed (DTM) SCS was used. Following a seven-day trial implantation, she experienced over 80% pain relief during the trial implantation as well as significant improvements in mood and functional ability. Notably, the patient did not require any neuropathic pain medication during the trial period. A permanent SCS was implanted at the same vertebral levels as the trial stimulator. Pain scores were reassessed after permanent implantation at one week, three months, and six months, with the patient continuing to experience significant pain relief and significant improvement with an ODI score of 0% at the six-month follow-up, which is consistent with no disability. There was a drastic improvement in pain as well as quality of life at the six-month follow-up for our patient. In addition, complete cessation of both NSAIDs and neuropathic pain medications was achieved at six-month follow-up Table .Postmastectomy pain syndrome can be challenging to treat as current treatment options are limited and many have sparse supporting literature. Often, patients need to heavily rely on neuropathic oral medications such as gabapentin and pregabalin. However, these medications are not always successful and also come with unwanted side effects such as drowsiness, altered mental status, and weight gain. Alternatively, peripheral nerve blocks have utility but are difficult to obtain long-lasting pain relief.Neuromodulation has been FDA-approved for various neuropathic pain conditions, including post-laminectomy pain syndrome, complex regional pain syndrome, and diabetic neuropathy. Absolute contraindications to SCS placement include previous dorsal root entry zone surgery or disruption, critical central canal stenosis, neurologic deficit with surgically correctable pathology, spine instability or deformity at risk for progression, need for future MRI or implantable cardioverter defibrillator (ICD) placement, pregnancy, severe cognitive impairment interfering with device operation, unacceptable living situation or social environment, and active substance use disorder. Relative contraindications that would preclude SCS placement include anatomic conditions , medical comorbidities , and psychosocial factors including reduced functional capacity, somatoform pain disorder, and significant psychosocial characteristics . We recoGiven the large neuropathic component of PMPS, we feel trialing a spinal cord stimulator among patients who have failed conventional therapy to assess the improvement in a patient’s ODI is warranted. Spinal cord stimulation involves the development and modulation of electric fields between electrodes, leading to an increased level of pain, attenuating neurotransmitters, and suppressing hyperexcitable neurons and neuronal pathways. Traditional SCS targets large-diameter dorsal column neurons, which in turn can inhibit pain signaling. Dorsal root ganglion stimulation, another form of spinal cord stimulation, directly targets the primary cell bodies of the dorsal root ganglion and has also shown efficacy in the management of chronic neuropathic pain. Dorsal root ganglion stimulation has increased root specificity, allowing for more targeted pain attenuation. Trials of neuromodulation for chronic neuropathic pain continue to grow; however, further data are needed to determine efficacy among PMPS patients.A seven-patient case series done at a major US cancer center for PMPS patients found that 85% of patients achieved >50% pain relief with neuromodulation . These cAs this case series showed, there is significant inter-patient variability as it relates to the technical aspects of spinal cord stimulator implantation. Lead placement in these cases varied from as high as C3 to as low as T8. The authors of this case series also used a variety of stimulators, including burst SCS and tonic SCS. Further investigation would need to be conducted to elucidate how lead placement or SCS type may impact outcomes in PMPS. However, the manifestation and localization of symptoms often vary between patients in PMPS, so the provider's ability to tailor therapy specific to the nature, location, and severity of pain with SCS is essential. In our case, we opted to place leads at the T2/T3 levels and use DTM stimulation. A 2021 multicenter trial of chronic low back pain patients comparing DTM stimulation to traditional SCS showed similar safety profiles and a significantly higher responder rate  within the DTM group as compared to the SCS group . DiffereGiven the unique pain patterns that follow a mastectomy and radiation treatment, we would stress the importance of mapping the stimulator during the trial, as lead placement will likely vary from patient to patient. As the pain in PMPS is unilateral, we also recommend lead placement midline or slightly off midline to the ipsilateral side of the symptom occurrence. We recommend close follow-up throughout the trial period to determine the appropriate programming of the SCS. Aside from pain relief, we looked for other factors, including sleep, mood, a decrease in oral medications, and overall well-being, in determining a successful trial and discussion of permanent implantation.Limitations of this case report include the lack of robust clinical trials for the use of neuromodulation in PMPS patients. In addition, given there is no control group to compare to, less invasive options should be trialed first, as described below in Figure This treatment modality should be considered in patients who are experiencing continued neuropathic pain after failing conservative therapies including desensitization, physical therapy, oral neuropathic medications, and peripheral nerve blocks. A recent review on the use of neuromodulation in chronic post-cancer pain  underscored the importance of further integration of neuromodulation in these debilitating and often difficult-to-treat conditions. To date, approximately 10 successful implantations of SCS for PMPS treatment have been reported in the literature .Our patient’s successful implantation eliminated oral medications completely and, more importantly, significantly improved her quality of life. She has returned to running and traveling, and she finally feels that she has healed from her breast cancer battle. We anticipate annual follow-up for this patient unless more frequent follow-up is needed or complications arise.To the best of our knowledge, this case represents an early successful use of SCS in the management of PMPS. Spinal cord stimulation has incredible potential in the management of neuropathic pain among PMPS patients, targeting specific vertebral levels with proper lead placement. Advances in SCS technology, including the use of dorsal column SCS and burst SCS, highlight the promise of further research and investigation into the use of neuromodulation to treat chronic postmastectomy pain.


