Pembrolizumab in Asian patients with microsatellite-instability-high/mismatch-repair-deficient colorectal cancer

The phase 3 KEYNOTE-177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite-instability-high (MSI-H)/mismatch-repair-deficient (dMMR) metastatic colorectal cancer (mCRC). Primary endpoints were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Here, we report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis (FA) of KEYNOTE-177. A total of 48 patients from Japan, Korea, Singapore, and Taiwan (pembrolizumab, n =?22; chemotherapy, n =?26) were included. At FA, median time from randomization to data cutoff (February 19, 2021) was 45.3 (range 38.1?57.8) months with pembrolizumab and 43.9 (range 36.6?55.1) months with chemotherapy. Median PFS was not reached (NR; 95% confidence interval [CI] 1.9 months?NR) with pembrolizumab versus 10.4 (95% CI 6.3?22.0) months with chemotherapy (hazard ratio [HR] 0.56, 95% CI 0.26?1.20). Median OS was NR (range 13.8 months?NR) versus 30.0 (14.7?NR) months (HR 0.65, 95% CI 0.27?1.55) and ORR was 50% (95% CI 28?72) versus 46% (95% CI 27?67). Grade 3/4 treatment-related adverse events (TRAEs) were reported by two patients (9%) in the pembrolizumab arm and 20 (80%) in the chemotherapy arm. Immune-mediated adverse events or infusion reactions were reported by six patients (27%) and 10 patients (40%), respectively. No deaths due to TRAEs occurred. These data support first-line pembrolizumab as a standard of care for patients from Asia with MSI-H/dMMR mCRC. ClinicalTrials.gov identifier: NCT02563002.FUNDING INFORMATION: The study was designed under the responsibility of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, in conjunction with the steering committee. The study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Pembrolizumab was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. All authors had full access to all of the data in the study and had final responsibility for the decision to submit for publication. ACKNOWLEDGMENTS: This work was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. We thank the patients and their families and caregivers for participating in this trial, and all investigators and site personnel. Medical writing and editorial assistance were provided by Jemimah Walker, PhD, Mehak Aggarwal, PharmD, and Doyel Mitra, PhD, CMPP, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA

Long Noncoding RNA NIHCOLE Promotes Ligation Efficiency of DNA Double-Strand Breaks in Hepatocellular Carcinoma

[Abstract] Long noncoding RNAs (lncRNA) are emerging as key players in cancer as parts of poorly understood molecular mechanisms. Here, we investigated lncRNAs that play a role in hepatocellular carcinoma (HCC) and identified NIHCOLE, a novel lncRNA induced in HCC with oncogenic potential and a role in the ligation efficiency of DNA double-stranded breaks (DSB). NIHCOLE expression was associated with poor prognosis and survival of HCC patients. Depletion of NIHCOLE from HCC cells led to impaired proliferation and increased apoptosis. NIHCOLE deficiency led to accumulation of DNA damage due to a specific decrease in the activity of the nonhomologous end-joining (NHEJ) pathway of DSB repair. DNA damage induction in NIHCOLE-depleted cells further decreased HCC cell growth. NIHCOLE was associated with DSB markers and recruited several molecules of the Ku70/Ku80 heterodimer. Further, NIHCOLE putative structural domains supported stable multimeric complexes formed by several NHEJ factors including Ku70/80, APLF, XRCC4, and DNA ligase IV. NHEJ reconstitution assays showed that NIHCOLE promoted the ligation efficiency of blunt-ended DSBs. Collectively, these data show that NIHCOLE serves as a scaffold and facilitator of NHEJ machinery and confers an advantage to HCC cells, which could be exploited as a targetable vulnerability.[Significance] This study characterizes the role of lncRNA NIHCOLE in DNA repair and cellular fitness in HCC, thus implicating it as a therapeutic target.This work was supported by the European FEDER funding (to the activities of the groups directed by P. Fortes, O. Llorca, and F. Moreno-Herrero) and grants from the Ministry of Economy and Competitiveness [SAF2015-70971-R to P. Fortes and BFU2017-83794-P (AEI/FEDER, UE) to F. Moreno-Herrero)]; MCIU/AEI/FEDER/UE (RTI2018-101759-B-I00 to P. Fortes), NIH program (CA92584 to S.P. Lees-Miller), Ligue National Contre le Cancer, Équipe Labellisée and ITMO Cancer: Consortium HETCOLI (to J. Zucman-Rossi), NIH program (P01CA092584 to G. Williams), NSERC (RGPIN-2018-04327 to G. Williams), and CFI (RCP-18-023-SEG to G. Williams), Gobierno de Navarra (33/2015 to P. Fortes), Scientific Foundation of the Spanish Association Against Cancer (AECC IDEAS20169FORT to P. Fortes); Fondo de Investigación Sanitaria (PI19/00742 to B. Sangro), financed by the National Institute of Health Carlos III and FEDER. CNIO and CIBERehd are funded by the National Institute of Health Carlos III. J.P. Unfried was a recipient of a University of Navarra's Asociación de Amigos fellowship. L. Prats-Mari is a recipient of a PFIS fellowship (FI20/00074) by the National Institute of Health Carlos III and FSE "Investing in Your Future." This work was also funded by grants from the Autonomous Region of Madrid (Tec4Bio—S2018/NMT-4443 and NanoBioCancer—Y2018/BIO-4747 to O. Llorca and F. Moreno-Herrero) and co-funded by the European Social Fund. F. Moreno-Herrero acknowledges support from the European Research Council (ERC) under the European Union Horizon 2020 Research and Innovation Program (grant agreement 681299). The GTEx Project was supported by the NIH and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS.Peer reviewe

