In contrast with other kinds of neoplasia, endocrine tumours are less frequently recorded, in part because many of these go undiagnosed. As endocrine tissues usually present several subtypes of cells, differentiation between normal and tumour tissue is difficult, as complex phenotypes and often paradoxical behaviour patterns are involved. This makes a reliable prognosis and successful management of endocrine tumours difficult to achieve. Hence, this situation has led to a relatively slow improvement in establishing the pathogenesis of endocrine tumours. The present Research Topic “Architects of Endocrine-Related Tumour Growth” focuses on the nature of the heterogeneous cellular features and pathways involved in the cellular growth programs that shape tumour development and considers their implications in the evolution and treatment of endocrine tumours. The involvement of inextricable signalling networks is addressed, in which the orchestration of many interdependent pathways and cellular fates may guide, preserve, or interfere with endocrine-related tumour growth.Zhu et al. This group develop a prediction model for testicular germ cell tumour metastasis and recurrence based on an mRNAlncRNA-miRNA regulatory network constructed from differentially expressed RNA profiles among tumoral and normal tissue, and integrated with RNA-Seq data and public clinical databases. They also describe the correlation between the dysregulation of mRNA with immunomodulation, cell migration and invasion, indicating a link between immune cell infiltration and testicular germ cell tumours. Finally, they identify GRK4, PCYT2, and RGSL1A as being potential specific biomarkers that could predict relapse-free survival, tumour immunity and chemotherapeutic resistance.A current approach for signalling network determination is presented by Guang et al. explores the ultrasonic features of preoperative clinical data combined with superb microvascular and contrast-enhanced ultrasound imaging of thyroid nodules and papillary thyroid cancer (PTC). These authors perform a multi-factor analysis to determine the predictive value of central lymph node metastasis from PTC. This provides a correlation between metastatic behaviour and ultrasound characteristics such as tumour size, multifocality, microcalcification particularities, vascularization, and contact with the adjacent capsule. In addition, the study establishes a criterion for a high risk of lymph node metastasis based on the grayscale ultrasound data, thereby contributing to the development of a clinical basis for the early diagnosis, treatment and prognosis of thyroid cancer.With the aim of improving early diagnosis of tumour growth, an original article by Martin et al. explore the role of nuclear localization of the insulin-like growth factor receptor (IGF1R) in the regulation of glioblastoma cellular behaviour. These authors modify a glioblastoma cell line to either allow or block IGF1R translocation to the nucleus. This study reveals that IGF1R nuclear localization increases cell motility, as well as the metabolic activity of glucose and lipids, without having any repercussions on proliferation. Furthermore, in vivo studies using subcutaneous tumour xenografts show that nuclear-localized IGF1R provoke metabolic shifts that result in increased proliferation and accelerated tumour growth. However, it also sensitised cells to pharmacological therapy with IGF1R inhibitors. These findings support the hypothesis that although IGF1R nuclear localization in glioblastoma cells may contribute to an aggressive phenotype, it also represents a potential therapeutic possibility for patients whose tumours exhibit this intracellular localization.To further the understanding of the intricate molecular dialogs involved in endocrine-related tumour growth, Sacca and Calvo review the impact of several factors and fatty acids secreted by the periprostatic adipose tissue (PPAT) on the prostate cancer (PCa) microenvironment. In this article, they describe how PPAT acts co-ordinately with PCa development by adjusting its metabolic performance according to the stage of tumour progression. These authors report that in advanced tumours, the metabolic secretome profile is enriched in energy balance and hormone response molecular signalling, with the catabolic metabolism of polyamine, protein, and nucleotide probably required for tumour growth. Thus, these metabolic reprogramming hallmarks of PPAT secretome may serve as indicators for the early diagnosis of high-risk tumours and provide positive therapeutic effects.Tumour development requires cellular physiology and metabolic reprogramming to deal with environmental modifications and new cellular demands. Moreover, the dynamical tumour ecosystem may adjust its needs and influence cellular neighbourhoods. In this regard, Ritch and Telleira extensively assess these events for epithelial ovarian cancer (EOC). In this review, they describe the sequence of microenvironments encountered by EOC cells during transcoelomic dissemination, and the special aspects of these scenarios that can influence cellular fates and tumour progression. These authors describe EOC cell fluctuations within the different cellular ecosystems, starting at the ovaries or the fallopian tubes, whose pro-inflammatory surroundings could favour precursor lesions. In addition, the detachment process is followed by the ability to survive in the peritoneal fluid, thereby evading cell death signalling and enabling suitable cellular communication. Metastatic EOC cells require adherence, and migrate as spheroids through the peritoneum, being able to reach distant tissue and invade as primary or secondary tumours. Related to this, the involvement of the microenvironment effects over EOC chemoresistance has been consistently reported. This extensive overview of the entire process allows for a better understanding of the role of cellular and non-cellular factors during EOC transcoelomic dissemination, promoting the creation of novel therapeutic strategies to treat this pathology.Tumour progression represents the coevolution and integration of phenotypic cellular changes within the microenvironment. Sabatino et al. summarise current findings in pituitary neuroendocrine tumours by examining the range of possible cellular fates involved throughout tumorigenesis. This article emphasises the relevance and importance of integrating emerging fields in pituitary research, such as cellular senescence, autophagy, mitochondrial function, metabolic reprogramming, stem cell niches and non-apoptotic cell death during tumour progression. These authors expose the need for innovative models that are able to reflect the complex interplay that occurs during tumour pathogenesis. This review also highlights the requirement for the incorporation and systematization of newly available data involving tumour origin, behaviour and plausible clinical results, in order to improve tumour classification.For tumour development to be achievable, cells must acquire new abilities beyond unregulated proliferation. Different cellular outcomes may emerge during tumour development that can either favour or constrain cell growth. Sousa et al. review existing knowledge about autophagy in adrenal tumours. As previously reported for different tumours, autophagy in this neoplasia presents a dual role towards pro-survival or pro-death, depending on the context, and its action is interconnected with other cellular processes. Both the induction and inhibition of autophagy have revealed possibilities for treatment strategies for adrenal neoplasms, with the impact of autophagy on tumour progression appearing to depend on the degree of tumour evolution and the type of therapy employed. Adrenal autophagy might be associated with steroid synthesis and extracellular vesicle biogenesis, suggesting potential targets for tumour diagnosis and management. These authors emphasise that further research is still required to clarify the clinical implication of autophagy modulation in adrenal tumours.In conclusion, the evidence presented here shows that the amount of data accumulated over recent decades highlights the complexity of endocrine-related tumorigenic mechanisms. Indeed, the pathogenesis of multiple endocrine neoplasia is still unclear, with their management mostly depending on histopathological criteria. Thus, a proper elucidation of the plethora of diverse genetic, epigenetic, and biochemical signalling pathways, together with a better understanding of the metabolically and physiological cellular outcomes implicated in tumourigenesis, would be particularly useful, as using histological characteristics alone restricts the accuracy of the diagnosis and prognosis. We have now reached a point where it is necessary to create broader modelling strategies that allow us to consider not only a single component, but the sophisticated and multifaceted network that influences tumour progression.MES, GD-T and ALD contributed to conception and design of the editorial. MES wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.This work was funded by Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET PIP 2020-2023 No. 11220200102210), Secretaría de Ciencia y Tecnología, Universidad Nacional de Córdoba (SECyT-UNC 2018-2022 Nº33620180100675CB), and Agencia Nacional de Promoción Científica y Tecnológica - Ministerio de Ciencia y Tecnología (FONCYT-PICT 0950-2020) to ALD.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The Japanese diagnostic criteria for autoimmune gastritis (AIG) were established by the “Study Group on the establishment of diagnostic criteria for type A gastritis,” which is related to a workshop associated with the Japan Gastroenterological Endoscopy Society (JGES) and the Committee of AIG Research Group (CARP). The criteria were set as follows: the cases of confirmed diagnosis are patients in whom either the endoscopic or histological findings, or both, meet the requirements for AIG and who are confirmed to be positive for gastric autoantibodies . The presentation of endoscopic findings of early-stage AIG in the diagnostic criteria was withheld owing to the need for further accumulation and characterization of endoscopic clinical data. Therefore, diagnosis of early-stage AIG only requires histological confirmation and gastric autoantibody positivity. Suspected cases are patients in whom either the endoscopic or histological findings, or both, meet only the requirements for AIG. Histological findings only meet the requirements for early stage. AIG has been underdiagnosed in the past, but our study group’s newly proposed diagnostic criteria will enable a more accurate and early diagnosis of AIG. The criteria can be used to stratify patients into various high-risk groups for gastric tumors and pernicious anemia. They would allow the establishment of an appropriate surveillance system in the coming years. Nevertheless, issues such as establishing the endoscopic findings of early-stage AIG and obtaining Japanese insurance coverage for gastric autoantibody tests require attention. In 1973, Strickland and Mackay   ) findinggen [PG] , iron degen [PG] –9, and ggen [PG] –16; closgen [PG] –24; and st (UBT) . Terao est (UBT)  retrospeA characteristic endoscopic finding of AIG is corpus-dominant advanced atrophy –31. In aSeveral factors have clinical significance in the diagnosis of AIG. First, vitamin B12 deficiency increases the risk of pernicious anemia and neurological diseases such as subacute combined degeneration of the spinal cord , 43, perHowever, currently, no clear diagnostic criteria for AIG have been established. Thus, a comprehensive diagnosis is made from findings such as atrophic endoscopic findings in the gastric body to the fundus, presence of gastric autoantibodies, high serum gastrin levels, and characteristic histological findings .In this article, we propose the diagnostic criteria for AIG in Japan, including its endoscopic and histologic characteristics.Numerous cases should be examined to create the diagnostic criteria for AIG. In 2015, the Committee of AIG Research Group (CARP) was established, which centered on approximately ten facilities in Japan that were actively conducting clinical research on AIG. An achievement of this meeting was that the results of a multicenter study involving a clinicopathological examination of 245 AIG cases were reported at the American College of Gastroenterology in 2017 (Digestive Disease Week) and published in Digestive Endoscopy in 2020 .