Editorial on the Research TopicInsights in coronary artery disease: 2022De Luca et al.).Atherosclerosis is a multifactorial disease that starts in childhood; inflammation plays a role at every step of atherogenesis, and risk factors further accelerate the underlying inflammatory process . AtherosCorti et al).An acute coronary event due to a thrombosed lesion developing after mechanical rupture of an atheroma causes sudden death. Various morphology and tissue composition factors such as the cap thickness, lipid core stiffness, remodeling index, and blood pressure play a role in its mechanical stability. More recently, the presence of microcalcifications has also been shown to be an important factor. In a well-designed study, the authors showed that microcalcifications and cap thickness are the two most alarming biomechanical traits that govern the risk of mechanical rupture . Computed tomography angiography (CTA) is used in a quick and easy way for coronary non-invasive evaluation. Intravascular ultrasound (IVUS) is used to show the morphological features of the lesion. Optical coherence tomography (OCT) has been observed to be more effective than IVUS in accurate anatomical assessment of coronary stenotic lesions with exceptionally high resolution during angiography . In addition, computational fluid dynamics (CFD) have been applied to estimate computational FFR from coronary CTA- or OCT-based three-dimensional coronary model without using additional pressure guide wires or hyperemic agents.It is difficult to decide on coronary revascularization in patients with chest pain and moderate coronary artery stenosis. Therefore, functional evaluation is essential besides the anatomical evaluation of the presence of coronary artery. Fractional flow reserve (FFR) has been accepted as the gold standard for functionality in avoiding unnecessary interventions in the intermediate stenoses (Abouelnour and Gori). Today, we can evaluate the pathophysiological changes in the coronary vessels with different techniques. Many biomechanical factors, some preventable and some not, may cause restenosis after stent implantation. Intravascular imaging provides unique insights into the biological and mechanical issues that cause stent restenosis (Abouelnour and Gori).Percutaneous coronary intervention (PCI) has a well-established role in revascularization for CAD. Despite the advances in PCI, the pathological changes that occur within the stent still remain a mystery . Furthermore, comprehensive evaluation and advanced techniques are important to increase success rates and decrease complications. Intravascular examinations used during the procedure increase the success rate in this context. A recent study concluded that pre-stent IVUS assessment in CTO PCI provides important information on vessel morphology and size .Revascularization of chronic total occlusion (CTO) is considered a complex PCI and carries a higher risk of procedural failure, complications, and in-stent restenosis than other PCIs . CTO revLeone et al.). A TARGET-FFR study found that FFR values of routine post-PCI physiology guidance can safely and effectively improve the final FFR values in a significant number of the worst-affected patients. FFR value ≥0.90 after PCI was shown to be associated with a reduced risk of adverse cardiovascular events  may be a potential prognostic index in patients with multi-vessel disease (MVD) if it correlates significantly with differences in outcome and LV remodeling . In a reLee et al.).The COMPARE II trial , a 5-yeaIn conclusion, there have been important developments in the diagnosis, treatment, and follow-up of CAD. Although there are significant improvements, some essential problems remain unsolved in the management of patients with CAD.