Predictive Power of the "Trigger Tool" for the detection of adverse events in general surgery: a multicenter observational validation study

Background In spite of the global implementation of standardized surgical safety checklists and evidence-based practices, general surgery remains associated with a high residual risk of preventable perioperative complications and adverse events. This study was designed to validate the hypothesis that a new “Trigger Tool” represents a sensitive predictor of adverse events in general surgery. Methods An observational multicenter validation study was performed among 31 hospitals in Spain. The previously described “Trigger Tool” based on 40 specific triggers was applied to validate the predictive power of predicting adverse events in the perioperative care of surgical patients. A prediction model was used by means of a binary logistic regression analysis. Results The prevalence of adverse events among a total of 1,132 surgical cases included in this study was 31.53%. The “Trigger Tool” had a sensitivity and specificity of 86.27% and 79.55% respectively for predicting these adverse events. A total of 12 selected triggers of overall 40 triggers were identified for optimizing the predictive power of the “Trigger Tool”. Conclusions The “Trigger Tool” has a high predictive capacity for predicting adverse events in surgical procedures. We recommend a revision of the original 40 triggers to 12 selected triggers to optimize the predictive power of this tool, which will have to be validated in future studies

Revisión y Control del Plan de Vigilancia Ambiental de las obras de dragado del Puerto de Maó

Se integra información hidrográfica, geomorfológica, sedimentológica y biológica, para la caracterización de los ecosistemas marinos en el punto de vertido y área adyacente previa al inicio de las obras de dragado del Puerto de Maó.RESUMEN: En este documento se presentan los trabajos científicos realizados por el Instituto Español de Oceanografía, dentro del Plan de Vigilancia Ambiental del dragado del Puerto de Maó (Menorca, Islas Baleares), para la caracterización de los ecosistema marino en el punto de vertido y área adyacente, previa al inicio de las obras. Se incluyen los resultados y las conclusiones de los estudios realizados por diversos grupos de investigación, principalmente en Enero-Marzo 2014, en relación al fondo marino, la hidrodinámica, las praderas de Posidonia oceanica y el molusco bivalvo Pinna nobilis, el macro-bentos de los fondos circalitorales blandos y los contaminantes en agua, sedimentos y biota, así como en especies de interés comercial para el consumo humano. Este informe se contempla en el contrato entre la Autoridad Portuaria de Baleares y el Instituto Español de Oceanografía, suscrito el 5 Febrero 2014, para los trabajos de asistencia técnica para la revisión y control del Plan de Vigilancia Ambiental del dragado del Puerto de Maó.RESUM: En aquest document es presenten els treballs científics realitzats per l’Instituto Español de Oceanografía, dins del Pla de Vigilància Ambiental del dragat del Port de Maó (Menorca, Illes Balears), per a la caracterització dels ecosistemes marins en el punt de vessament i àrea adjacent, prèvia a l’inici de les obres. S’inclouen els resultats i les conclusions del estudis realitzats per diversos grups de recerca, principalment durant Gener-Març 2014, en relació al fons marí, la hidrodinàmica, les praderies de Posidonia oceanica i el mol•lusc bivalve Pinna nobilis, el macro-bentos dels fons circalitorals tous i els contaminants en aigua, sediments i biota, així com en espècies d’interès comercial pel consum humà. Aquest informe es contempla en el contracte entre l’Autoritat Portuària de Balears i el Instituto Español de Oceanografía, subscrit el 5 Febrer 2014, pels treballs d’assistència tècnica per a la revisió i control del Pla de Vigilància Ambiental del dragat de Port de Maó.ABSTRACT: This document presents the scientific actions developed by the Instituto Español de Oceanografía within the Environmental Monitoring Plan of the works of dredging the Port of Maó (Minorca, Balearic Islands), for the characterization of the marine ecosystems in the point of discharge of dredged material and adjacent area, before the beginning of the dredging. The results and conclusions of the studies developed by several research groups, mainly in January-March 2014, in relation to the bottom, hydrodynamics, Posidonia oceanica meadows, and the bivalve mollusc Pinna nobilis, the macro-benthos of the circalittoral soft bottoms and the contaminants in water, sediments and biota, as well as in commercial species for human consumption, are included. This report is contemplated within the contract between the Autoridad Portuaria de Baleares and the Instituto Español de Oceanografía, signed on 5 February 2014, for the technical assistance activities to review and control the Environmental Monitoring Plan of the works of dredging the Port of Maó.Autoridad Portuaria de Baleare

