ERK5 Inhibition Induces Autophagy-Mediated Cancer Cell Death by Activating ER Stress

ERK5 kinase; Antitumor drug; ApoptosisKinasa ERK5; Medicament antitumoral; ApoptosiQuinasa ERK5; Medicamento antitumoral; ApoptosisAutophagy is a highly conserved intracellular process that preserves cellular homeostasis by mediating the lysosomal degradation of virtually any component of the cytoplasm. Autophagy is a key instrument of cellular response to several stresses, including endoplasmic reticulum (ER) stress. Cancer cells have developed high dependency on autophagy to overcome the hostile tumor microenvironment. Thus, pharmacological activation or inhibition of autophagy is emerging as a novel antitumor strategy. ERK5 is a novel member of the MAP kinase family that is activated in response to growth factors and different forms of stress. Recent work has pointed ERK5 as a major player controlling cancer cell proliferation and survival. Therefore small-molecule inhibitors of ERK5 have shown promising therapeutic potential in different cancer models. Here, we report for the first time ERK5 as a negative regulator of autophagy. Thus, ERK5 inhibition or silencing induced autophagy in a panel of human cancer cell lines with different mutation patterns. As reported previously, ERK5 inhibitors (ERK5i) induced apoptotic cancer cell death. Importantly, we found that autophagy mediates the cytotoxic effect of ERK5i, since ATG5ˉ/ˉ autophagy-deficient cells viability was not affected by these compounds. Mechanistically, ERK5i stimulated autophagic flux independently of the canonical regulators AMPK or mTORC1. Moreover, ERK5 inhibition resulted in ER stress and activation of the Unfolded Protein Response (UPR) pathways. Specifically, ERK5i induced expression of the ER luminal chaperone BiP (a hallmark of ER stress), the UPR markers CHOP and ATF4, and the spliced form of XBP1. Pharmacological inhibition of UPR with chemical chaperone TUDC, or ATF4 silencing, resulted in impaired ERK5i-mediated UPR, autophagy and cytotoxicity. Overall, our results suggest that ERK5 inhibition induces autophagy-mediated cancer cell death by activating ER stress. Since ERK5 inhibition sensitizes cancer cells and tumors to chemotherapy, future work will determine the relevance of UPR and autophagy in the combined use of chemotherapy and ERK5i to tackle Cancer.This work was supported by the Spanish Ministry of Economy and Competitiveness (MINECO, grant SAF2015-64237-R), the Spanish Ministry of Science and Innovation (Grant PID2019-107561RB-I00), and cofounded by the European Regional Development Fund (ERDF)

The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival

Apoptosis; Endometrial cancer; Map kinaseApoptosis; Cáncer endometrial; Mapa quinasaApoptosi; Càncer d'endometri; Mapa quinasaEndometrial cancer (EC) is the most common type of gynecologic cancer in women of developed countries. Despite surgery combined with chemo-/radiotherapy regimens, overall survival of patients with high-risk EC tumors is poor, indicating a need for novel therapies. The MEK5-ERK5 pathway is activated in response to growth factors and to different stressors, including oxidative stress and cytokines. Previous evidence supports a role for the MEK5-ERK5 pathway in the pathology of several cancers. We investigated the role of ERK5 in EC. In silico analysis of the PanCancer Atlas dataset showed alterations in components of the MEK5-ERK5 pathway in 48% of EC patients. Here, we show that ERK5 inhibition or silencing decreased EGF-induced EC cell proliferation, and that genetic deletion of MEK5 resulted in EC impaired proliferation and reduced tumor growth capacity in nude mice. Pharmacologic inhibition or ERK5 silencing impaired NF-kB pathway in EC cells and xenografts. Furthermore, we found a positive correlation between ERK5 and p65/RELA protein levels in human EC tumor samples. Mechanistically, genetic or pharmacologic impairment of ERK5 resulted in downregulation of NEMO/IKKγ expression, leading to impaired p65/RELA activity and to apoptosis in EC cells and xenografts, which was rescued by NEMO/IKKγ overexpression. Notably, ERK5 inhibition, MEK5 deletion or NF-kB inhibition sensitized EC cells to standard EC chemotherapy (paclitaxel/carboplatin) toxicity, whereas ERK5 inhibition synergized with paclitaxel to reduce tumor xenograft growth in mice. Together, our results suggest that the ERK5-NEMO-NF-κB pathway mediates EC cell proliferation and survival. We propose the ERK5/NF-κB axis as new target for EC treatment.Open Access Funding provided by Universitat Autonoma de Barcelona. The JM Lizcano research group was supported by grants from the Spanish Ministry of Economy and Competitiveness (MINECO, grant SAF2015-64237-R), and the Spanish Ministry of Science and Innovation (grant PID2019-107561RB-I00), and co-funded by the European Regional Development Fund (ERDF)

The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival

Endometrial cancer (EC) is the most common type of gynecologic cancer in women of developed countries. Despite surgery combined with chemo-/radiotherapy regimens, overall survival of patients with high-risk EC tumors is poor, indicating a need for novel therapies. The MEK5-ERK5 pathway is activated in response to growth factors and to different stressors, including oxidative stress and cytokines. Previous evidence supports a role for the MEK5-ERK5 pathway in the pathology of several cancers. We investigated the role of ERK5 in EC. In silico analysis of the PanCancer Atlas dataset showed altera- tions in components of the MEK5-ERK5 pathway in 48% of EC patients. Here, we show that ERK5 inhibition or silencing decreased EGF-induced EC cell proliferation, and that genetic deletion of MEK5 resulted in EC impaired proliferation and reduced tumor growth capacity in nude mice. Pharmacologic inhibition or ERK5 silencing impaired NF-kB pathway in EC cells and xenografts. Furthermore, we found a positive correlation between ERK5 and p65/RELA protein levels in human EC tumor samples. Mechanistically, genetic or pharmacologic impairment of ERK5 resulted in downregulation of NEMO/ IKKγ expression, leading to impaired p65/RELA activity and to apoptosis in EC cells and xenografts, which was rescued by NEMO/IKKγ overexpression. Notably, ERK5 inhibition, MEK5 deletion or NF-kB inhibition sensitized EC cells to standard EC chemotherapy (paclitaxel/carboplatin) toxicity, whereas ERK5 inhibition synergized with paclitaxel to reduce tumor xenograft growth in mice. Together, our results suggest that the ERK5-NEMO-NF-κB pathway mediates EC cell prolifera- tion and survival. We propose the ERK5/NF-κB axis as new target for EC treatment.The online version contains supplementary material available at 10.1007/s00018-022-04541-

Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains

This is the author accepted manuscript. The final version is available from American Chemical Society via the DOI in this recordBromodomains have been pursued intensively over the past several years as emerging targets for the devel-opment of anti-cancer and anti-inflammatory agents. It has recently been shown that some kinase inhibitors are able to potently inhibit the bromodomains of BRD4. The clinical activities of PLK inhibitor BI-2536 and JAK2-FLT3 inhibitor TG101348 have been attributed to this unexpected poly-pharmacology, indicating that dual-kinase/bromodomain activity may be advantageous in a therapeutic context. However, for target validation and biological investigation, a more selec-tive target profile is desired. Here we report that benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones, versatile ATP-site di-rected kinase pharmacophores utilized in the development of inhibitors of multiple kinases including a number of previ-ously reported kinase chemical probes, are also capable of exhibiting potent BRD4-dependent pharmacology. Using a dual kinase-bromodomain inhibitor of the kinase domains of ERK5 and LRRK2, and the bromodomain of BRD4 as a case study, we define the structure-activity relationships required to achieve dual kinase/BRD4 activity as well as how to di-rect selectivity towards inhibition of either ERK5 or BRD4. This effort resulted in identification of one of the first report-ed kinase-selective chemical probes for ERK5 (JWG-071), a BET selective inhibitor with 1 μM BRD4 IC50 (JWG-115), and additional inhibitors with rationally designed polypharmacology (JWG-047, JWG-069). Co-crystallography of seven representative inhibitors with the first bromodomain of BRD4 demonstrate that distinct atropisomeric conformers rec-ognize the kinase ATP-site and the BRD4 acetyl lysine binding site, conformational preferences supported by rigid dock-ing studies.This work was supported by NIH (Grant No. U54HL127365, to N.S.G. and J.W.; No. NIH P50 GM107618, to X.X. and S.C.B.; Nos. NIH U54 HD093540 and P01 CA066996, to J.Q.), the Medical Research Council (No. MC_UU_12016/2, to D.R.A.), the Spanish Ministerio de Economia y Competitividad (MINECO) (Grant No. SAF2015-60268R, to J.M.L.), and Fondo Europeo de Desarrollo Regional (FEDER) funds (to J.M.L.). D.L.B. was supported as a Merck Fellow of Damon Runyon Cancer Research Foundation (No. DRG-2196-14)

MAP quinasa ERK5 : una nueva diana antitumoral en cáncer endometrioide y neuroblastoma

La via de senyalització de la MAP quinasa ERK5 s'activa en resposta a factors de creixement i diferents formes d'estrès. Durant els últims anys, diversos treballs han mostrat que ERK5 juga un paper important en la proliferació i supervivència en diferents paradigmes del càncer. No obstant això, aquestes evidències experimentals s'han aconseguit utilitzant inhibidors d'ERK5 que posteriorment han demostrat no ser específics. Entre altres, aquests inhibidors d'ERK5 també afecten l'activitat del regulador transcripcional BRD4 (una coneguda diana antitumoral), per la qual cosa recentment s'ha posat en qüestió el paper d'ERK5 com a regulador de la proliferació i de la supervivència tumoral. En aquest treball hem caracteritzat JWG-071, un inhibidor competitiu i específic d'ERK5 (ERK5i) sense activitat BRD4. Aquest petit compost mostra uns excel·lents paràmetres farmacocinètics, i inhibeix ERK5 eficientment en línies cel·lulars i en tumors xenografts. Per al desenvolupament preclínic d'aquest inhibidor d'ERK5 de nova generació s'han utilitzat models de càncer ginecològic endometrioide i cervical, no estudiats fins avui. Els nostres resultats mostren que ERK5 regula la proliferació de línies cel·lulars de càncer ginecològic, a través del factor de transcripció AP-1. Així, la inhibició farmacològica (JWG-071) o genètica (cèl·lules CRISPR/Cas9 MEK5-/-) d'ERK5 redueix la proliferació cel·lular i el creixement de tumors xenografts de càncer endometrioide (cèl·lules Ishikawa). D'altra banda, presentem evidències que mostren que l'activitat quinasa d'ERK5 és necessària per a la supervivència de línies cel·lulars de càncer endometrioide i cervical. Així, la inhibició d'ERK5 indueix apoptosi en aquestes línies i en tumors xenografts de cèl·lules Ishikawa, a través de la inhibició de la via canònica de NF-kB, una via que regula la proliferació i supervivència del càncer endometrioide. Mecanísticament, la inhibició d'ERK5 resulta en una dràstica reducció del regulador apical NEMO/IKKg, cosa que porta a la inhibició de l'expressió, localització nuclear i activitat transcripcional de p65/RELA. Així mateix, vam mostrar que la inhibició de NF-kB en resposta al JWG-071 resulta en l'activació de la via apoptótica regulada per JNK, tant in vitro (línies cel·lulars) com in vivo (tumors xenografts). D'acord amb aquests resultats, que mostren una relació funcional entre ERK5 i NF-kB, mostres de pacients amb càncer endometrioide presenten una elevada expressió proteica d'ERK5 i p65/RELA, comparada amb el teixit peritumoral. Finalment, la inhibició d'ERK5 sensibilitza cèl·lules de càncer endometrioide i cervical a la quimioteràpia estàndard. D'interès, l'administració sistèmica de JWG-071 sensibilitza a tumors xenogratfs endometrioides (Ishikawa) al tractament amb paclitaxel. En definitiva, proposem ERK5 com una nova diana per al tractament del càncer endometrioide. D'altra banda, en aquest treball s'han obtingut evidències preliminars que mostren que ERK5 nuclear juga un rol important en la supervivència i resistència a la quimioteràpia del neuroblastoma (NBL) humà. Utilitzant un panell de línies cel·lulars NBL, vam mostrar que cèl·lules NBL quimiosensibles (p53 funcional) presenten ERK5 citosólica i són sensibles als ERK5i. Per contra, cèl·lules NBL d'alt risc quimiorresistents (p53 no-funcional) presenten ERK5 nuclear i escassa sensibilitat als ERK5i. D'interès, la sobreexpressió d'una forma constitutivament nuclear d'ERK5 confereix resistència al cisplatí en cèl·lules NBL quimiosensibles, mitjançant la reducció de l'expressió i activitat transcripcional de p53. Finalment, s'ha dut a terme un estudi amb la finalitat de valorar l'impacte del silenciament d'ERK5 en el transcriptoma de dues línies cel·lulars de NBL quimiorresistents. Els resultats preliminars mostren que l'absència d'ERK5 indueix canvis en l'expressió de gens relacionats amb el cicle cel·lular, transcripció i apoptosi, la qual cosa ens porta a proposar al NBL quimiorresistent com a model per a validar l'acció antitumoral de fàrmacs degraders (PROTACs) d'ERK5.La vía de señalización de la MAP quinasa ERK5 se activa en respuesta a factores de crecimiento y diferentes formas de estrés. Durante los últimos años, varios trabajos han mostrado que ERK5 juega un papel importante en la proliferación y supervivencia en diferentes paradigmas del cáncer. Sin embargo, estas evidencias experimentales se han conseguido utilizando inhibidores de ERK5 que posteriormente han demostrado no ser específicos. Entre otros, estos inhibidores de ERK5 también afectan a la actividad del regulador transcripcional BRD4 (una conocida diana antitumoral), por lo que recientemente se ha puesto en cuestión el papel de ERK5 como regulador de la proliferación y de la supervivencia tumoral. En este trabajo hemos caracterizado JWG-071, un inhibidor competitivo y específico de ERK5, sin actividad BRD4. Este pequeño compuesto muestra unos excelentes parámetros farmacocinéticos, e inhibe ERK5 eficientemente en líneas celulares y en tumores xenografts. Para el desarrollo preclínico de este inhibidor de ERK5 de nueva generación se han utilizado modelos de cáncer ginecológico endometrioide y cervical, no estudiados hasta la fecha. Nuestros resultados muestran que ERK5 regula la proliferación de líneas celulares de cáncer ginecológico, a través del factor de transcripción AP-1. Así, la inhibición farmacológica (JWG-071) o genética (células CRISPR/Cas9 MEK5-/-) de ERK5 reduce la proliferación celular y el crecimiento de tumores xenografts de cáncer endometrioide (células Ishikawa). Por otra parte, presentamos evidencias que muestran que la actividad quinasa de ERK5 es necesaria para la supervivencia de líneas celulares de cáncer endometrioide y cervical. Así, la inhibición de ERK5 induce apoptosis en estas líneas y en tumores xenografts de células Ishikawa, al inhibir la vía canónica de NF-kB, una vía que regula la proliferación y supervivencia del cáncer endometrioide. Mecanísticamente, la