A peripheral pulmonary artery aneurysm (PAA) is a dilatation involving all 3-vessel wall layers  of a distal pulmonary artery. It represents a rare but potentially life-threatening condition. There are only some reviews of transcatheter embolization of unruptured idiopathic peripheral PAAs. Association with cardiac diseases, infections, vascular anomalies, pulmonary hypertension, and vasculitis has been noted. We report a case of a 38-year-old woman, with a history of third-degree atrioventricular (AV) block, treated with pacemaker placement, who presented a PAA in the left pulmonary lobe. Transcatheter coil embolization was performed, using a triple coaxial catheter system  to prevent rupture and the aneurysm was successfully embolized. Although there is no consensus on the treatment for unruptured idiopathic peripheral PAAs, transcatheter embolization may be a promising treatment option. Pulmonary artery aneurysms (PAAs) are uncommon. An incidence rate of 0.007% was reported in autopsies. A peripheral pulmonary artery aneurysm (PAA) is a dilatation involving all 3-vessel wall layers  of a distal pulmonary artery A 38-year-old woman presented a medical history of third-degree atrioventricular (AV) block, treated with 2 pacemaker placement, and previous episodes of pulmonary embolism. When she was affected by COVID-19 infection, she was admitted to the thoracic surgery department, due to her increased thrombotic risk, although she did not present any COVID-19 pneumonia. She did not have any CT scans during her initial presentation from COVID-19. A chest CT scan, 2 months after the infection, showed a round lesion in the left upper lobe. This finding was consistent with a PAA . The lesPulmonary artery aneurysms represent a potentially life-threatening condition, although their low incidence, and could present a challenge for timely diagnosis and treatment. A dilatation of the distal pulmonary artery involving all 3-vessel wall layers  is defined as PPA. The most accepted cutoff to describe a PAA is a diameter 1.5 times bigger than the greatest diameter of a proximal segment of the same artery. Although the real occurrence of peripheral PAA is uncertain, autopsy research proved an incidence of 0.007% An anatomic classification differentiates peripheral PAA (11%), arising from the distal vessels , and central PAA, originating from a major pulmonary vessel (89%) Another morphological classification distinguishes saccular, which is defined as a noncircumferential outpouching of the vessel wall, and fusiform aneurysms, which include the entire circumference of the vessel Symptoms are nonspecific and may overlap with different conditions. In addition, patients may remain asymptomatic. Reported symptoms include hemoptysis, which might be suggestive of imminent aneurysm rupture, shortness of breath, chest pain, palpitations, or syncopal episodes Etiologies of PAA can be distinguished as congenital or acquired. A subgroup of acquired etiologies is represented by idiopathic aneurysms. Congenital causes were recognized as the main reason for PAA formation. More than 50% of all cases have been associated with congenital heart disease . Other common congenital causes of PAA include diseases affecting connective tissue and vessels  PAAs should be distinguished from pulmonary arteriovenous malformations (AVM), due to the risk of paradoxical embolism of AVM. AVM are abnormal direct connections between the pulmonary arterial and venous circulation that bypasses the capillaries developing a high-flow system. This lesion could mimic an aneurysmal sac of PAA at imaging The mortality rate associated with rupture was about 50%-100%; death is mainly related to aspiration and asphyxia following intrapulmonary hemorrhage PAA may be suspected at standard radiography when a hilar enlargement, lung nodule, or pulmonary mass is found. Computed tomography angiography (CTA) is the mainstay of imaging for diagnosis and follow-up of PAA, assessing the presence, size, location, and characteristics of PAAs and providing information on the etiology of aneurysms.Catheter-directed angiography represents the gold standard for the diagnosis of PAA. This technique describes the extension of vascular involvement, assesses the right-sided cardiac pressures, and allows simultaneous endovascular treatments. Major limitations are not to provide information regarding extra-luminal structures, important to determine etiology, and to be an invasive exam Once a PAA is diagnosed, the next step is to establish the appropriate treatment. There are no clear guidelines for the best management.Conservative treatment appears reasonable for asymptomatic patients with stability in PAA diameter and without significant PAH In patients with PAH, surgical treatment  should be considered. Although specific guidelines for endovascular versus surgical treatment of PAA do not exist, many case reports support first-line endovascular treatment with coil embolization (or vascular plugs), when feasible, due to the high morbidity and mortality rates of surgical treatment. Nevertheless, central fusiform aneurysms require surgical management There is no sufficient evidence about the rate of rupture of idiopathic peripheral PAAs, although high mortality rates have been described for solitary peripheral PAAs In the present case, intrasaccular embolization was achieved using coils. The patient had not any complications.Despite the infrequency of peripheral PAAs, prompt recognition and diagnosis are imperative for both radiologists and clinicians, due to the high mortality rates related to rupture. Accurate guidelines for the management of PAAs are still needed, to help clinicians in defining when intervention is appropriate. Endovascular coil embolization is the cornerstone of treatment due to its minimal invasiveness and lower rates of complications compared to surgery, although further studies are required.This is to state that the patient gives her full permission for the publication, reproduction, broadcast, and other use of photographs, recordings, and other audio-visual material of herself (including of her face) and textual material (case histories) in all editions of the above-named product and in any other publication , as well as in any advertising or promotional material for such product or publications.She declares, in consequence of granting this permission, that she has no claim on ground of breach of confidence or any other ground in any legal system against authors and their agents, publishers, successors and assigns in respect of such use of the photograph(s) and textual material (case histories).