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Revisión y Control del Plan de Vigilancia Ambiental de las obras de dragado del Puerto de Maó

Se integra información hidrográfica, geomorfológica, sedimentológica y biológica, para la caracterización de los ecosistemas marinos en el punto de vertido y área adyacente previa al inicio de las obras de dragado del Puerto de Maó.RESUMEN: En este documento se presentan los trabajos científicos realizados por el Instituto Español de Oceanografía, dentro del Plan de Vigilancia Ambiental del dragado del Puerto de Maó (Menorca, Islas Baleares), para la caracterización de los ecosistema marino en el punto de vertido y área adyacente, previa al inicio de las obras. Se incluyen los resultados y las conclusiones de los estudios realizados por diversos grupos de investigación, principalmente en Enero-Marzo 2014, en relación al fondo marino, la hidrodinámica, las praderas de Posidonia oceanica y el molusco bivalvo Pinna nobilis, el macro-bentos de los fondos circalitorales blandos y los contaminantes en agua, sedimentos y biota, así como en especies de interés comercial para el consumo humano. Este informe se contempla en el contrato entre la Autoridad Portuaria de Baleares y el Instituto Español de Oceanografía, suscrito el 5 Febrero 2014, para los trabajos de asistencia técnica para la revisión y control del Plan de Vigilancia Ambiental del dragado del Puerto de Maó.RESUM: En aquest document es presenten els treballs científics realitzats per l’Instituto Español de Oceanografía, dins del Pla de Vigilància Ambiental del dragat del Port de Maó (Menorca, Illes Balears), per a la caracterització dels ecosistemes marins en el punt de vessament i àrea adjacent, prèvia a l’inici de les obres. S’inclouen els resultats i les conclusions del estudis realitzats per diversos grups de recerca, principalment durant Gener-Març 2014, en relació al fons marí, la hidrodinàmica, les praderies de Posidonia oceanica i el mol•lusc bivalve Pinna nobilis, el macro-bentos dels fons circalitorals tous i els contaminants en aigua, sediments i biota, així com en espècies d’interès comercial pel consum humà. Aquest informe es contempla en el contracte entre l’Autoritat Portuària de Balears i el Instituto Español de Oceanografía, subscrit el 5 Febrer 2014, pels treballs d’assistència tècnica per a la revisió i control del Pla de Vigilància Ambiental del dragat de Port de Maó.ABSTRACT: This document presents the scientific actions developed by the Instituto Español de Oceanografía within the Environmental Monitoring Plan of the works of dredging the Port of Maó (Minorca, Balearic Islands), for the characterization of the marine ecosystems in the point of discharge of dredged material and adjacent area, before the beginning of the dredging. The results and conclusions of the studies developed by several research groups, mainly in January-March 2014, in relation to the bottom, hydrodynamics, Posidonia oceanica meadows, and the bivalve mollusc Pinna nobilis, the macro-benthos of the circalittoral soft bottoms and the contaminants in water, sediments and biota, as well as in commercial species for human consumption, are included. This report is contemplated within the contract between the Autoridad Portuaria de Baleares and the Instituto Español de Oceanografía, signed on 5 February 2014, for the technical assistance activities to review and control the Environmental Monitoring Plan of the works of dredging the Port of Maó.Autoridad Portuaria de Baleare

Goodbye Hartmann trial: a prospective, international, multicenter, observational study on the current use of a surgical procedure developed a century ago

Background: Literature suggests colonic resection and primary anastomosis (RPA) instead of Hartmann's procedure (HP) for the treatment of left-sided colonic emergencies. We aim to evaluate the surgical options globally used to treat patients with acute left-sided colonic emergencies and the factors that leading to the choice of treatment, comparing HP and RPA. Methods: This is a prospective, international, multicenter, observational study registered on ClinicalTrials.gov. A total 1215 patients with left-sided colonic emergencies who required surgery were included from 204 centers during the period of March 1, 2020, to May 31, 2020. with a 1-year follow-up. Results: 564 patients (43.1%) were females. The mean age was 65.9 ± 15.6&nbsp;years. HP was performed in 697 (57.3%) patients and RPA in 384 (31.6%) cases. Complicated acute diverticulitis was the most common cause of left-sided colonic emergencies (40.2%), followed by colorectal malignancy (36.6%). Severe complications (Clavien-Dindo ≥ 3b) were higher in the HP group (P &lt; 0.001). 30-day mortality was higher in HP patients (13.7%), especially in case of bowel perforation and diffused peritonitis. 1-year follow-up showed no differences on ostomy reversal rate between HP and RPA. (P = 0.127). A backward likelihood logistic regression model showed that RPA was preferred in younger patients, having low ASA score (≤ 3), in case of large bowel obstruction, absence of colonic ischemia, longer time from admission to surgery, operating early at the day working hours, by a surgeon who performed more than 50 colorectal resections. Conclusions: After 100&nbsp;years since the first Hartmann's procedure, HP remains the most common treatment for left-sided colorectal emergencies. Treatment's choice depends on patient characteristics, the time of surgery and the experience of the surgeon. RPA should be considered as the gold standard for surgery, with HP being an exception

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries