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BACKGROUND: Congenital anomalies are a leading cause of morbidity and mortality worldwide. We aimed to review the common surgically correctable congenital anomalies with recent updates on the global disease burden and identify the factors affecting morbidity and mortality. METHOD: A literature review was done to assess the burden of surgical congenital anomalies with emphasis on those that present within the first 8000\u00a0days of life. The various patterns of diseases were analyzed in both low- and middle-income countries (LMIC) and high-income countries (HIC). RESULTS: Surgical problems such as digestive congenital anomalies, congenital heart disease and neural tube defects are now seen more frequently. The burden of disease weighs more heavily on LMIC. Cleft lip and palate has gained attention and appropriate treatment within many countries, and its care has been strengthened by global surgical partnerships. Antenatal scans and timely diagnosis are important factors affecting morbidity and mortality. The frequency of pregnancy termination following prenatal diagnosis of a congenital anomaly is lower in many LMIC than in HIC. CONCLUSION: Congenital heart disease and neural tube defects are the most common congenital surgical diseases; however, easily treatable gastrointestinal anomalies are underdiagnosed due to the invisible nature of the condition. Current healthcare systems in most LMICs are still unprepared to tackle the burden of disease caused by congenital anomalies. Increased investment in surgical services is needed.
\n \n\n \n \nPURPOSE: A comprehensive operative report for cancer surgery is crucial for accurate disease staging, risk stratification, and therapy escalation/de-escalation, which affects the outcome. Narrative operative reports may fail to include some critical findings. Furthermore, standardized operative reports can form the basis of a local registry, which is often lacking in limited-resource settings (LRSs). In adult literature, synoptic operative reports (SOR) contain more key findings than narrative operative reports. In the LRSs, where the capacity of diagnostic pathology services is typically suboptimal, the value of a thorough operative report is even greater. The aim of this study was to develop a SOR template to help standardize childhood cancer surgery reporting in LRSs. METHODS: Twenty-three experts in pediatric cancer with extensive experience practicing in LRSs were invited to participate in a modified Delphi procedure. SOR domains for pediatric oncology surgery were drafted based on a literature search and then modified based on experts' opinions. The experts anonymously answered multiple rounds of online questionnaires until all domains and subdomains reached a consensus, which was predefined as 70% agreement. RESULTS: Sixteen experts participated in the study, and two rounds of the survey were completed. Twenty-one domains were considered relevant, including demographics, diagnosis, primary site, preoperative disease stage, previous tumor biopsy or surgery, preoperative tumor rupture, neoadjuvant therapy, surgical access, type of resection, completeness of resection, tumor margin assessment, locoregional tumor extension, organ resection, intraoperative tumor spillage, vascular involvement, lymph node sampling, estimated blood loss, intraoperative complications and interventions to address them, specimen names, and specimen orientation. CONCLUSION: We developed a SOR template for pediatric oncology surgery in LRSs. Consensus for all 21 domains and associated subdomains was achieved using a modified Delphi procedure.
\n \n\n \n \nThe global burden of paediatric and congenital heart disease (PCHD) is substantial. We propose a novel public health framework with recommendations for developing effective and safe PCHD services in low-income and middle-income countries (LMICs). This framework was created by the Global Initiative for Children's Surgery Cardiac Surgery working group in collaboration with a group of international rexperts in providing paediatric and congenital cardiac care to patients with CHD and rheumatic heart disease (RHD) in LMICs. Effective and safe PCHD care is inaccessible to many, and there is no consensus on the best approaches to provide meaningful access in resource-limited settings, where it is often needed the most. Considering the high inequity in access to care for CHD and RHD, we aimed to create an actionable framework for health practitioners, policy makers and patients that supports treatment and prevention. It was formulated based on rigorous evaluation of available guidelines and standards of care and builds on a consensus process about the competencies needed at each step of the care continuum. We recommend a tier-based framework for PCHD care integrated within existing health systems. Each level of care is expected to meet minimum benchmarks and ensure high-quality and family centred care. We propose that cardiac surgery capabilities should only be developed at the more advanced levels on hospitals that have an established foundation of cardiology and cardiac surgery services, including screening, diagnostics, inpatient and outpatient care, postoperative care and cardiac catheterisation. This approach requires a quality control system and close collaboration between the different levels of care to facilitate the journey and care of every child with heart disease. This effort was designed to guide readers and leaders in taking action, strengthening capacity, evaluating impact, advancing policy and engaging in partnerships to guide facilities providing PCHD care in LMICs.
\n \n\n \n \nBACKGROUND: Surgical site infections (SSIs) are common and serious complications of surgery. Guidelines on preventing SSIs have been developed, but the role of preoperative bathing with plain soap among paediatric population is unclear. We aimed to assess the effectiveness of pre-operative bathing using plain soap in preventing SSIs among paediatric surgical patients. MATERIALS AND METHODS: An open-label, randomised trial was conducted at Muhimbili National Hospital in Tanzania. Preoperatively, patients in the intervention group washed their body using plain soap, while those in the control group did not. The primary outcome was SSI postoperatively. Statistical tests included \u03c72, Wilcoxon rank sum, and univariate and multivariable logistic regression. RESULTS: Of the 252 patients recruited,114 were randomised to the intervention arm. In the control arm, 40.6% (56/138) of participants developed SSIs compared to 11.4% (13/114) in the intervention arm (p < 0.01). After adjusting for confounding factors in multivariable analysis, the intervention reduced the odds of an SSI by 80% (OR: 0.20 [95% CI: 0.10, 0.41]; p < 0.01). Preoperative antibiotics were deemed to be an effect modifier of the association between the intervention and SSI (p\u00a0=\u00a00.05). The intervention significantly reduced the odds of an SSI by 88% among participants not given preoperative antibiotics (OR: 0.12 [95% CI: 0.05, 0.30]; p < 0.01). CONCLUSION: This study has shown that preoperative bathing with soap significantly reduces SSIs in paediatric surgical patients. It is a simple, cost effective and sustainable intervention. LEVEL OF EVIDENCE: Level II.
\n \n\n \n \nExport of datafile SPSS v27.0 used to generate results for mHLA-DRd paper
\n \n\n \n \nOBJECTIVE: To provide mechanistic insight into key biological alterations in donation after circulatory death kidneys during continuous pefusion we performed mass spectrometry profiling of perfusate samples collected during a phase 3 randomized double-blind paired clinical trial of hypothermic machine perfusion with and without oxygen (COMPARE). BACKGROUND: Despite the clinical benefits of novel perfusion technologies aiming to better preserve donor organs, biological processes that may be altered during perfusion have remained largely unexplored. The collection of serial perfusate samples during the COMPARE clinical trial provided a unique resource to study perfusate proteomic profiles, with the hypothesis that in-depth profiling may reveal biologically meaningful information on how donor kidneys benefit from this intervention. METHODS: Multiplexed liquid chromatography-tandem mass spectrometry was used to obtain a proteome profile of 210 perfusate samples. Partial least squares discriminant analysis and multivariate analysis involving clinical and perfusion parameters were used to identify associations between profiles and clinical outcomes. RESULTS: Identification and quantitation of 1716 proteins indicated that proteins released during perfusion originate from the kidney tissue and blood, with blood-based proteins being the majority. Data show that the overall hypothermic machine perfusion duration is associated with increasing levels of a subgroup of proteins. Notably, high-density lipoprotein and complement cascade proteins are associated with 12-month outcomes, and blood-derived proteins are enriched in the perfusate of kidneys that developed acute rejection. CONCLUSIONS: Perfusate profiling by mass spectrometry was informative and revealed proteomic changes that are biologically meaningful and, in part, explain the clinical observations of the COMPARE trial.
\n \n\n \n \nAIM: Paediatric-preoperative anaemia management is challenging in settings where clinical judgment is used to diagnose anaemia owing to a lack of timely, affordable preoperative haemoglobin testing. We analysed anaemia management in such a setting after the introduction of point-of-care bedside haemoglobin testers. METHOD: 1033 children who underwent surgery at a hospital in Bangladesh were included in this study. 569 underwent major surgery, and 464 underwent minor surgery and belonged to predominantly ASA category 1 or 2. RESULTS: 940/1033 children underwent preoperative anaemia testing. Average haemoglobin was 11.7\u00a0g/dL. 103/1033 children were deemed clinically anaemic. However, 285 children were found to have anaemia based on bedside testing. Sensitivity of clinical judgement was 33.68% (95 % CI 28.22%-39.49%), and the specificity was 99.08% (95 % CI 98.02%-99.66%). 63/1033 had preoperative anaemia treatment, of whom 60 underwent transfusion. Subgroup analysis of children with haemoglobin <10\u00a0g/dL (n\u00a0=\u00a0124) was done to compare conservative vs liberal transfusion strategy. 43/124 of this subset was transfused. Average length of stay for those transfused was 11.7 days, and those who weren't was 9.9 days (p\u00a0=\u00a00.087). 4 patients in the transfused subgroup required post-op ICU, and only 1 patient in the conservatively managed arm required ICU (p\u00a0=\u00a00.048). CONCLUSION: This study demonstrates the positive impact of bedside haemoglobin testers as they have resulted in a significantly higher proportion of children diagnosed with anaemia at a fraction of the cost and logistics involved in laboratory testing. Further research on haemoglobin thresholds is required to understand the safety and long-term impact of restrictive transfusion in the surgical context. LEVEL OF EVIDENCE: 2c (Grading as per the Oxford Centre for Evidence Based Medicine).
\n \n\n \n \nINTRODUCTION: Many small molecules and biologic therapeutics have been developed for solid tumor therapy. However, the unique physiology of tumors makes the actual delivery of these drugs into the tumor mass inefficient. Such delivery requires transport from blood vessels, across the vasculature and into and through interstitial space within a tumor. This transportation is dependent on the physiochemical properties of the therapeutic agent and the biological properties of the tumor. It was hoped the application of nanoscale drug carrier systems would solve this problem. However, issues with poor tumor accumulation and limited drug release have impeded clinical impact. In response, these carrier systems have been redesigned to be paired with targetable external mechanical stimuli which can trigger much enhanced drug release and deposition. AREAS COVERED: The pre-clinical and clinical progress of thermolabile drug carrier systems and the modalities used to trigger the release of their cargo are assessed. EXPERT OPINION: Combined application of mild hyperthermia and heat-responsive liposomal drug carriers has great potential utility. Clinical trials continue to progress this approach and serve to refine the technologies, dosing regimens and exposure parameters that will provide optimal patient benefit.
\n \n\n \n \nBACKGROUND: Interstitial lung abnormalities (ILA) are specific spatial patterns on computed tomography (CT) scan potentially compatible with early interstitial lung disease. A proportion will progress; management involves risk stratification and surveillance. Elevated blood monocyte levels have been shown to associate with progression of idiopathic pulmonary fibrosis. The aims of the present study were: 1) to estimate the proportion of \"early fibrotic\" (EF)-ILAs (reticular\u00b1ground-glass opacities, excluding traction bronchiectasis and honeycombing) on CT scans of patients attending all-indications thoracic CTs, and proportion demonstrating radiological progression; and 2) to explore association between peripheral blood leukocyte levels and ILA progression. METHODS: We analysed all thoracic CT reports in individuals aged 45-75\u2005years performed between January 2015 and December 2020 in one large teaching hospital (Oxford, UK) to identify patient CT reports consistent with EF-ILA. CT-contemporaneous blood leukocyte counts were examined to explore contribution to progression and all-cause mortality, using multivariate Cox regression. RESULTS: 40\u2009711 patients underwent thoracic CT imaging during this period. 1259 (3.1%) demonstrated the EF-ILA pattern (mean\u00b1sd age 65.4\u00b17.32 years; 735 (47.8%) male). EF-ILA was significantly associated with all-cause mortality (hazard ratio 1.87, 95% CI 1.25-2.78; p=0.002). 362 cases underwent at least one follow-on CT. Radiological progression was observed in 157 (43.4%) cases: increase in reticulation n=51, new traction bronchiectasis n=84, honeycombing n=22. Monocyte count, neutrophil count, monocyte:lymphocyte ratio, neutrophil:lymphocyte ratio and \"systemic inflammatory response index\" were significantly associated with radiological progression. CONCLUSION: 3.1% of subjects requiring thoracic CT during a 6-year period demonstrated EF-ILA. Monocyte levels and blood leukocyte-derived indexes were associated with radiological progression and could indicate which patients may require closer follow-up.