inhibición de ERK5 resulta en una drástica reducción del regulador apical NEMO/IKKg, lo que conduce a la inhibición de la expresión, localización nuclear y actividad transcripcional de p65/RELA. Asimismo, mostramos que la inhibición de NF-kB en respuesta al JWG-071 resulta en la activación de la vía apoptótica regulada por JNK, tanto in vitro (líneas celulares) como in vivo (tumores xenografts). De acuerdo con estos resultados, que muestran una relación funcional entre ERK5 y NF-kB, muestras de pacientes con cáncer endometrioide presentan una elevada expresión proteica de ERK5 and p65/RELA, comparada con el tejido peritumoral. Finalmente, la inhibición de ERK5 sensibiliza células de cáncer endometrioide y cervical a la quimioterapia estándar. De interés, la administración sistémica de JWG-071 sensibiliza a tumores xenogratfs endometrioides (Ishikawa) al tratamiento con paclitaxel. En definitiva, proponemos ERK5 como una nueva diana para el tratamiento del cáncer endometrioide. Por otra parte, en este trabajo se han obtenido evidencias preliminares que muestran que ERK5 nuclear media en la supervivencia y resistencia a la quimioterapia del neuroblastoma (NBL) humano. Utilizando un panel de líneas celulares NBL, mostramos que células NBL quimiosensibles (p53 funcional) presentan ERK5 citosólica y son sensibles a los ERK5i. Por el contrario, células NBL de alto riesgo quimorresistentes (p53 no-funcional) presentan ERK5 nuclear y escasa sensibilidad a los ERK5i. De interés, la sobreexpresión de una forma constitutivamente nuclear de ERK5 confiere resistencia al cisplatino en células NBL quimiosensibles, al reducir la expresión y actividad transcripcional de p53. Finalmente, se ha llevado a cabo un estudio con el fin de valorar el impacto del silenciamiento de ERK5 en el transcriptoma de dos líneas celulares de NBL quimiorresistentes. Los resultados preliminares muestran que la ausencia de ERK5 induce cambios en la expresión de genes relacionados con el ciclo celular, transcripción y apoptosis, lo que nos lleva a proponer al NBL quimiorresistente como modelo para validar la acción antitumoral de fármacos degraders (PROTACs) de ERK5.The MAP kinase ERK5 signaling pathway is activated in response to growth factors and different forms of stress. During the last few years, several works have shown that ERK5 plays an important role in regulating cell proliferation and survival in different cancer paradigms. However, these experimental evidences were achieved using ERK5 inhibitors that, subsequently, were shown to be non-specific. Among others, first generation ERK5 inhibitors also impair the activity of the transcriptional regulator BRD4 (a known antitumor target). Consequently, the role of ERK5 as a regulator of tumor proliferation and survival has recently been questioned. Here, we have characterized JWG-071, a new generation competitive and specific ERK5 inhibitor, without BRD4 activity. This small compound exhibits excellent pharmacokinetic parameters, and inhibits ERK5 efficiently in cell lines and in xenograft tumors (systemic administration). To perform the preclinical development of JWG-071, we have used endometrioid and cervical gynecological cancer models. The role of ERK5 in these cancer models has not been previously reported. We show that ERK5 regulates proliferation of gynecological cancer cell lines, through activation of the transcription factor AP-1. Thus, pharmacological (JWG-071) or genetic (CRISPR/Cas9 MEK5-/- cells) inhibition of ERK5 impairs proliferation and growth of endometrioid cancer cells and xenografts (Ishikawa cells). Moreover, in this work we present evidences supporting that ERK5 kinase activity is required for the survival of endometrioid and cervical cancer cell lines. Thus, ERK5 inhibition induces apoptosis in cell lines and in xenografts tumors (Ishikawa cells), by impairing the canonical NF-kB pathway. The NF-kB pathway regulates endometrioid cancer proliferation and survival. Mechanistically, ERK5 inhibition results in a drastic reduction of the upstream regulator NEMO/IKKg, leading to inhibition of p65/RELA expression, nuclear localization and transcriptional activity. Furthermore, we show that inhibition of NF-kB in response to JWG-071 results in activation of the JNK-regulated apoptotic pathway, both in vitro (cell lines) and in vivo (tumor xenografts). In agreement with this, human endometrioid tumors show elevated levels of ERK5 and RELA proteins, compared to peritumoral tissue. Finally, we show that ERK5 inhibition sensitizes endometrioid and cervical cancer cells to standard chemotherapy. Of interest, systemic administration of JWG-071 sensitizes endometrioid xenografts tumors (Ishikawa cells) to paclitaxel treatment. Overall, we propose ERK5 as a new target to tackle endometrioid cancer. We also provide preliminary evidences showing that nuclear ERK5 plays a role in modulating neuroblastoma cancer survival and resistance to chemotherapy. Using a panel of NBL cell lines, we found that chemosensitive (functional p53) NBL cells are sensitive to ERK5 inhibitors, and show a cytosolic ERK5 localization. On the contrary, high-risk chemoresistant (non-functional p53) NBL cells are less sensitive to ERK5 inhibitors and show nuclear ERK5 localization. Interestingly, chemosensitive NBL IMR-32 and SH-SY5Y cells became resistant to cisplatin in response to overexpression of a constitutively nuclear form of ERK5, by a mechanism that impairs p53 expression and transcriptional activity. Finally, we performed a transcriptome (DNA microarrays) analysis to investigate the impact of ERK5 silencing (shRNAi) in high-risk chemoresistant NBL CHLA-90 and SK-N-BE(2) cell lines. Preliminary analysis show that depletion of the ERK5 protein induces changes in the expression of genes related to cell cycle, transcription and apoptosis. These results leads us to propose chemoresistant NBL as a model to validate the antitumor action of ERK5 degrader drugs (PROTACs)

