Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

"PULSED" versus "CONTINUOUS" application of the prodrug 5-FC for enhancing oncolytic effectiveness of a measles vaccine virus armed with a suicide gene

Die onkolytische Virotherapie stellt einen neuen Therapieansatz dar, der seinen Ursprung in gut dokumentierten Beobachtungen von Krebspatienten hat, die nach einer sich zufällig zeitgleich zur Tumorerkrankung ereignenden Virus­infektion eine komplette Remission ihrer Erkrankung erfuhren. Mittlerweile wurden verschiedene Virusarten präklinisch und klinisch für die Behandlung unterschiedlicher Tumorerkrankungen untersucht. Diese Viren zeich­­nen sich durch ihre Eigenschaft aus, Tumorzellen selektiv zu infizieren und sich in ihnen rasant zu vermehren, was innerhalb kurzer Zeit zu deren virusver­mittelter Zerstörung (“Onkolyse”) führt. Gesunde Zellen bleiben dagegen unbe­trof­fen. Um die onkolytische Wirksamkeit dieser Viren noch zusätzlich zu ver­bessern, gibt es Ansätze, durch Insertion von Fremdgenen in das Virus-Genom (sog. “Armierung”) eine weiter verbesserte Tumorzellabtötung zu erreichen. Ein solcher Ansatz kann beispielsweise in der Armierung mit einem Fusionsgen bestehen, das für eine Enzymkombination aus Cytosindeaminase und Uracil­phospho­ribosyltransferase (sog. “SCD-Suizidenzym”) kodiert, die das Pro-Phar­ma­kon (sog. “Prodrug”) 5-FC in das hochpotente Chemothera­peu­ti­kum 5-FU um­wandelt. Die Tatsache, dass die Infektion und Suizidgen-Expression selektiv Tumor­­zellen trifft, ermöglicht somit eine zusätzliche lokale Hochdosis-Chemo­therapie ohne begleitende sytemische Nebenwirkungen. Obwohl gezeigt wurde, dass diese Armierungs-Methode den onkolytischen Effekt signifikant verstärkt, wurde bisher kein optimales Dosierungsschema auf der Basis einer systema­ti­schen Variation der Applikationsbedingungen erarbeitet. Das Ziel dieser Arbeit war es dementsprechend, Suizidgen-verstärkte Masern­­impf­viren für die onkolytische Virotherapie einzusetzen, verschiedene Regime der Pro-Pharmakongabe zu vergleichen und im Resultat ein optimales Anwendungsschema zu ermitteln (Yurttas et al, 2014). Nachdem in einem umfangreichen Vorversuch für jede Tumor-Zelllinie eine für Folgeversuche jeweils am besten geeignete Virusmenge ermittelt wurde, konnten die entworfenen Behandlungs­pläne untersucht werden: 5-FC wurde zu verschiedenen Zeitpunkten nach der Infektion mit den Suizid­gen-ver­stärkten Masernimpfviren zugegeben und das Pro-Pharmakon blieb ent­weder kontinuierlich und für unterschiedliche Zeitspannen (kontinuierliche 5-FC Gabe) oder nur temporär und für definierte, kurze Zeitspannen (gepulste 5-FC Gabe) auf den Tumorzellen. Die Ergebnisse zeigen, dass eine kontinuierliche Pro-Phar­makongabe die effektivste anti-tumorale Wirkung bewirkt und einer gepulsten Applikations­weise deutlich überlegen ist (Yurttas et al, 2014). Es wurde jedoch weiterhin festgestellt, dass die Pro-Pharmakonzugabe einen unter­drückenden Effekt auf die Virusvermehrung hat. Allerdings ist bislang nicht erkenntlich, ob die erniedrigten Virustiter unter Einwirkung von 5-FC durch direkte Hemmung der Virusvermehrung oder indirekt durch die verstärkte Onkolyse und damit durch den Entzug von Wirtszellmasse für das Virus zustande kommt. Interessanterweise zeigte eine frühe und kontinuierliche 5-FC Zugabe trotz des blockierenden Effekts auf die Bildung von Virusnachkommen eine signifikante Verstärkung des onkolytischen Effekts (Yurttas et al, 2014). Unser experimenteller in vitro-Ansatz ist wohlwissend von Natur aus sehr künstlich und damit nicht direkt auf die klinische Anwendung übertragbar. Wir betrachten unsere Ergebnisse daher als vorläufige Anhaltspunkte, um nachfolgend in Kooperation mit einem Sponsor aus der biopharmazeutischen Industrie ein entsprechendes klinisches Anwen­dungsregime mit zeitlich optimal getakteter Behandlung mit unserem Viro­thera­peu­­tikum MeV-SCD und dem Prodrug-Medikament 5-FC zu erarbeiten. Wir planen außerdem, dieses der zuständigen Bundesoberbehörde (Paul-Ehrlich-Institut) zur Genehmigung vorzulegen. Die Daten einer entsprechenden ersten klinischen Phase I-Studie wer­den dann weiteren Aufschluss über Sicherheit und anti-tumorale Effizienz dieses sehr vielversprechenden Ansatzes erbringen

Reply to: “Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Definitively Does Not Deserve Its Bad Reputation”

Background!#!The presence or future development of metastatic pheochromocytomas or paragangliomas (mPPGLs) can be difficult to diagnose or predict at initial presentation. Since production of catecholamines from mPPGLs is different from non-metastatic tumors (non-mPPGLs), this study aimed to clarify whether presenting catecholamine-related signs and symptoms (cSS) might also differ.!##!Methods!#!The study included 249 patients, 43 with mPPGL and 206 with non-mPPGL. Clinical data at the time of biochemical diagnosis (i.e. at entry into the study) were used to generate a cumulative score of cSS for each patient.!##!Results!#!Patients with mPPGL were significantly younger (43.3 ± 14 vs. 48.9 ± 16.1 years) and included a lower proportion of females (39.5% vs. 60.7%) than patients with non-mPPGLs. Frequencies of signs and symptoms did not differ between the two groups. Patients with mPPGLs had lower (P < 0.001) urinary excretion of epinephrine (3.5 (IQR, 1.9-6.5) µg/day) than those with non-mPPGLs (19.1 (IQR, 4.3-70.2) µg/day). There was no difference in urinary excretion of norepinephrine. In patients with mPPGLs a high cSS score was associated with high urinary excretion of norepinephrine and normetanephrine. In contrast, in patients with non-mPPGLs, a high cSS was associated with high urinary excretion of epinephrine and metanephrine.!##!Conclusion!#!Although presenting signs and symptoms were associated with production of norepinephrine in patients with mPPGLs and of epinephrine in patients with non-mPPGLs, there were no differences in signs and symptoms between the two groups. Therefore, consideration of signs and symptoms does not appear helpful for distinguishing patients with and without mPPGLs

ASO Author Reflections: First Do No Harm—Revisiting Adjuvant Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Trials to Reduce the Risk of Peritoneal Metastasis

The current study evaluated the effect of location and amount of various superdisintegrants on the properties of tablets made by twin-screw melt granulation (TSMG). Sodium-croscarmellose (CCS), crospovidone (CPV), and sodium starch glycolate (SSG) were used in various proportions intra- and extra-granular. Tabletability, compactibility, compressibility as well as friability, disintegration, and dissolution performance were assessed. The extra-granular addition resulted in the fasted disintegration and dissolution. CPV performed superior to CCS and SSG. Even if the solid fraction (SF) of the granules was lower for CPV, only a minor decrease in tabletability was observed, due to the high plastic deformation of the melt granules. The intra-granular addition of CPV resulted in a more prolonged dissolution profile, which could be correlated to a loss in porosity during tableting. The 100% intra-granular addition of the CPV resulted in a distinct decrease of the disintegration efficiency, whereas the performance of SSG was unaffected by the granulation process. CCS was not suitable to be used for the production of an immediate-release formulation, when added in total proportion into the granulation phase, but its efficiency was less impaired compared to CPV. Shortest disintegration (78 s) and dissolution (

Limitations of laparoscopy to assess the peritoneal cancer index and eligibility for cytoreductive surgery with HIPEC in peritoneal metastasis

PURPOSE: We aimed to determine the value of laparoscopy to assess the intra-abdominal tumor extent and predict complete cytoreduction. METHODS: All patients at our department in the period from 2017 to 2021 that underwent laparoscopy to assess peritoneal metastasis and subsequent open exploration with the intention to perform cytoreductive surgery (CRS) with HIPEC were retrospectively identified in a continuously maintained database. RESULTS: Forty-three patients were analyzed. Peritoneal cancer index (PCI) determination by laparoscopy compared to open surgery was overestimated in five patients (11.6%), identical in eleven patients (25.6%), and underestimated in 27 patients (62.8%). PCI differences were independent of surgeons, tumor entities, and prior chemotherapy. Thirty-four patients (79.1%) were determined eligible for CRS with HIPEC during open exploration, whereas nine patients (20.9%) underwent a non-therapeutic laparotomy. Complete or almost complete cytoreduction was achieved in 33 patients (76.7%). In one patient, completeness of cytoreduction was not documented. CONCLUSIONS: We demonstrate a moderate agreement according to weighted Cohen’s kappa analysis of PCI values calculated during laparoscopy and subsequent open exploration for CRS with HIPEC. Uncertainty of PCI assessment should therefore be kept in mind when performing laparoscopy in patients with peritoneal metastasis