Immediate and long-term impact of the COVID-19 pandemic on delivery of surgical services.

BACKGROUND: The ongoing pandemic is having a collateral health effect on delivery of surgical care to millions of patients. Very little is known about pandemic management and effects on other services, including delivery of surgery. METHODS: This was a scoping review of all available literature pertaining to COVID-19 and surgery, using electronic databases, society websites, webinars and preprint repositories. RESULTS: Several perioperative guidelines have been issued within a short time. Many suggestions are contradictory and based on anecdotal data at best. As regions with the highest volume of operations per capita are being hit, an unprecedented number of operations are being cancelled or deferred. No major stakeholder seems to have considered how a pandemic deprives patients with a surgical condition of resources, with patients disproportionally affected owing to the nature of treatment (use of anaesthesia, operating rooms, protective equipment, physical invasion and need for perioperative care). No recommendations exist regarding how to reopen surgical delivery. The postpandemic evaluation and future planning should involve surgical services as an essential part to maintain appropriate surgical care for the population during an outbreak. Surgical delivery, owing to its cross-cutting nature and synergistic effects on health systems at large, needs to be built into the WHO agenda for national health planning. CONCLUSION: Patients are being deprived of surgical access, with uncertain loss of function and risk of adverse prognosis as a collateral effect of the pandemic. Surgical services need a contingency plan for maintaining surgical care in an ongoing or postpandemic phase.

ANTECEDENTES: La pandemia en curso tiene un efecto colateral sobre la salud en la prestación de atención quirúrgica a millones de pacientes. Se sabe muy poco sobre el manejo de la pandemia y sus efectos colaterales en otros servicios, incluida la prestación de servicios quirúrgicos. MÉTODOS: Se ha realizado una revisión de alcance de toda la literatura disponible relacionada con COVID-19 y cirugía utilizando bases de datos electrónicas, páginas web de sociedades, seminarios online y repositorios de pre-publicaciones. RESULTADOS: Se han publicado varias guías perioperatorias en un corto período de tiempo. Muchas recomendaciones son contradictorias y, en el mejor de los casos, se basan en datos anecdóticos. A medida que las regiones con el mayor volumen de operaciones per cápita se ven afectadas, se cancela o difiere un número sin precedentes de operaciones. Ninguna de las principales partes interesadas parece haber considerado cómo una pandemia priva de recursos a los pacientes que necesitan una intervención quirúrgica, con pacientes afectados de manera desproporcionada debido a la naturaleza del tratamiento (uso de anestesia, quirófanos, equipo de protección, contacto físico y necesidad de atención perioperatoria). No existen recomendaciones sobre cómo reanudar la actividad quirúrgica. La evaluación tras la pandemia y la planificación futura deben incluir a los servicios quirúrgicos como una parte esencial para mantener la atención quirúrgica adecuada para la población también durante un brote epidémico. La prestación de servicios quirúrgicos, debido a su naturaleza transversal y a sus efectos sinérgicos en los sistemas de salud en general, debe incorporarse a la agenda de la OMS para la planificación nacional de la salud. CONCLUSIÓN: Los pacientes se ven privados de acceso a la cirugía con una pérdida de función incierta y riesgo de un pronóstico adverso como efecto colateral de la pandemia. Los servicios quirúrgicos necesitan un plan de contingencia para mantener la atención quirúrgica durante la pandemia y en la fase post-pandemia.

Enhanced recovery after surgery for liver resection.

INTRODUCTION: Enhanced recovery after surgery (ERAS) reduces postoperative length of hospital stay and patient stress response to liver surgery. The aim of the present study was to evaluate the efficacy and feasibility of an ERAS programme for liver resection. METHODS: A multidisciplinary ERAS protocol was implemented for both open and laparoscopic liver resection in a tertiary hospital in Hong Kong. The clinical outcomes of patients who underwent liver resection and underwent the ERAS perioperative programme were compared with those who received a conventional perioperative programme between September 2015 and July 2016. Propensity score matching analysis was used to minimise background differences. RESULTS: A total of 20 patients who underwent liver resection were recruited to the ERAS programme. Their clinical outcomes were compared with another 20 patients who received hepatectomy under a conventional perioperative programme after propensity score matching. The ERAS programme was associated with a significantly shorter length of hospital stay (P=0.033) without an increase in complication rates in patients who underwent open liver resection. There was no such significant association in patients who underwent laparoscopic liver resection. No patients required readmission in this cohort. CONCLUSIONS: The ERAS perioperative programme for liver resection is safe and feasible. It significantly shortened the hospital stay after open liver resection but not after laparoscopic liver resection.