“Study Group on the establishment of diagnostic criteria for type A gastritis”, an affiliated study group of the JGES, was established in 2019. By May 2021, three study groups were held (published in 2020), and in May 2022, the diagnostic criteria were published as a report of results . The endIn Western countries, AIG diagnosis is based on the characteristic histopathological findings, the presence of PCA, and/or anti-intrinsic factor antibody (IFA) tests –54, sincTable Histological findings of early-stage AIG were included in this proposed diagnostic criteria, although its endoscopic findings were not presented owing to the need to accumulate further endoscopic clinical data , 37, 41.AIG is characterized by corpus-dominant advanced atrophy, wherein uniform mucosal blood vessels are visible in the corpus –31; thisH. pylori due to the sticky mucus associated with achlorhydria in AIG led to false-positive 13C-UBT results and misdiagnosis in patients who were refractory to eradication therapy [In addition to corpus-dominant advanced atrophy, the sticky adherent dense mucus Fig. a and rem therapy .Fig. 2EnRemnant oxyntic mucosa (oxyntic mucosa pseudopolyps ) refers Foveolar-type hyperplastic polyps are more frequently observed than conventional atrophic gastritis. Maruyama et al.  analyzedH. pylori infection or bile reflux. Furthermore, patients with H. pylori infection also experience atrophy and/or inflammation; thus, the antral area is not necessarily a normal color. Additionally, patchy redness  and the greater curvature of the upper gastric body . Furthermore, one biopsy of each of the gastric angles and middle lesser curvature of the gastric body is recommended to determine the presence or absence of atrophy in the gastric body and the presence or absence of H. pylori infection. Avoiding intestinal metaplasia as much as possible during a biopsy is important to accurately detect G and ECL cells [Chief cells often transform to pyloric gland cells/mucous neck cells (pseudopyloric gland cells); thus, the normal two-layered structure of fundic glands, i.e., the parietal cell/ mucous neck cell layer and the chief cell layer are obscured, although the parietal and mucous neck cell layer is preserved. Many parietal cells remain, although swelling, intraluminal protrusion, and shedding  are observed. Hyperplasia of ECL is either absent or mild, and mild-to-moderate lymphocytic/plasma cell infiltration is observed between the gastric glands. Gastrin (G) cells in the pyloric gland mucosa also show mild hyperplasia in the early stage.Early-stage AIG is diagnosed when the above-mentioned histological findings are observed. Lymphocytic infiltration/plasma cell infiltration in the stroma between the oxyntic glands and hyperplasia of G cells in the pyloric glands is also used as a diagnostic aid.(1) Early stage Fig. , Table 3Gastric glands of the fundic mucosa are occupied by many-to-moderate numbers of mucous neck cell glands (pseudopyloric glands) and/or pyloric glands. Moreover, parietal cells are markedly decreased or absent if parietal cells are present, and marked degeneration would be noted. Additionally, elongation of the gastric pit and shortening of the fundic gland are observed, and hyperplasia of ECL cells is observed.Marked decrease or disappearance of parietal cells is an important finding, and cases of this with ECL cell hyperplasia are diagnosed as advanced florid-stage AIG. G cell hyperplasia is also used as a diagnostic aid.(2) Advanced florid stage Fig. , Table 3This is a progression of the advanced florid stage. End stage findings may be additionally seen in some cases. The gastric glands are dominated by moderate-to-severe intestinal metaplasia and contain a small amount of pyloric and mucous neck glands (pseudopyloric glands). Elongation of the gastric pit is more advanced, only a small number of gastric glands remain, and hyperplasia of ECL cells can be observed. The diagnosis is the same as that of the advanced florid stage.3) Advanced end stage Fig. , Table 3 AdvancedTo objectively recognize various cells, chromogranin A (synaptophysin is recommended if chromogranin A cannot be used) immunohistochemical staining can support the histological evaluation for ECL cells, HCL cells , 63, 64.An autoimmune mechanism causes AIG; thus, gastric autoantibodies (PCA and IFA) are important diagnostic items, and their sensitivity and specificity are reported to be 81% and 90%, respectively, for PCA and 27% and 100%, respectively, for IFA . HoweverNotably, PCA is evaluated using a fluorescent antibody test in which the patient’s serum is diluted tenfold; a > tenfold result is considered positive, although a tenfold result may be a false positive. Therefore, the diagnostic criteria were set as “at least tenfold is positive, but there is a possibility of changes in the future in consideration of false positives.” Currently, the lack of insurance coverage in Japan for both gastric autoantibody tests is an issue, and it is hoped that the publication of our proposed diagnostic criteria will be a tool for soliciting insurance coverage for these tests.AIG diagnosis is significant for classifying patients into high-risk groups for gastric tumors, such as gastric cancer and NETs, and pernicious anemia, as well as for conducting regular surveillance. Our study group’s newly proposed diagnostic criteria in this article are expected to decrease the rate of underdiagnosis of AIG and promote the detection of early-stage AIG. Furthermore, the criteria can act as a framework for determining appropriate medical care. Urgent issues requiring resolution include establishing the endoscopic findings of early-stage AIG obtaining national health insurance coverage in Japan for gastric autoantibody tests.


Animal cells display great diversity in their shape. These morphological characteristics result from crosstalk between the plasma membrane and the force-generating capacities of the cytoskeleton macromolecules. Changes in cell shape are not merely byproducts of cell fate determinants, they also actively drive cell fate decisions, including proliferation and differentiation. Global and local changes in cell shape alter the transcriptional program by a multitude of mechanisms, including the regulation of physical links between the plasma membrane and the nuclear envelope and the mechanical modulation of cation channels and signalling molecules. It is therefore not surprising that anomalies in cell shape contribute to several diseases, including cancer. In this review, we discuss the possibility that the constraints imposed by cell shape determine the behaviour of normal and pro-tumour cells by organizing the whole interconnected regulatory network. In turn, cell behaviour might stabilize cells into discrete shapes. However, to progress towards a fully transformed phenotype and to acquire plasticity properties, pro-tumour cells might need to escape these cell shape restrictions. Thus, robust controls of the cell shape machinery may represent a critical safeguard against carcinogenesis. Animal cells exhibit great diversity in their shape. Cell shape is often regulated by cell fate determinants, in order to adapt cell geometry to a particular cellular function ,2. HowevDrosophila haemocytes transit between five pre-existing shapes in a switch-like manner but never acquire stable intermediate shapes distinct from the pre-existing ones ,6564,65]To explain cell fate switching driven by changes in cell shape, specific signalling pathways have been identified. Accordingly, protein–protein interaction maps indicate that cytoskeleton proteins are closely interconnected with signalling components ,74. HoweBecause cell shape is a key determinant of cell behaviour, it is therefore not surprising that alterations in cell architecture is also associated with carcinogenesis. Cancer cells display drastic alterations in their shape, cytoskeletal architecture, intracellular tension and force-generating capabilities . MoreoveOncogenes and tumour suppressors are well known to affect the expression of cytoskeleton genes, cell shape and cell mechanics. For instance, expressing a mutated form of the RAS oncogene in the untransformed MCF10A cells induces a striking change in cell shape from flat to cuboidal . These mDrosophila wing imaginal disc, the behaviour of clones of cells depleted of the neoplastic tumour suppressor gene lethal giant larvae (lgl) or scribble (scrib) depends on the location of the pro-tumour cells. Mutant cells located in the most central blade domain, formed of tall columnar cells, extrude basally and undergo apoptosis. In contrast, in the peripheral hinge region, composed of shorter epithelial cells, mutant clones delaminate apically and show dysplastic growth. These region-specific behaviours correlate with the differential accumulation of apical and basal MTs and depend on the cell-intrinsic architecture, as clones in the blade domain knocked down for lgl or scrib and p115 RhoGEF accumulate basal MTs and extrude apically, similarly to lgl or scrib-depleted clones localized in the hinge domain [KRAS and mutants for the Fbw7 tumour suppressor depends on their location within pancreatic ducts. In smaller ducts composed of elongated cells, mutant clones evaginate basally away from the duct lumen and display aggressive behaviour. In contrast, in large ducts formed of cuboidal cells, pro-tumour clones invaginate apically towards the duct lumen and display less aggressive behaviour. These differential responses are not tissue specific, as they can be recapitulated in ducts of the lung. They are also independent of the oncogenic combination, as clones expressing oncogenic KRAS and deleted for the p35 tumour suppressor display identical behaviours. Computational simulations suggest that changes in apical–basal tension in transformed cells and the bending modulus that mimics small and large ducts, dictate the behaviour of mutant clones. Thus, differences in tension imbalance and whole tissue curvature appear to determine tumour morphology and aggressiveness [In addition, the initial shape of untransformed cells might also dictate whether cells are more susceptible to initiate tumorigenesis. Not all cells within a tissue respond equally to tumorigenic triggers. In the e domain . Likewissiveness . Even thsiveness  or that siveness ,102.diaphanous in Drosophila epithelia induces tissue overgrowth through activation of the YAP/TAZ oncogene Yorkie [Dystonin also restricts YAP activity and consequently cell growth, anchorage-independent growth, self-renewal and resistance to doxorubicin in the untransformed human mammary epithelial cell line MCF10A [myosin IIa (Myh9) using an epithelial-specific Keratin 14-Cre recombinase induces multiple invasive squamous cell carcinoma in TGFβ-Receptor II conditional knockout mice, suggesting that a decrease in cell mechanics enhances tumour susceptibility [Drosophila when compared with younger individuals [Caenorhabditis elegans, actin cytoskeletal disorganization resulting from ageing can be prevented by overexpressing the heat shock factor (HSF-1). Conversely, inhibiting HSF-1 function causes the actin cytoskeleton to age prematurely [Drosophila cells and are fewer and/or shorter in old rats [Anomalies in cell shape, cytoskeleton structure and dynamics could also provide a favourable ground for tumour initiation. Accordingly, altering the expression of cytoskeleton genes triggers or predisposes to tumorigenesis. For instance, inactivating actin-capping proteins or overexpressing the actin nucleator e Yorkie ,104. Thee MCF10A . Moreovetibility . Change tibility . Cells dtibility . Cellulatibility ,110. Actividuals ,112. Desividuals ,114. In maturely . Ageing old rats ,117. Altold rats . HoweverThus, when considering the Waddington’s epigenetic landscape, in the presence of an oncogenic trigger, the ability of cells to climb up hills and fall into distinct basins of attraction could depend on the constraints imposed by cell shape. Depending on the stability of each attractor (depth and climbing distance of the basin), mutations in genes affecting the cytoskeleton’s structure and dynamics could also reprogram the whole signalling network, allowing cells to reach other basins of attraction . HoweverTaken all together, these observations provide evidence that cell shape, dictated by the organization and mechanical properties of the cytoskeleton, has a central role in controlling the behaviour of normal and pro-tumour cells. To coordinate cell fate switching, global and local changes in cell shape affect many signalling molecules simultaneously within the whole interconnected signalling network. Because the cytoskeleton constitutes a coherent, unified system running all over the cytoplasm and linking a variety of cellular compartments, including AJs and FAs or the plasma membrane and the nuclear envelop, it fits into a suitable position to coordinate signalling events and therefore the cell response through changes in gene transcription. The cell shape-dependent control on signalling networks can help to explain why alterations in the expression or activity of cytoskeletal components can drive cancer-associated phenotypes or may provide a favourable ground for tumorigenesis in the presence of an oncogenic trigger, such as in elderly cells. It can also explain why tumours arise in specific locations. Thus, a robust control of the cell shape machinery may represent a critical safeguard against tumorigenesis that needs to be neutralized by cancer cells in order to survive assaults from the microenvironment. This raises the question of how pro-tumour cells could override these shape-dependent constraints. Further work is required to elucidate the rules underlying the control of regulatory networks by the cytoskeleton in normal cells and how this control is affected in cancer cells.


Wolbachia’s Cif proteins in PLOS Biology provides supportive evidence for the “Host modification model,” although the alternative “Toxin–antidote model” is still in the running.The mechanism of symbiont-induced cytoplasmic incompatibility (CI) has been a long-standing mystery. A new study on  The mechanism of symbiont-induced cytoplasmic incompatibility has been a long-lasting mystery. This Primer explores a new study on Wolbachia’s Cif proteins in PLOS Biology that provides supportive evidence for the “Host-Modification Model,” although the alternative “Toxin-Antidote Model” is still in the running. Wolbachia, Cardinium, and others, for driving their infections to spread into host populations. Typically, CI manifests as complete or partial offspring lethality specific to mating between infected males and uninfected females, which entails defective segregation of paternal chromosomes at the first mitotic division and subsequent developmental aberrations. Since the first recognition of symbiont-induced CI in Culex mosquitos in the 1970s, the molecular basis of CI has been elusive, with the abovementioned reproductive phenotypes being accounted for by “toxin–antidote,” “modification rescue,” or other conceptual hypotheses [Cytoplasmic incompatibility (CI) is an elaborate strategy of some microbial symbionts, such as potheses .Wolbachia strains wMel of Drosophila melanogaster (cifA and cifB) and wPip of Culex mosquitoes (cidA and cidB) [Drosophila flies carrying the Wolbachia-derived genes were generated and mated with wild-type flies, by which means the host phenotypes analogous to CI were reproduced: The transgenic male flies suffered embryonic lethality of their offspring when mated with uninfected wild-type female flies [Wolbachia-infected wild-type female flies [In 2017, this long-standing stasis was broken by identification of CI genes of nd cidB) ,4. Notable flies ,4 and rele flies .Wolbachia’s CI proteins in detail during the host’s gametogenesis and pre- and postfertilization processes.By the breakthrough-making studies, the previously conceptual CI factors were embodied as real genes and proteins, which boosted accumulation of information regarding the dynamics, interactions, and functioning of the CI proteins, called CifA (or CidA) and CifB (or CidB) –10 here and the PLOS Biology, Kaur and colleagues [Wolbachia strain wMel during the early developmental course of wild-type and transgenic D. melanogaster. What they demonstrate are the following: In testis, (i) CifA and CifB localize to nuclear DNA throughout spermatogenesis; (ii) Cif proteins cause abnormal histone retention in elongating spermatids and protamine deficiency in mature sperm; and (iii) in mature sperm, CifA and CifB dissociate from nuclei and relocate to the acrosome and/or sperm tail. In ovary, (iv) CifA localizes to the germ cell nuclei and cytoplasm of early-stage egg chambers; (v) by contrast, CifA is not detected in late-stage oocytes; and (vi) Cif proteins remain undetectable in fertilized embryos. In addition, using protamine mutants of D. melanogaster, they demonstrate that (vii) protamine gene knockout results in increased protamine deficiency in mature sperm as well as enhanced intensity of CI. Furthermore, they identify a newly annotated bipartite nuclear localization signal (bNLS) sequence in CifA and demonstrate that (viii) bNLS of CifA plays a role in expression of CI and rescue. Taken together, these observations are generally concordant with the “Host modification model” of CI (In this issue of lleagues  provide l” of CI . The expcifA is identified as the essential gene for rescue [However, unsolved mysteries still remain. Kaur and colleagues  report tr rescue ,6, CifA r rescue  highlighNotably, in contrast to the “Host modification model”  supporteWolbachia strain wPip, which is comparable, although not perfectly, to the cytological work on CifA and CifB of the Wolbachia strain wMel by Kaur and colleagues [Wolbachia strains wMel and wPip? Or is it because of differences between the originally endogenous Cif proteins and the foreign transgenic Cif proteins under the D. melanogaster background? Or could other potential factors be in operation?Recently, Horard and colleagues  reportedlleagues . Here, wlleagues  with tholleagues  in the clleagues , while Clleagues , by contlleagues  report alleagues  observedlleagues  distinctlleagues ? Is thisWolbachia-induced CI have been identified as CifA and CifB, it has not yet been established how these proteins interact with each other, with paternal chromosomes, with developing oocytes, and with fertilized embryos, thereby accounting for the dramatic host phenotypes of CI. The current observations, which seem sometimes to conflict with each other, must be clarified, confirmed, and/or reconciled by forthcoming studies expected in the near future. To enable the intricate microbial manipulation of host reproduction by CI, sophisticated and finely tuned interactions must take place across the symbiont proteins and the host cellular components. Do CifA and CifB act on host elements separately or hand in hand? Do Cif proteins firmly stick to paternal chromosomes or merely leave a footprint for modification? How quickly and with what timing do CifA and/or CifB disappear from paternal and maternal germ cells? How does CifA behave in oocytes, with or without interactions with CifB, to perform rescue? Are there any pivotal coactors? Observation, description, and understanding of how the microbial proteins are dancing in the host cellular ballroom will reveal the secret of what makes Wolbachia the most successful endosymbiont across the enormous diversity of the arthropods.In conclusion, although the main players involved in the


Background: Advances in cancer medicines have resulted in tangible health impacts, but the magnitude of benefits of approved cancer medicines could vary greatly. Health Technology Assessment (HTA) is a multidisciplinary process used to inform resource allocation through a systematic value assessment of health technology. This paper reviews the challenges in conducting HTA for cancer medicines arising from oncology trial designs and uncertainties of safety-efficacy data. Methods: Multiple databases  and grey literature  were searched to inform this policy narrative review. Results: A lack of robust efficacy-safety data from clinical trials and other relevant sources of evidence has made HTA for cancer medicines challenging. The approval of cancer medicines through expedited pathways has increased in recent years, in which surrogate endpoints or biomarkers for patient selection have been widely used. Using these surrogate endpoints has created uncertainties in translating surrogate measures into patient-centric clinically  and economically (cost-effectiveness and budget impact) meaningful outcomes, with potential effects on diverting scarce health resources to low-value or detrimental interventions. Potential solutions include policy harmonization between regulatory and HTA authorities, commitment to generating robust post-marketing efficacy-safety data, managing uncertainties through risk-sharing agreements, and using value frameworks. Conclusion: A lack of robust efficacy-safety data is a central problem for conducting HTA of cancer medicines, potentially resulting in misinformed resource allocation. The past decades have seen remarkable progress in cancer care because of advances in prevention, treatment, and palliative care. The advent of some new classes of cancer medicines has redefined treatment paradigm with transformative impacts on patient health outcomes . HoweverIn the context of competing health priorities, health system designs and the ambition of providing universal health coverage, there have been ongoing policy debates about how best to ensure affordable access to effective cancer medicines and improve health system efficiency while incentivizing enterprise and innovation ,7. To thConducting HTA is inherently data-intensive, and one of its key prerequisites is robust data collected from pivotal clinical trials. When data is insufficient or inadequate, assumptions are needed in HTA for estimating