SUMOylation Is Required for ERK5 Nuclear Translocation and ERK5-Mediated Cancer Cell Proliferation

The MAP kinase ERK5 contains an N-terminal kinase domain and a unique C-terminal tail including a nuclear localization signal and a transcriptional activation domain. ERK5 is activated in response to growth factors and stresses and regulates transcription at the nucleus by either phosphorylation or interaction with transcription factors. MEK5-ERK5 pathway plays an important role regulating cancer cell proliferation and survival. Therefore, it is important to define the precise molecular mechanisms implicated in ERK5 nucleo-cytoplasmic shuttling. We previously described that the molecular chaperone Hsp90 stabilizes and anchors ERK5 at the cytosol and that ERK5 nuclear shuttling requires Hsp90 dissociation. Here, we show that MEK5 or overexpression of Cdc37-mechanisms that increase nuclear ERK5-induced ERK5 Small Ubiquitin-related Modifier (SUMO)-2 modification at residues Lys6/Lys22 in cancer cells. Furthermore, mutation of these SUMO sites abolished the ability of ERK5 to translocate to the nucleus and to promote prostatic cancer PC-3 cell proliferation. We also show that overexpression of the SUMO protease SENP2 completely abolished endogenous ERK5 nuclear localization in response to epidermal growth factor (EGF) stimulation. These results allow us to propose a more precise mechanism: in response to MEK5 activation, ERK5 SUMOylation favors the dissociation of Hsp90 from the complex, allowing ERK5 nuclear shuttling and activation of the transcription

Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p<0·0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63·0% vs 82·7%; OR 0·35 [0·23–0·53]; p<0·0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer. Interpretation: Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised. Funding: National Institute for Health and Care Research

Delaying surgery for patients with a previous SARS-CoV-2 infection

Not availabl