Preoperative serum α-fetoprotein and prognosis after hepatectomy for hepatocellular carcinoma.

BACKGROUND: While the majority of studies report that a raised serum α-fetoprotein (AFP) level before operation is associated with a high risk of recurrence and death in patients who undergo hepatectomy for hepatocellular carcinoma (HCC), results are conflicting. The aim of this study was to assess the prognostic value of AFP. METHODS: Serum AFP levels were measured in patients with hepatitis-associated HCC who underwent hepatectomy between 1995 and 2012. Kaplan-Meier and multivariable analyses were performed to identify risk factors for overall and disease-free survival. Univariable and multivariable Cox proportional hazards regression was used to evaluate the predictive value of AFP. Receiver operating characteristic (ROC) curves were generated to identify the AFP level that had the highest accuracy in discriminating between survivors and non-survivors. RESULTS: Some 376 patients with hepatitis B virus (HBV)-associated HCC were included in the study. The overall survival rate was 58·8 per cent in patients with an AFP level of 400 ng/ml or less compared with 40·4 per cent for those with a level exceeding 400 ng/ml (P = 0·001). AFP concentration above 400 ng/ml was an independent risk factor for shorter disease-free and overall survival after surgery. ROC analysis indicated that the optimal cut-off values for AFP varied for different subtypes of HCC. The sensitivity and specificity were lower with areas under the ROC curve of less than 0·600. An AFP level greater than 400 ng/ml was not sensitive enough to predict the prognosis in patients with an HCC diameter smaller than 3 cm. CONCLUSION: A serum AFP level above 400 ng/ml predicts poor overall and recurrence-free survival after hepatectomy in patients with HBV-associated HCC. AFP is not a strong prognostic marker given its poor discriminatory power, with low sensitivity and specificity.

Effect of local injection of mesenchymal stem cells on healing of sutured gastric perforation in an experimental model.

BACKGROUND: Mesenchymal stem cells are proposed to facilitate repair of organ injuries. The aim of this study was to investigate whether local injection of mesenchymal stem cells could accelerate healing of sutured gastric perforations. METHODS: Sutured gastric perforations in rats were treated either with local injection of mesenchymal stem cells (injected MSC group) or by topically spraying with fibrin glue containing mesenchymal stem cells (sprayed MSC group). Controls were treated by local injection of saline or topical spray of fibrin glue without mesenchymal stem cells. Healing of sutured gastric perforations was assessed on days 3, 5 and 7. RESULTS: Local injection of mesenchymal stem cells significantly promoted the healing of gastric perforations, with the highest pneumatic bursting pressure (mean(s.e.m.) 112·3(30·2) mmHg on day 5 versus 71·2(17·4) mmHg in saline controls; P = 0·001), minimal wound adhesions, and lowest incidence of wound dehiscence (3, 6, 5 and 1 animal on day 5 in control, fibrin, sprayed MSC and injected MSC groups respectively; n = 10 per group) and abdominal abscess (2, 2, 1 and no animals respectively on day 5). Histological examination showed that gastric perforations in the injected MSC group displayed reduced inflammation, and increased granulation and re-epithelialization. Sutured gastric perforations in the injected MSC group showed decreased expression of interleukin 6, and increased expression of transforming growth factor ß1 and epithelial proliferating cell nuclear antigen, compared with the other groups. CONCLUSION: Local injection of mesenchymal stem cells was more effective than topical application, and enhanced the healing of sutured gastric perforations by an anti-inflammatory process, enhanced cellular proliferation and earlier onset of granulation. Surgical relevance Abnormal healing of gastric perforation may cause morbidity and increase the risk of death. Adipose tissue-derived mesenchymal stem cells have been found to promote the healing of organ injuries through cellular differentiation and secretion of cytokines that stimulate cellular proliferation and angiogenesis, and suppress inflammation. This study explored the therapeutic potential of such mesenchymal stem cells for promotion of the healing of sutured gastric perforations. Mesenchymal stem cells delivered by local injection significantly enhanced the healing of gastric perforations with reduced severity of wound adhesion, and a decreased incidence of wound dehiscence and abdominal abscess. The increased expression of transforming growth factor ß1, proliferating cell nuclear antigen and reduced level of interleukin 6 provide evidence for enhancement of the healing process. Engrafted mesenchymal stem cells expressed α-smooth muscle actin as a marker of myofibroblasts. This preclinical study indicates that local injection of allogeneic adipose tissue-derived mesenchymal stem cells may have a potential therapeutic role in enhancing the healing of peptic ulcer disease and prevention of ulcer-related complications.

HBx mutants differentially affect the activation of hypoxia-inducible factor-1α in hepatocellular carcinoma.

BACKGROUND: Mutations in HBx gene are frequently found in HBV-associated hepatocellular carcinoma (HCC). Activation of hypoxia-inducible factor-1α (HIF-1α) contributes to HCC development and progression. Wild-type HBx has been demonstrated to activate HIF-1α, but the effect of HBx mutations on HIF-1α has not been elucidated. METHODS: HBx mutations were identified by gene sequencing in 101 HCC tissues. Representative HBx mutants were cloned and transfected into HCC cells. Expression and activation of HIF-1α were analysed by western blot and luciferase assays, respectively. The relationship between HBx mutants and HIF-1α expression in HCC tissues was also evaluated. RESULTS: The dual mutations K130M/V131I enhanced the functionality of HBx as they upregulated the expression and transcriptional activity of HIF-1α. The C-terminal truncations and deletion mutations, however, weakened the ability of HBx to upregulate HIF-1α. Meanwhile, the C-terminus was further found to be essential for the stability and transactivation of HBx. In the HCC tissues, there was a positive association between the HBx mutants and HIF-1α expression. CONCLUSION: Different mutations of HBx exert differentiated effects on the functionality of HIF-1α, however, the overall activity of HBx mutants appears to increase the expression and transcriptional activity of HIF-1α.

Hepatitis B virus x protein induces autophagy via activating death-associated protein kinase.

Hepatitis B virus x protein (HBX), a product of hepatitis B virus (HBV), is a multifunctional protein that regulates viral replication and various cellular functions. Recently, HBX has been shown to induce autophagy; however, the responsible mechanism is not fully known. In this study, we established stable HBX-expressing epithelial Chang cells as the platform to study how HBX induced autophagy. The results showed that the overexpression of HBX resulted in starvation-induced autophagy. HBX-induced autophagy was related to its ability to dephosphorylate/activate death-associated protein kinase (DAPK). The block of DAPK by its siRNA significantly counteracted HBX-mediated autophagy, confirming the positive role of DAPK in this process. HBX also induced Beclin 1, which functions at the downstream of the DAPK-mediated autophagy pathway. Although HBX could activate JNK, a kinase known to participate in autophagy in certain conditions, the change in JNK failed to influence HBX-induced autophagy. In conclusion, HBX induces autophagy via activating DAPK in a pathway related to Beclin 1, but not JNK. This new finding should help us to understand the role of autophagy in HBX-mediated pathogenesis and thus may provide targets for intervening HBX-related disorders.

Randomized clinical trial of open hepatectomy with or without intermittent Pringle manoeuvre.

BACKGROUND: The intermittent Pringle manoeuvre (IPM) is commonly applied during liver resection. Few randomized trials have addressed its effectiveness in reducing blood loss and the results have been conflicting. The present study investigated the hypothesis that IPM could reduce blood loss during liver resection by 50 per cent. METHODS: Between May 2008 and April 2011, patients who underwent elective open hepatectomy were randomized into an IPM or no Pringle manoeuvre (NPM) group and stratified according to the presence or absence of cirrhosis. Data on demographics, type of hepatectomy, operative blood loss, duration of operation, mortality, morbidity and postoperative liver function were recorded and analysed. The primary endpoint was operative blood loss. RESULTS: There were 63 patients in each group. Median (range) operative blood loss was 370 (50-3600) ml in the IPM group versus 335 (40-3160) ml in the NPM group (P = 1·000). There were no differences in blood loss in different phases of the operation, blood loss per area of liver transected or blood transfusion rate, nor in total duration of operation or liver transection time. Postoperative serum alanine aminotransferase levels were higher in the IPM group (P < 0·001). There were more postoperative complications in the IPM group (41 versus 24 per cent; P = 0·036). CONCLUSION: The IPM did not reduce blood loss, but was associated with raised levels of postoperative liver parenchymal enzymes and more complications. REGISTRATION NUMBER: NCT00730743 (http://www.clinicaltrials.gov).

Clinical significance of CDX2-positive circulating tumour cells in colorectal cancer patients.

BACKGROUND: Our recent work has shown the feasibility of using a refined immunomagnetic enrichment (IE) assay to detect cytokeratin 20-positive circulating tumour cells (CK20 pCTCs) in colorectal cancer (CRC) patients. We attempted to improve the sensitivity for CRC by detecting another intestinal-type differentiation marker, CDX2 pCTCs, using the same methodology. METHODS: CDX2 pCTCs were detected in patients with CRC, colorectal adenoma (CAD), benign colorectal diseases (BCD), other common cancers (OCC) and normal subjects (NS). Statistical analysis was used to correlate CDX2 pCTCs to the clinicohistopathological factors, recurrence, metastasis and survival after follow-up for 42 months in CRC patients. RESULTS: CDX2 pCTCs were detected in 81% CRC patients (73 out of 90, median number=21.5 CTCs), 7.5% CAD patients (3 out of 40), 0% patients with BCD (0 out of 90), 2.5% patients with OCC (2 out of 80) and 0% NS (0 out of 40). Furthermore, statistical analysis showed that CDX2 pCTC numbers were associated with tumour- node-metastasis stage and lymph node status. Using the median CDX2 pCTC numbers as the cutoff points, stratified groups of CRC patients had significant differences in their recurrence and survival. CONCLUSIONS: This study showed that the refined IE assay can detect CDX2 pCTCs with high sensitivity and that CDX2 pCTCs can generate clinically important information for CRC patients.

Acute kidney injury following hepatectomy and its impact on long-term survival for patients with hepatocellular carcinoma.

BACKGROUND: Acute kidney injury (AKI) is increasingly being recognized after hepatectomy. This study aimed to identify factors predicting its occurrence and its impact on long-term outcome among patients with hepatocellular carcinoma (HCC). METHODS: This was a retrospective analysis of the incidence of AKI, factors predicting its occurrence, and its impact on patients undergoing hepatectomy between September 2007 and December 2018. A subgroup analysis included patients with histologically proven HCC. RESULTS: The incidence of AKI was 9.2 per cent in 930 patients. AKI was associated with increased mortality, morbidity, posthepatectomy liver failure (PHLF), and a longer hospital stay. On multivariable analysis, study period December 2013 to December 2018, diabetes mellitus, mean intraoperative BP below 72.1 mmHg, operative blood loss exceeding 377ml, high Model for End-Stage Liver Disease (MELD) score, and PHLF were predictive factors for AKI. Among 560 patients with HCC, hypertension, BP below 76.9 mmHg, blood loss greater than 378ml, MELD score, and PHLF were predictive factors. The 1-, 3-, and 5-year overall survival rates were 74.1, 59.2, and 51.6 per cent respectively for patients with AKI, and 91.8, 77.9, and 67.3 per cent for those without AKI. Corresponding 1-, 3-, and 5-year disease-free survival rates were 56.9, 42.3, and 35.4 per cent respectively in the AKI group, and 71.7, 54.5, and 46.2 per cent in the no-AKI group. AKI was an independent predictor of survival in multivariable analysis. CONCLUSION: AKI is associated with longer hospital stay, and higher morbidity and mortality rates. It is also associated with shorter long-term survival among patients with HCC. To avoid AKI, control of blood loss and maintaining a reasonable BP (72-77 mmHg) during hepatectomy is important.

Therapeutic effect of alpha-fetoprotein promoter-mediated tBid and chemotherapeutic agents on orthotopic liver tumor in mice.

Previous studies have shown that the application of Ad/AFPtBid significantly and specifically killed hepatocellular carcinoma (HCC) cells in culture and subcutaneously implanted in mice. This study was to test the therapeutic efficacy of Ad/AFPtBid in an orthotopic hepatic tumor model. Four weeks after implantation of tumor cells into the liver, nude mice were treated with Ad/AFPtBid alone or in combination with 5-fluorouracil (5-FU). Serum alpha-fetoprotein (AFP) was measured as a marker for tumor progression. The results showed that Ad/AFPtBid significantly inhibited Hep3B tumor growth. Ad/AFPtBid and 5-FU in combination was more effective than either agent alone. Tumor tissues of Ad/AFPtBid alone or combination treatment groups showed a decrease in cells positive for proliferation cell nuclear antigen, but an increase in apoptosis. Ad/AFPtBid did not suppress the hepatic tumor formed by non-AFP-producing hepatoma SK-HEP-1 cells or colorectal adenocarcinoma DLD-1 cells. The survival rate was higher in mice treated with Ad/AFPtBid plus 5-FU than those treated with either agent alone. No acute toxic effect was observed in mice receiving Ad/AFPtBid. Collectively, Ad/AFPtBid can specifically target and effectively suppress the AFP-producing orthotopic liver tumor in mice without obvious toxicity, indicating that it is a promising tool in combination with chemotherapeutic agents for treatment of AFP-producing HCC.

The analgesic efficacy of continuous wound instillation with ropivacaine after open hepatic surgery.

The analgesic efficacy of continuous local anaesthetic wound instillation after open hepatic surgery was evaluated. Forty-eight patients scheduled for elective liver surgery were assigned to receive either ropivacaine 0.25% or saline infusion at 4 ml.h(-1) for 68 h via two multi-orifice indwelling catheters placed within the musculo-fascial layer before skin closure; plasma ropivacaine concentrations were measured during the infusion. Supplemental analgesia was provided by intravenous patient-controlled analgesia morphine. Patients in the ropivacaine group had decreased mean (SD) total morphine consumption (58 (30) mg vs 86 (44) mg, p = 0.01) and less pain at rest as well as after spirometry at 4, 12, 24, 48 and 72 h postoperatively (p < 0.01). Forced vital capacity was reduced postoperatively in both groups, but the reduction was greater in the saline group at 12 and 24 h (p = 0.03). The mean plasma concentration of ropivacaine increased to 2.05 (0.78) µg.ml(-1) at the point when the infusion was terminated.

Peri-operative blood transfusion increases length of hospital stay and number of postoperative complications in non-cardiac surgical patients.

OBJECTIVES: To test the hypothesis that blood transfusion alone was a significant risk factor for in-hospital morbidity in non-cardiac patients. DESIGN: Propensity analysis. SETTING: University teaching hospital, Hong Kong. PATIENTS: Consecutive non-cardiac patients seen in our department from 2006 to early 2009 who underwent a major procedure under general or spinal anaesthesia were included. Propensity analysis was performed to neutralise the confounding effects of preoperative variables and identify the true effects of transfusions on surgical outcomes. MAIN OUTCOME MEASURES: Receipt of intra-operative and postoperative blood transfusion was established and the difference in proportions between patients who did and did not receive donor blood tested for mortality, overall morbidity, individual complications, and number of adverse events. RESULTS: Transfused patients were significantly older and sicker, more likely to be male, to have lower haemoglobin values and undergo longer and more emergency surgical procedures than those not receiving a transfusion. Blood transfusion was predictive of length of postoperative hospital stay and number of complications before discharge. The amount of transfused blood was predictive of in-hospital mortality, with an odds ratio of 1.4 for each unit of blood received. The risk of a surgical wound infection was almost doubled when the patient had received a blood transfusion. CONCLUSION: After controlling for the factors associated with an increased likelihood for receiving a blood transfusion, the actual transfusion was predictive of a slower and more eventful postoperative recovery with associated costs to both the patient and health services.