an intervention’s benefits, costs, cost-effectiveness and budget impacts. Depending on the set of assumptions, such assumptions could introduce substantial uncertainties, rendering the findings of HTA unreliable and potentially directing resources towards lower-value and non-priority interventions. These low-value interventions could yield worse population health outcomes and cause inefficient resource allocation, defeating the very purpose of undertaking HTA ,13,14,15In recent years, the quest to facilitate early access to new cancer medicines through fast-track regulatory pathways and other regulatory flexibilities has attracted considerable debates about the robustness of clinical trial designs and data . These iTo this end, this paper presents a literature review to describe selected challenges of clinical trial designs and data in oncology as they are applied to HTA of cancer medicines. It first briefly presents what HTA encompasses for health technologies in cancer. It then addresses specific challenges, including translating surrogate measures into clinically and economically meaningful outcomes, using single-arm and basket clinical trials, and lacking data to inform HTA. This paper concludes with suggestions for consideration when conducting HTA of cancer medicines.This is a narrative policy review. A search of peer-reviewed literature from PubMed, Scopus and Google Scholar for “HTA” and “cancer medicines” was conducted. Online resources of grey literature from international public health agencies, including United Nations agencies, governmental HTA bodies and Ministries of Health were also consulted. The literature was initially reviewed to identify potential gaps and challenges in conducting HTA. Initially, we focused on non-structural barriers in implementing HTA  by expanding on the determinants of uncertainties when conducting HTA. Preparatory research for this paper (DT) identified the lack of quality data on efficacy-safety as the major non-structural barrier to conducting HTA at the global level . AccordiHTA has been defined as “a multidisciplinary process that uses explicit methods to determine the value of health technology at different points in its lifecycle”, with the purpose of “informing decision-making in order to promote an equitable, efficient, and high-quality health system” ,18. FiguIn HTA, the notion of value is broadly conceived. Value encompasses clinical effectiveness; safety, costs, and economic implications; ethical, social, cultural and legal issues; and organizational and environmental aspects, as well as wider implications for the patient, relatives, caregivers, and the population ,19. In pHTA can be applied at different points in the lifecycle of health technology, from the pre-market phase , during assessment for market approval, and post-market to eventual disinvestments. Reassessment of value is particularly relevant for cancer medicines because of the rapidly changing therapeutic landscape and standard of care and the considerable budgetary impacts of cancer medicines. It is also essential to re-assess the HTA of marketed medicines as country regulators and payer organizations have become more willing to grant early access to new medicines based on preliminary evidence of positive benefit-risk profiles on the condition that additional evidence will be generated .HTA requires considerable human and financial resources for managing technical, administrative and governance issues during implementation. HTA also requires robust information technology infrastructure and reliable data (cancer registries and administrative databases). In recent years, countries have developed a considerable capacity to support HTA implementation, particularly following the World Health Organization’s resolution WHA67.23 on health intervention and technology assessment in support of universal health coverage .Surrogate measures are laboratory values or radiologic measurements used in place of direct clinical outcomes, such as how long a patient survives, feels or functions , patient-reported outcomes (PROs)) ,26,27. TSurrogate measures are used in clinical trials of investigational cancer medicines to facilitate earlier regulatory approval because they can be measured sooner and with smaller sample size requirements and lower investments for drug development than “direct” clinical endpoints, such as overall survival (OS) and QoL. Moreover, they can be preferred in the context of rare tumors and rare genetic alterations in common tumors and for diseases with long post-trial survival, when several post-progression lines of treatment could jeopardize or dilute the ultimate OS benefit. In a key example, for a third of the medicines investigated in a study using the “PACE Continuous Innovation Indicators” platform, the first regulatory approval based on surrogate metrics was at least 4 years earlier than when OS evidence was published .Regulatory agencies worldwide have accepted surrogate endpoints as the primary evidentiary basis for granting marketing authorization . For exaSurrogate measures are problematic when they have not been fully validated as predictive of clinically-meaningful and patient-centric outcomes . SpecifiWhen ascertaining the benefits of cancer medicines through HTA, improvements in surrogate measures would need to be translated into OS or QoL estimates, extrapolated over time and inform key metrics for HTA, including cost-effectiveness. Such transformation and extrapolation can add substantial uncertainty to the assessment, as their robustness is subject to the assumptions used and the selected methodologies ,42,43,44HTA agencies also lack clear and consistent guidance on evaluating surrogate measures when considering coverage, pricing, and reimbursement decisions. In a recent review, half of the guidance from HTA agencies stated the acceptability of surrogate endpoints for HTA purposes. Still, fewer than 20% of the guidelines reflected a clear difference between surrogate and direct endpoints ,52.The uncertainties associated with surrogate measures could lead to the uptake of low-value interventions at costs that do not align with their true value. A recent study evaluated the budget implications of selected medicines approved through accelerated pathways, which subsequently failed to show a benefit on patient outcomes . The invA major aim of HTA is to evaluate the benefits and costs of new medicine in a context-specific manner, to address local health needs. HTA aims to assess the generalizability of clinical trial results of medicines with consideration to various factors influencing the circumstances of use, such as target population, existing standard of care, and availability of certain clinical services ,65. Any Outcomes in patients who experience different standards of care are also a challenge for HTA ,70,71. FIn recent years, evidence from single-arm trials (SATs) has frequently formed the basis of regulatory approval. In a single-arm trial, statistical approaches have been used for comparing efficacy endpoints indirectly against a historical control or descriptive studies with no comparisons ,76,77. OThe main justification for accepting SATs as the only evidence supporting a positive regulatory decision is the existence of a high clinical unmet need if no other alternatives exist for treating a severe illness. The medicine has shown a likelihood of conferring beneficial therapeutic effects. Some have argued that historical control arms could be developed from previous trials, evidence from routine clinical care or registries, or health claims or electronic health records to complement missing data and fill relevant knowledge gaps in SATs ,78. HoweHTAs based on SATs do not always include external comparators–an important limitation considering the comparative characteristics of HTA. A report analyzing SAT-based HTAs from 21 countries showed that 40% of the HTAs submitted for reimbursement approval did not include any external comparator. In contrast, the remaining 60% of the studies included descriptive external comparators, with no formal statistical assessment of the comparative effectiveness versus the standard of care treatments . AnotherUsing SATs to support regulatory decisions can also hamper the ability to conduct confirmatory randomized clinical trials subsequently. This can happen because clinicians would be more reluctant to enroll patients to participate in the confirmatory trials when the medicine under investigation is already available for clinical use to their patients, perceiving the control arm as not their contemporary standard of care.In summary, SAT study design not only introduces uncertainties on efficacy-safety but also further affects the robustness of HTA because of a lack of a formal comparison arm to assess the incremental costs and benefits. SAT also limits or delays the generation of robust data in future confirmatory trials. Therefore, HTA bodies must deal with highly uncertain and mostly descriptive data to inform recommendations, with a higher likelihood of making misinformed decisions. These challenges are even more pronounced in the context of rare tumors, including childhood cancers, of the issues in completing enrolment in large clinical trials.Basket clinical trials have emerged in recent years to study the effects of medicine targeting certain molecular characteristics in a group, or “basket”, of patients with different tumors but common actionable genetic alterations. New trial designs have tested cancer medicines based on actionable mutations, regardless of the tumor histology, on the assumption of histology-tumor agnosticism. Agnostic indications are approved across cancer types insofar as the tumor harbors a specific molecular characteristic. For example, the US FDA approved tissue-agnostic indication for pembrolizumab based on tumor mutational burden (TMB) as the predictive marker .However, it has been reported that tumor responsiveness can vary by tumor type across several histologies. In the case of pembrolizumab, the pivotal KEYNOTE-158 clinical trial showed that some tumors with high TMB were refractory to pembrolizumab, while others could derive benefits despite low TMB . These dThe challenges faced by HTA when evaluating cancer medicines and other complex health interventions have been the subject of a systematic European study undertaken by members of an umbrella organization called EUnetHTA. In this study, most EUnetHTA member organizations rated the evaluation of gene therapies and histology-agnostic indications of cancer medicines as highly challenging . They noAnother contributor to the lack of timely and adequate data to inform HTA is delays in or absence of post-marketing research. For example, an analysis of data sharing from pharmaceutical companies to US FDA showed a common failure in attaining the agreed deadlines for reporting the numbers and outcomes of the data requests . In addiThe absence of regulatory guidance on resolving the uncertainty that reliance on surrogate measures brings, together with the indiscriminate enthusiasm in the uptake of innovative treatments, necessitates reforming pharmaceutical policy. Uncertainty is inherent in expedited pre-approval drug testing, for too much uncertainty harms patients or wastes resources that could have been invested elsewhere , as showThe development of harmonized requirements for regulatory approvals and HTA can serve to provide clarity and coordination in decision-making. One such approach is presented in the Pharmaceutical Strategy for Europe recently launched by the European Commission . The strIt is worth noting that critics of the harmonization processes had expressed their concern that overarching and dominant, general decisions may be too inflexible to respond to local contexts. Therefore, some degree of autonomy is desirable to enable context-appropriate implementation–one of the core aims of HTA ,24. WhilGeneration of post-marketing data from the companies for new medicines must be a prerequisite for all expedited approval pathways. Post-marketing studies might prompt regulatory re-assessments to inform disinvestments from low-value or even detrimental interventions when the performance of a specific medicine, for example, is lower than or in contrast to what was previously presented for regulatory or reimbursement decisions. However, post-market studies have not been optimally useful in informing post-market HTA and revision of decisions because of various problems, such as delays in organizing these studies, difficult enrolments, and absence of clinically meaningful outcomes ,91,96. TThe uncertainties in HTA due to poor data could be addressed with a risk-based approach. Risk-sharing aims to distribute the consequences of the uncertainties across multiple actors. Specifically, adequate penalties should be imposed on companies when post-market evidence demonstrates benefits lower than previously claimed or when companies do not fulfill a commitment to report post-marketing evidence generation. This could be included as part of the agreement when granting earlier access to the market based on results from earlier clinical trials or less robust clinical trial data .An agreement with the payments to be subject to achieving certain pre-agreed health outcomes or other milestones is called an outcome-based agreement . This meHTA can inform and orient risk-sharing decisions using risk charts and similar tools. For example, a proposed HTA approach to tackle limited evidence regarding safety-efficacy is based on probabilistic models to measure the overall risk from uncertainties . Such anImplementing outcome-based systems based on HTA outputs will require reliable, transparent and solid information system infrastructures and should be expanded only in priorities for high-value interventions.More recently, the introduction of value frameworks has offered the opportunity to operationalize the HTA outcomes and accelerate progress toward priority-setting and performance-based agreements. The scale most widely utilized with HTA applications in cancer is the Magnitude of Clinical Benefit Scale (MCBS) of the European Society for Medical Oncology (ESMO) ,111. ValHTA methods are not perfect and need to be better developed. Still, HTA will primarily benefit from better and more robust data on the safety-efficacy of health interventions. Healthcare systems will need to consider adjusting their evaluative methods and processes so that they can continue to robustly assess the value for money of new treatments and services.Another initiative is the Choosing Wisely campaign, which has helped raise awareness on low-value care by compiling evidence-based lists of such technologies ,122. ThiThe central problem with using HTA for cancer medicines to drive resource allocation decisions is the lack of robust data arising from the extensive use of surrogate endpoints in regulatory approvals, a lack of generalizability of trials to the context of use, SATs and basket clinical trials. Uncertainties in the estimates of the added benefit of health interventions affect how scarce resources should be prioritized, diluting efforts toward decision-making informed by a systematic assessment of benefits and risks and achieving equitable access to beneficial medicines. Where uncertainties exist, risk-sharing policies might help improve efficiency in resource allocation. Value-based frameworks and stakeholder networks can improve the operationalization of HTA, especially in resource-constrained settings. Improving robustness and quality of data, including through better designs of clinical trials based on patient-centered direct endpoints and post-marketing studies, will improve resource allocations and catalyze disinvestments from low-value care. There is a need to end narratives about the estimated benefits of cancer medicines entirely based on speculations and assumptions on surrogate endpoints. There is a need to shift entirely towards data-driven decision-making based on direct-OS and QoL–endpoints while encouraging research on new metrics that can accelerate progress while still measuring patient-centric endpoints . The cen


Cardiac computed tomography (CCT) is now considered a first-line diagnostic test for suspected coronary artery disease (CAD) providing a non-invasive, qualitative, and quantitative assessment of the coronary arteries and pericoronary regions. CCT assesses vascular calcification and coronary lumen narrowing, measures total plaque burden, identifies plaque composition and high-risk plaque features and can even assist with hemodynamic evaluation of coronary lesions. Recent research focuses on computing coronary endothelial shear stress, a potent modulator in the development and progression of atherosclerosis, as well as differentiating an inflammatory from a non-inflammatory pericoronary artery environment using the simple measurement of pericoronary fat attenuation index. In the present review, we discuss the role of the above in the diagnosis of coronary atherosclerosis and the prediction of adverse cardiovascular events. Additionally, we review the current limitations of cardiac computed tomography as an imaging modality and highlight how rapid technological advancements can boost its capacity in predicting cardiovascular risk and guiding clinical decision-making. Cardiac computed tomography (CCT) has emerged in the last decade as an important non-invasive modality for the evaluation of coronary artery disease (CAD) with actively expanding indications. Initial research led to the establishment of a coronary artery calcium score (CACS) for improved risk stratification of asymptomatic patients with intermittent probability for adverse atherosclerotic events; a CACS of zero is associated with low rates of future adverse events . Similarvia CCTA including endothelial shear stress. We elaborate on the role of perivascular fat inflammation in relation to CCTA. Finally, we appraise the limitations of CCT and discuss how technological advances can enhance the capability of CCT in cardiovascular risk prediction in the near future.In the current review, we aim to delineate the contribution of CCT in predicting future adverse cardiovascular outcomes across different clinical scenarios. First, we discuss how CCT can quantitatively assess coronary calcium, the degree of luminal stenosis and total plaque burden, and how these are related to adverse events. We then discuss the role of CCTA based-plaque characterization and its clinical role. Furthermore, we summarize the current state of functional and hemodynamic assessment CCT allows quantification of plaque calcium burden by measuring the Agatston score . CACS isNevertheless, the clinical application of CACS must take into account the pre-test probability of CAD, even when CACS is zero, as plaque can be non-calcified, particularly in younger, high-risk patients. Along these lines, clinical decisions for symptomatic patients should not be based solely on CACS, and in fact, CACS is not recommended in that scenario, as shown in the CORE64 trial where >10% of symptomatic patients with CACS of zero had obstructive CAD .via CCTA include the evaluation of symptomatic patients with suspected CAD. The degree of luminal stenosis as well as the presence of obstructive disease on CCTA, defined as >70% stenosis, correlate very well with mortality risk   .Low attenuation (<30 Hounsfield units) is typically used to easily describe plaques with a large lipid-rich necrotic core, as lipids typically have the lowest CCTA attenuation value. Ruptured plaques tend to have lower attenuation compared to stable lesions (p = 0.001)  . However= 0.001) . Moreove= 0.001) . TherefoNapkin-ring” sign. Refers to a specific plaque attenuation pattern with is a central area of low CCTA attenuation in contact with the arterial lumen surrounded by a ring-like higher attenuation plaque tissue (p < 0.001) indicating a strong and statistically significant association , while large calcification was observed less frequently in ACS lesions than in stable angina   . An impo < 0.05) .CCTA cannot reliably say whether a lesion is mild, moderate, or severe and thus, current research is focused on achieving a complementary functional assessment of coronary plaques that so far has been obtained by stress testing and invasive indices. If successful, it would tremendously improve the prognostic value of CCTA. Functional flow reserve (FFR) is defined as the ratio between the maximum achievable blood flow in the presence of coronary stenosis and the theoretical maximum flow if the stenosis was not present . FFR is Another technique that can add functional information in CCT is myocardial computed tomography perfusion (CTP) . MoreoveEndothelial shear stress (ESS) is the frictional force produced when blood flows through an artery and has proven to trigger biological signaling in the endothelium . PhysiolRecent evidence suggests that perivascular adipose tissue (PVAT) is linked to atherosclerosis as a key regulator and sensor of coronary inflammation , 78. PVADespite its many strengths, CCT for the evaluation of CAD has a few limitations. First, a variety of factors can introduce noise, therefore limiting image quality. Examples include increased heart rate, arrhythmias, high-density materials , high body mass index, and poor patient cooperation . It is typical for calcifications to appear falsely enlarged due to blooming or partial volume artifacts and thus, result in overestimation of the extent of CAD . StudiesThe development of radiomics, as well as the integration of proteomics and lipidomics with CCT images, show promise for increased diagnostic and prognostic performance of CCT images, yielding potentially important clinical benefits. In fact, a radiomic-based machine learning model to identify advanced atheromatous lesions was found to be superior when compared to visual assessment . SimilarIn the past few years, new CCT techniques such as dual-energy CCT and photon-counting CCT have aimed at improving the spatial resolution and the contrast-to-noise ratio of CT scanners . Dual-enCCT has become more widely available and is currently viewed as a first-line diagnostic test CAD. In certain asymptomatic patients, it also provides improved risk stratification, guiding prevention of future adverse events. Further research on image processing could bridge the diagnostic accuracy gap between invasive and non-invasive coronary angiography in regards to grading of calcified plaques and hemodynamic evaluation of lesions. Evaluation of pericoronary fat inflammation could also be broadly adopted for the prediction of future adverse events. In addition, technologic developments aiming at reducing radiation  could reAll authors contributed to the writing and revision of the manuscript and approved the final manuscript.MINOCA-GR study , an investigator-initiated study, supported by Menarini Hellas S.A (Ref. No. 27.11.2020/72059).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Most patients suffering from neoplastic diseases will at some point during their illness be approached surgically. Surgery itself may be unfortunately responsible for tumor proliferation and metastatic spread. With the perioperative period increasingly becoming a focus of research in anesthesia, anesthesiologists have looked at the chance to influence cancer progression based on their choice of anesthesia regimen and strategy. Many anesthetic agents have been investigated for their potential impact on the course of cancer disease. There is an abundance of retrospective studies and very few prospective ones that tackled this issue. The aim of this article is to review the current state of the evidence on general anesthesia involving volatile and intravenous agents as substrates, focusing on halogenated inhalational agents and propofol, to guide clinical decision making in assessments of the best practice for perioperative management of cancer surgery. Neoplastic disease is a one of the major causes of mortality. Worldwide, over 19 million new cancer cases and 10 million cancer-related deaths were estimated for 2020, and for the first-time, female breast cancer, with 2.3 million new cases , surpassed lung cancer (11.4%), followed by colorectal disease (10%) and prostate cancer (7.3%) [Most solid tumors are at some stage approached surgically, and over 80% of new cancer cases will require surgery at least once if not several times during the course of the disease .General anesthetics (GA) are used to facilitate surgical procedures and can be generally divided in volatile  and intravenous agents. Both induce, as a primary effect, unconsciousness in the patient. The exact mechanism of actions, even after over decades of safe clinical use, are still being investigated .Perioperative medicine has become a major focus for modern anesthesiologists  and has Among these many effects, of particular interest are the effects on extracellular matrix (ECM)-degrading proteins such as matrix metalloproteinases (MMP). These proteins are potent remodelers of the ECM, and their abnormal expression bears the potential of enhancing metastatic disease . The effVolatile anesthetics have shown a beneficial effect in ischemia reperfusion injury ,8,9. ThrThe results of in vitro studies using volatile anesthetics in cancer cells are heterogeneous. The in vitro exposure of renal carcinoma cells to sevoflurane increased cancer resistance to the chemotherapeutic agent cisplatin, and increased cell migration and viability . Interesreduce ECM breakdown through the down-regulation of Matrix metalloproteinase 9 (MMP-9), thus reducing the metastatic cancer cell potential [Exposure of human ovarian carcinoma cells to halogenated inhalational anesthetics  enhanced the expression of numerous genes associated with metastatic proliferation  and, witotential .The intravenous general anesthetic propofol has also been investigated regarding its potential effects on cancer cells .In human pancreatic cancer cells, propofol has been found to decrease cell proliferation and migration as well to increase apoptosis rates, possibly through the upregulation of microRNA miR-133a . PropofoIn ovarian cancer cells, it modulated microRNA miR-let-7i, inhibited cell proliferation, and increased apoptosis . Its actLooking at hepatocellular carcinoma (HCC), propofol also efficiently inhibited the growth of HCC cells and activated both caspase-8 and caspase-9, suggesting that both intrinsic and extrinsic pathways induce apoptosis. This is thought to occur through the modulation of miR-199a microRNA . PropofoIn lung adenocarcinoma cells, the inhibition of MMPs via propofol also resulted in diminished cell invasion and migration . SimilarOn the other hand, recent work has shown that propofol promoted tumor metastasis, probably through its affinity for the GABAAR receptor, downregulating the expression of the tripartite motif protein family TRIM21 and subsequently increasing the expression of the Src protein . It is iIn breast cancer, propofol has been shown to significantly downregulate microRNA miR-24, the overexpression of which promotes cell proliferation and inhibits apoptosis . On the There is an abundance of retrospective clinical trials assessing potential differences in general anesthesia regimes in cancer surgery, with many of them favoring the use of propofol, e.g., as in colon cancer , esophagSince immunomodulation plays a significant role in immunosuppression, inflammation, and cancer recurrence , a recenOn the other hand, in a large retrospective study over a three-year period, looking at long-term survival in patients, Wigmore et al. found an increased hazard ratio  for patients undergoing surgery under general inhalational anesthesia , acknowlIn fact, very few prospective clinical studies have tackled the question of whether propofol clinically offers benefits over inhalational anesthesia in cancer surgery.Oh et al. hypothesized that propofol would be less immunosuppressive than sevoflurane in breast surgery; looking at regulatory T cells, Oh et al. found that there was no difference in the tumor-cell-killing capabilities of natural killer- and cytotoxic T-cells .Yan et al. showed in patients undergoing breast cancer surgery that vascular endothelial growth factor (VEGF) serum concentrations where higher after general anesthesia with sevoflurane when compared with propofol but, despite the increase in this angiogenesis promoting marker, found no difference in the recurrence-free survival when comparing the two anesthesiologic strategies .In metastatic disease, one factor affecting the distant spread of the disease is the number and characteristics of circulating tumor cells (CTC) ,51,52,53The question of which anesthesia regimen is better suited for patients undergoing cancer surgery cannot be definitively answered without further prospective clinical research. Most of the evidence at this time seems to favor propofol, but most probably, this will not become a “magic cancer bullet”. A thorough evaluation of the risk–benefit profiles of inhalational/intravenous strategies for individual patients is key in choosing a tailored anesthesiologic regimen.After all, informed, individual, and precise perioperative management is the best help an anesthesiologist can offer its patients for a safe sleep.


The prediction of long-term mortality following acute illness can be unreliable for older patients, inhibiting the delivery of targeted clinical interventions. The difficulty plausibly arises from the complex, multifactorial nature of the underlying biology in this population, which flexible, multimodal models based on machine learning may overcome. Here, we test this hypothesis by quantifying the comparative predictive fidelity of such models in a large consecutive sample of older patients acutely admitted to hospital and characterise their biological support.A set of 804 admission episodes involving 616 unique patients with a mean age of 84.5 years consecutively admitted to the Acute Geriatric service at University College Hospital were identified, in whom clinical diagnoses, blood tests, cognitive status, computed tomography of the head, and mortality within 600 days after admission were available. We trained and evaluated out-of-sample an array of extreme gradient boosted trees-based predictive models of incrementally greater numbers of investigational modalities and modelled features. Both linear and non-linear associations with investigational features were quantified.Predictive models of mortality showed progressively increasing fidelity with greater numbers of modelled modalities and dimensions. The area under the receiver operating characteristic curve rose from 0.67 (sd = 0.078) for age and sex to 0.874 (sd = 0.046) for the most comprehensive model. Extracranial bone and soft tissue features contributed more than intracranial features towards long-term mortality prediction. The anterior cingulate and angular gyri, and serum albumin, were the greatest intracranial and biochemical model contributors respectively.High-dimensional, multimodal predictive models of mortality based on routine clinical data offer higher predictive fidelity than simpler models, facilitating individual level prognostication and interventional targeting. The joint contributions of both extracranial and intracranial features highlight the potential importance of optimising somatic as well as neural functions in healthy ageing. Our findings suggest a promising path towards a high-fidelity, multimodal index of frailty.The online version contains supplementary material available at 10.1186/s12916-022-02698-2. As a clinical outcome of the greatest concern, mortality demands predictive instruments of the highest fidelity: to guide expectations, target interventions, and illuminate modifiable mechanisms of disease . Ordinarmultiple clinical domains and investigational modalities, and the likely presence of heterogeneous causal interactions plausibly accessible only to complex, high-dimensional models. No survival instrument in current use attempts to draw power from the synthesis of multiple, individually weakly predictive features—clinical or investigational—that may in aggregate be both highly predictive and robust to the distributional heterogeneities commonly observed in real-world healthcare data. Mortality risk distributed across multiple investigational modalities, driven by non-linear interactions between remote variables, remains unquantified.Several short and medium-term mortality prediction instruments exist, such as APACHE-III , HELP 66, BISEP Recent advances in complex modelling now permit a different approach. We can move beyond simple, unimodal, low-dimensional models to complex, multimodal, high-dimensional models that integrate rich information acquired during routine care . This alHere, we study a large, consecutive, unselected, fully inclusive cohort of older patients acutely admitted to a single acute general hospital, with the following complementary aims: (a) to quantify the predictability from routinely acquired multimodal clinical data of death within 2 years, (b) to compare the performance of predictive models varying in input modality and dimensionality, (c) identify candidate mechanisms of increased mortality, and (d) establish the foundations of a readily deployable clinical tool for predicting all-cause mortality in unselected older patients admitted to acute hospitals, to be fully developed in future large-scale, multi-centre studies. We focus on demographics, primary diagnosis, and cognitive status as simple, readily available clinical descriptors, and routine blood tests and cranial imaging as rich yet objectively quantifiable and reproducible descriptors of physiology and anatomy commonly available in our target population.The full study cohort consisted of 2951 consecutive admissions to the acute geriatrics service at University College London Hospital (UCLH) between March 2015 and March 2017 evaluated in the course of an unselected audit of the service. The cohort was drawn from all patients over the age of 70 admitted with any acute general medical problem: the indication for entry into the acute geriatrics service at UCLH. The cohort excluded patients whose admission diagnosis was surgical, or those directly admitted to the intensive care unit. Each patient was reviewed by a consultant geriatrician within 24 h of hospital admission and clinically classified as having (i) delirium only; (ii) dementia only; (iii) delirium superimposed on dementia; or (iv) no or minimal cognitive impairment, from the medical notes and bedside clinical assessment. Admissions were considered as a single episode if the patient was readmitted within 28 days of the prior discharge date. We linked contemporaneous admission information to this clinical dataset, laboratory and imaging investigations, corresponding as closely as possible to the index admission . The full complement of variables was available for 804 admission episodes involving 616 unique patients  investigation performed or not performed (one binary variable); (2) counts of investigation performed over the first 48 ours ; (3) investigative intention level 1 and the first test value (two variables); (4) investigative intention level 2 and the mean test value (two variables); and (5) the first test value, mean, and standard deviation (three variables).Data were modelled at different investigative intention levels to quantify the relative predictive content of the intention to investigate vs the actual test values thereby obtained.https://www.fil.ion.ucl.ac.uk/spm/) pipeline that included, in order, rigid-body realignment to Montreal Neurological Institute (MNI) space, resampling to 1 mm3 isotropic resolution, and non-linear unified spatial segmentation and normalisation to MNI space based on a CT-optimised extension of SPM’s unified segmentation and normalisation routine ).Though imaging provides the greatest incremental boost in fidelity, integration of multimodal data within a unified predictive model yields the best performance. Given the comparative ease of modelling routine clinical and non-imaging investigations, their incorporation would be justified even by small improvements in model prediction. Whether or not the addition of any modality increases model performance nonetheless remains an empirical question that depends both on the informativity of a given modality and the cross-modal redundancy of the predictive signal. The use of modalities, such as brain imaging, that provide a rich, distinctive, detailed perspective on biology reduces the likelihood of redundancy even if it always remains a possibility. A degree of redundancy is in any event desirable in providing some insurance against the missingness—both during model training and at test time—common in real-world clinical environments.Our mass-univariate analyses of haematological, biochemical, and especially imaging features point to a unifying association of mortality with sarco- and osteopenia, with especially striking modulation of parietal and occipital bone and cranial soft tissue. Sarcopenia, defined as the progressive generalised loss of skeletal muscle, is associated with increased mortality risk , potentiWithin the brain, striking modulation of medial frontal cortical areas implicated in voluntary motor behaviour and autonomic function—principally the anterior cingulate—may be explained by the potential impact of dysfunction in either domain. The potential importance of motor function is reinforced by the enhanced multivariate feature importance of voxels falling within the primary motor cortex and the corticospinal tract. Note that these changes may be explained not only by brain pathology—such as small vessel disease—that either directly or indirectly reduces grey matter concentrations locally but potentially by neural adaptation to long term reduced mobility of non-neural origin. The involvement of areas with dense (angular gyrus) or remote  connectivity may also reflect differential rates of length-dependent degeneration in white matter and the grey matter it connects. Further exploration of these biologically intelligible patterns—yet to be interrogated by others in this population—is merited.A predictive model with high fidelity at the individual level has the potential to support clinical decision-making. Here quantifying the risk of death early on in the course of a hospital admission enables proportionate pre-emptive action—by both patients and clinicians—to minimise it. Grounding an index of frailty in multimodal signals in principle renders it more robust to incidental variations by broadening its evidential support, and potentially widens the field of manipulable factors critical in any one patient, permitting more closely individuated interventions. Adapting the predictive model to absorb greater population heterogeneity, and incorporating machinery for causal inference, require further algorithmic development with larger-scale data that this proof-of-concept now justifies. Crucially, since routine clinical and investigational data models appear to be sufficiently powerful here, real-world implementation of a decision-support tool does not require any changes to clinical pathways, substantially lowering barriers to adoption. Indeed, it may be argued that clinicians have a moral duty to maximise the guiding intelligence extracted from the data they obtain from patients, often at individual, and always at institutional, cost.Some may be tempted to use models of this kind to guide withdrawal of treatment. Where a plausible causal chain—and its clinical modifiability—are not established, such use cannot be justified and should be proscribed, not just in the case of complex, high-dimensional models but any predictive model. Indeed, demonstrating the predictability of individual variations in risk provides a strong argument against any generic approach to treatment withdrawal.A high-fidelity individual index of frailty also has applications in stratifying patients in observational and interventional research studies, where unmodelled structured variability could otherwise conceal or distort inferred effects. Furthermore, multimodal models may reveal heterogeneities between subpopulations exhibiting the same risk, suggesting potential differences in causation that would confound inferences unless explicitly modelled. Attention to heterogeneity is paramount in the older patient, where the multiplicity and diversity of observed pathologies is high. Identifying subpopulations of especially elevated risk facilitates the identification of mechanistic factors of potential interventional value concealed by noise or non-linearities. Although highlighting sarcopenia and the integrity of motor brain areas provides actionable targets, downstream studies are needed to quantify the clinical utility of any intervention.We do not advocate scanning patients purely for prognostic purposes, only using CT data acquired commonly enough for a model based on it to be widely applicable. If the fidelity of the approach is established over larger scale, multi-site studies, and clinical utility is demonstrated—in guiding preventative interventions, for example—a case could be made on the specific balance of risk and benefit. But since the model’s support is drawn from those in whom CT is clinically indicated, transfer to the wider population would need careful evaluation. The increasing digital maturity of radiological systems and their widespread integration with electronic healthcare records make this potentially feasible at substantial scale and with broad inclusivity.The synthesis of multimodal signals spanning demographics, clinical features, blood tests, and CT imaging data is unique amongst prognostic models in this population. The use of objectively quantifiable features derived only from routinely collected data without the need for pre-admission information or potentially subjective clinical assessment is a central strength, promoting generalisation across healthcare systems and enabling implementation without disrupting established pathways. Model development and out-of-sample validation on one of the largest unselected cohorts of older patients evaluated for acute illness in frail patients is grounds for confidence in the robustness of the findings.An array of limitations should be noted. Though the largest of its kind, this is a retrospective study validated on held-out but retrospective data from the same institution: generalisability over time and location must be established in subsequent studies. In keeping with all observational analyses of routine clinical data, a degree of corruption by  missingness, acquisition, and documentation errors, and clinical uncertainty is inevitable. Specifically, the diagnoses of delirium and dementia, though made by a senior clinician, were not validated by dedicated instruments or (in the case of dementia) corroborative imaging. Equally, though our cohort is fully inclusive of the clinical stream, only those with CT imaging of the head, carried out for indications individual to each patient, were retained in the analysis. We pursued this approach to maximise ecological validity, replicating the quality of data a real-world institution would naturally see. The impact of potential biases is minimised by the use of sequential, unselected data, enabling inference across all those in receipt of the criteria investigations. We explicitly quantify the effects of intention to investigate in relation to individual blood tests, finding it to contain negligible predictive signal. Institutional-level variability in clinical practices could, of course, impact generalisation and need exploration in future multi-centre studies. Because it was not available, we do not model the cause of death, only the primary diagnosis on the admission that triggers entry into the cohort. Co-morbidities were omitted for the same reason. There is no reason to expect the distribution of causes of death to differ substantially from that observed for the underlying population, and our focus here is the fact of it rather than its cause. But incorporating cause of death and co-morbidities, in further escalation of model complexity, may well increase performance and ought to be evaluated where possible. Finally, the use models that are high-dimensional in proportion to the number of training instances always presents a risk of overfitting, here addressed by strong regularisation, a modelling architecture relatively resistant to overfitting, and careful evaluation of the model with both cross-validation and a fully held-out definitive test set. It is for this reason that further evaluation, within larger, multi-site studies is recommended here.Examining the distribution of a wide array of multimodal predictive factors in older patients acutely admitted to hospital and imaged with cranial CT, we have established the foundations of a multimodal approach to predicting medium-term mortality, operational at the point of admission, and validated for unselected oldest-old patients. Our analysis demonstrates the benefit of using machine learning to enable models incorporating multiple modalities, highlighting the predictive potential of defining ‘multimodal frailty’. Inferences drawn from the prediction model suggest that unimpaired higher motor and autonomic function is associated with medium-long term survival. These results justify further investigation of the application of high-dimensional modelling to predicting mortality in the older patient.Additional file 1: Fig. S1. Intention to investigate effects in blood tests. Fig. S2. The effect of feature number and modality on predictive performance. Fig. S3. Decision threshold diagnostics for the best multimodal model. Fig. S4. Subpopulation performance. Table S1. Blood test missingness, ordered by magnitude. Table S2. Hyperparameter cross-validation grid search range and XGboost final hyperparameters.


We aimed to examine brain tumour grade, a marker of biological aggressiveness, tumour size and cancer treatment are associated with cerebrovascular mortality among patients with malignant glioma, the most common and aggressive type of brain tumour.We conducted a retrospective, observational cohort study using the US National Cancer Institute’s state and regional population-based cancer registries. We identified adult patients with glioma in 2000 to 2018 . The primary outcome was death from cerebrovascular disease. Cox regression modelling was used to estimate the associations with cerebrovascular mortality of tumour grade, tumour size and treatment , calculating hazard ratios (HR) adjusted for these factors as well as for age, sex, race, marital status and calendar year.Higher grade  and larger brain tumours  were associated with increased cerebrovascular mortality. Cancer treatment was associated with decreased risk . However, among patents surviving five years or more from cancer diagnosis radiotherapy was associated with higher risk of cerebrovascular mortality .More aggressive tumour characteristics are associated with increased cerebrovascular mortality. Radiotherapy increased risk of cerebrovascular mortality five-year after cancer diagnosis. Further research is needed to better understand the long-term cardiovascular consequences of radiation therapy, and whether the consequent risk can be mitigated. Cerebrovascular diseases, including stroke, are the commonest life threatening and disabling neurological disorders. Higher mortality rates from stroke have been reported for cancer patients compared with the general population , particuMany brain tumours are associated with significant morbidity and mortality. The high cerebrovascular mortality rate in patients with brain tumours, including both benign and malignant tumours, should therefore prompt consideration of preventive intervention. This could improve survival outcomes, particularly in the subset of longer-term survivors , but alsDespite the high risk for fatal stroke outcome, it remains largely unknown which tumour and treatment factors are associated with cerebrovascular mortality in patients with brain tumours. Although cancer treatment associated cardiovascular toxic effects, particularly radiation -induced cerebrovascular mortality has been well established in the long-term survivors of childhood brain tumours , cerebroWith a focus on glioma, the most common adult primary brain tumour, we aimed to examine to what extent brain tumour grade, a marker of biological aggressiveness, tumour size and treatment are each associated with cerebrovascular mortality using population-based data from the US. We also examined the effect of tumour treatment on cerebrovascular mortality during different time periods after diagnosis.We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines . We usedWe identified adults ≥18 years) diagnosed with glioma between 2000 and 2018 from SEER. Gliomas were classified based on histological and molecular type  years di. InclusiThe primary exposures include tumour grade, tumour size and treatments. Based on World Health Organisation (WHO) criteria, glioma is classified into four grades, with higher grade indicating increasing tumour aggressiveness : Grade IThe outcome of interest was primary cause of death from cerebrovascular disease using ICD-10 codes (I60-69), including the following subtypes: non-traumatic intracranial haemorrhage, cerebral infarction, occlusion and stenosis of cerebral of precerebral vessels without infarction, other cerebrovascular diseases, and sequelae of cerebrovascular disease (late effect) .We included the following covariates in our analysis: age at diagnosis, sex , race/ethnicity , marital status  and calendar years, diagnostic confirmation by microscopy or not.We performed descriptive analyses of baseline characteristics of patients with glioma, overall and according to glioma grade, summarising categorical variables as numbers and percentages per category. The Pearson’s Chi-squared test was used for comparison across glioma grades. We compared continuous variables across glioma grade subgroups using analysis of variance for normally distributed variables (summarized as means and standard deviations [SD]) or the Kruskal–Wallis test for non-normally distributed variables (summarized as medians and interquartile ranges). Deaths from other causes were censored at the time of death. Survival time from the date of diagnosis until date of death or last contact  were computed. We used multiple imputation with chained equations to impute missing values for tumour size. The imputation model included all variables in the We restricted survival analyses to those with grade II-IV gliomas because of small numbers of cerebrovascular deaths among patients with grade I glioma (N=6) and lack of events in some subgroups. Univariable analyses were performed and variables with p-value<0.10 were retained in the final multivariable regression model, which included age, sex, ethnicity/race, marital status, calendar year, tumour grade, tumour size, and treatment status. We assessed the potential for effect modification by age group , sex, and race/ethnicity by including interaction terms between the exposures  and these variables. Where we found a significant interaction, we conducted subgroup analyses to demonstrate the different HRs for relevant subgroups according to age, sex and/or ethnicity.In sensitivity analyses to assess the robustness of our results, we repeated the above analyses with the study period limited to after 2005 to assess whether the introduction of adjuvant chemotherapy treatment from 2005 influenced the results , 23. To Anonymized data not published within this article will be made available by request from any qualified investigator. No additional informed consent was required as there was no individual patient involvement.We identified 91,655 patients diagnosed with a malignant brain tumour in SEER between 2000 and 2018. There were 72, 916 cases of glioma with a total follow-up time of 266,491 person-years  Table 1.We observed increased cerebrovascular mortality in glioma patients with higher grade , and those with larger brain tumours  after adjusted by age, sex, race/ethnicity, marital status and calendar yearsFigure 1We found a significant interaction (p<0.001) between tumour grade and age group with no evidence of interaction for sex and ethnic group. In subgroup analyses of the effects of tumour grade on cerebrovascular mortality by age group, the relative risk of cerebrovascular mortality was significantly higher in younger than older patients with grade IV  Figure 2Overall, having cancer treatment was associated with decreased risk of cerebrovascular mortality:  Figure 1Similar results to those noted above were observed when we restricted analyses to those patients who survived one month from tumour diagnosis 2. BroadOur analysis of over 70,000 cases of primary gliomas using population-based data from SEER found that patients with higher grade, particularly the most aggressive gliomas, Grade IV, and larger gliomas were at increased risk of cerebrovascular mortality. Receiving cancer treatments was associated with lower risk for cerebrovascular mortality in patients surviving less than 5 years. However, radiation therapy significantly increased the risk of cerebrovascular mortality in longer-term survivors.The association of high-grade glioma with cerebrovascular mortality suggests an important biological role for tumour aggressiveness in the risk of stroke. This is consistent with previous studies showing that patients with more advanced stage cancer, including lung, pancreatic, colorectal and gastric cancer, have increased risk of stroke . These fThe findings of a particularly strong association between high grade glioma and cerebrovascular mortality in younger patients may further support the independent role of tumour aggressiveness-related hypercoagulation, because younger patients are relatively healthy and less likely than older individuals to have conventional stroke risk factors . The weaOur findings showed that tumour treatment, particularly chemotherapy and radiation therapy, were associated with lower risk of cerebrovascular mortality in glioma patients surviving less than 5 years, while having radiation increased cerebrovascular mortality risk in those surviving more than 5 years. While cancer treatment reduces cancer activity, it has been recognised that treatment increases risk of fatal and non-fatal cardiovascular outcomes including stroke in brain tumour survivors , 31. OurRadiation treatment remains the cornerstone of therapy for patients with brain tumour such as glioma. An awareness of the long-term risk of cerebrovascular mortality is not intended to detract from this standard care therapy, but rather to encourage incorporation of screening, mitigation and prevention methods where supported by an evidence-base . This maUsing the large population-based data, our study showed the important role of tumour aggressiveness and radiation therapy in cerebrovascular mortality in patients with gliomas. Our study is the largest and most comprehensive analysis to date of the associations of tumour characteristics and cancer treatments factors with cerebrovascular mortality in glioma patients, and used population-based data, enhancing the generalizability of our findings. Our findings provide important evidence for planning future clinical trials to understand the role of prophylaxis against arterial thrombosis and to guide clinical management. Our findings of long-term fatal cerebrovascular outcome from radiotherapy should enable better identification of groups of high-risk patients requiring surveillance and prevention of cerebrovascular complications, for example, assessing and treating cardiovascular risk factors such as hypertension. Importantly, long-term glioma survivors who have a more favourable oncologic prognosis may benefit the most from follow-up clinical screening and monitoring to improve their survival outcomes, particularly in those who have had radiotherapy.The absolute number of glioma patients who died from cerebrovascular deaths are low in this population. However, this number may be under reported and not reflect the true burden of this disease, because in patients with a brain tumour a cerebrovascular event may not be considered as a cause of clinical deterioration. Prompt diagnosis of cerebrovascular diseases, including stroke is needed to achieve maximal functional recovery, and quality of life . This isOur study has limitations. First, it was retrospective in nature, and lacked granular details of stroke diagnosis, including stroke subtypes. Future prospective studies are needed with more granular detail of stroke diagnosis such as stroke subtypes, timing of the event, biomarkers by including neuroimaging and laboratory data to improve the diagnosis of stroke and determine the cause of stroke. Second, we did not have baseline cardiovascular risk factors  and/or cardiovascular disease . However, our analysis in the younger age group who were relatively healthy has shown the strong association between tumour aggressiveness and cerebrovascular mortality. In addition, a population-based cohort study using UK Clinical Practice Research Datalink (CPRD) showed adjustment for shared CVD risk factors had little effect on CVD risk including stroke in adult survivors of multiple site-specific cancer including central nervous system (CNS) tumours compared with the general population . Third, More aggressive tumour characteristics are associated with increased cerebrovascular mortality. While receiving cancer treatments was associated with lower risk for cerebrovascular mortality, having radiation increased long-term fatal outcome for cerebrovascular disease. The complex interplay of putative risk and benefit from the tumour and its treatment underscore the need for further research. As early detection and more effective anticancer therapies extend the survival of cancer patients, avoiding treatment-related long-lasting fatal cerebrovascular outcome becomes increasingly vital. Knowledge of the risks can help clinicians be more vigilant for signs and symptoms of potential neurological complications and guide the management of long-term glioma survivors.https://seer.cancer.gov/data/. Approval to access the SEER data was granted by the US National Cancer Institute (NCI). Data not published within this article will be made available by request from any qualified investigator.Publicly available datasets were analyzed in this study. This data can be found here: Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.KJ conceived and designed the study, analysed data, developed figures, interpreted data, and developed the draft of the manuscript. PB designed the study, interpreted data, contributed to the writing, reviewing and editing of the manuscript. MP contributed to data interpretation and reviewing the manuscript. CS conceived and designed the study, interpreted and verified data, contributed to the writing, reviewing and editing of the manuscript. JF conceived and designed the study, interpreted and verified data, contributed to the writing, reviewing and editing of the manuscript. All authors critically revised the manuscript for important intellectual content. All authors approved the manuscript to submit for publication. All authors contributed to the article and approved the submitted version.