Radiofrequency ablation for 110 malignant liver tumours: preliminary results on percutaneous and surgical approaches.

BACKGROUND: Radiofrequency ablation (RFA) has been widely applied for the treatment of hepatocellular carcinoma and liver metastases. The reported mortality and morbidity rates are low. The aim of this study is to evaluate the safety and efficacy of RFA, and compare the results performed percutaneously versus surgically. PATIENTS AND METHODS: From 2003 to 2006, 79 patients with hepatic malignancies (59 hepatocellular carcinoma, 20 liver metastases) with a total of 110 lesions underwent RFA in our centre. Postablation assessment by CT scan was performed in all patients at 1-, 3- and 6-month intervals. Post-procedural complications, recurrence and survival were analysed. RESULTS: The patients' mean age was 60.0 years. In 46.8% of cases, we used a percutaneous approach; in 53.2% of cases, a surgical approach (8.9% laparoscopic; 44.3% open) was used if percutaneous approach was not feasible. The mean tumour size was 2.4 cm. Within the surgical group, 69% of patients received concomitant operative procedures such as cholecystectomy and hepatectomy. No treatment-related mortality was observed. Immediate complications occurred in five patients (6.3%), including gastric serosal burn (n = 1), ground pad superficial skin burn (n = 1), intra-abdominal bleeding (n = 2) and pleural effusion (n = 1). All patients except one attended subsequent follow-up, with a mean period of 16 months. Ablation was considered complete in 82.3% of patients (percutaneous approach 81.1%, surgical approach 83.3%, p = 0.72). Intrahepatic recurrence was observed in 52.3%, the majority of them located away from the RFA site. Extrahepatic recurrences were observed in 16.9% (percutaneous approach 16.7%, surgical approach 17.1%, p = 0.76). The overall one- and two-year survival rate was 93.7% and 74.4% respectively, and no statistically significant difference was observed between the two approaches. CONCLUSION: RFA is a safe and effective procedure for treating patients with malignant liver tumours. No difference in short term outcomes was observed between percutaneous and surgical approaches. A more prolonged follow-up study is required to assess longer-term outcomes.

Multicentre validation of a clinical prognostic score integrating the systemic inflammatory response to the host for patients treated with curative-intent for colorectal liver metastases: The Liverpool score.

BACKGROUND: This study aimed to create a new prognostic score integrating the systemic inflammatory response to predict survival in patients treated with curative intent for colorectal liver metastases (CLM). METHODS: We identified independent prognostic factors in patients who underwent liver surgery for CLM in a tertiary centre in the United Kingdom (UK) between 2010 and 2015. A pre- and a postoperative score (Liverpool score) were created by combining these factors to stratify patients into different risk groups. These new scores were validated in an international cohort of 219 patients from China and France. RESULTS: Multivariate cox regression analysis of the 364 patients of the UK cohort identified 6 preoperative and 1 postoperative prognostic factors for overall survival (OS): American society of anaesthesiologists (ASA) score, location and node status of the primary tumour, number and size of CLM, neutrophil-to-lymphocyte ratio (NLR) and resection margin. Both pre- and postoperative scores can be calculated with an online calculator at https://jscalc.io/calc/PXatrmjfrEFpYy2t. Using the pre-operative model on the UK cohort, median OS was 61.22 (50.23, not reached) months in the low-risk group (n = 162) and 30.36 (23.68, 35.95) months in the high-risk group (n = 162, p < 0.0001). The same difference was observed in the validation cohort. The Liverpool score outperformed previously published scoring system with a c-index of 0.619 pre-operatively and of 0.637 post-operatively. CONCLUSION: We developed a new prognostic score based on clinicopathologic characteristics including the site of the primary tumour location and on measurement of the systemic inflammatory response which could help to tailor patients' management.