\n \n\n \n \nThe limitation of the function of antitumour immune cells is a common hallmark of cancers that enables their survival. As such, the potential of immune checkpoint inhibition (ICI) acts as a paradigm shift in the treatment of a range of cancers but has not yet been fully capitalised. Combining minimally and non-invasive locoregional therapies offered by radiologists with ICI is now an active field of research with the aim of furthering therapeutic capabilities in medical oncology. In parallel to this impending advancement, the \"imaging toolbox\" available to radiologists is also growing, enabling more refined tumour characterisation as well as greater accuracy in evaluating responses to therapy. Options range from metabolite labelling to cellular localisation to immune checkpoint screening. It is foreseeable that these novel imaging techniques will be integrated into personalised treatment algorithms. This growth in the field must include updating the current standardised imaging criteria to ensure they are fit for purpose. Such criteria is crucial to both appropriately guide clinical decision-making regarding next steps of treatment, but also provide reliable prognosis. Quantitative approaches to these novel imaging techniques are also already being investigated to further optimise personalised therapeutic decision-making. The therapeutic potential of specific ICIs and locoregional therapies could be determined before administration thus limiting unnecessary side-effects whilst maintaining efficacy. Several radiological aspects of oncological care are advancing simultaneously. Therefore, it is essential that each development is assessed for clinical use and optimised to ensure the best treatment decisions are being offered to the patient. In this review, we discuss state of the art advances in novel functional imaging techniques in the field of immuno-oncology both pre-clinically and clinically.
\n \n\n \n \nMacrophage migration inhibitory factor (MIF) was one of the first cytokines to be discovered, over 40 years ago. Since that time a burgeoning interest has developed in the role that MIF plays in both the regulation of normal physiology and the response to pathology. MIF is a pleotropic cytokine that functions to promote inflammation, drive cellular proliferation, inhibit apoptosis and regulate the migration and activation state of immune cells. These functions are particularly relevant for the development of cancer and it is notable that various solid tumours over express MIF. This includes tumours of the gastrointestinal tract and MIF appears to play a particularly prominent role in the development and progression of colonic adenocarcinoma. Here we review the role that MIF plays in colonic carcinogenesis through the promotion of colonic inflammation, as well as the progression of primary and metastatic colon cancer. The recent development of various antagonists and antibodies that inhibit MIF activity indicates that we may soon be able to classify MIF as a therapeutic target in colon cancer patients.
\n \n\n \n \nOBJECTIVE: To systematically review studies reporting clinicopathological features of intraductal papillary neoplasm of the bile duct (IPNB) to provide evidence-based guidance for management. BACKGROUND: IPNB is a rare tumor type. Management decisions are currently based upon anecdotal evidence and small case series. To data, there has been no systematic review of IPNB literature. METHODS: MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews were searched and data were extracted from relevant studies. Meta-analysis was used to pool study estimates. Evidence of association was determined by comparing pooled crude odds ratios (OR) derived from abstracted data. RESULTS: Fifty-seven retrospective case series were included. At least 43% of 476 specimens contained invasive disease. Invasive tumors were found at significantly higher frequency in pancreaticobiliary than intestinal, gastric or oncocytic-type IPNB [pooled OR 2.5, 95% confidence interval (CI) 1.5-4.2, P < 0.001]. A significantly higher proportion of pancreaticobiliary tumors compared with intestinal tumors expressed MUC-1 [86.4% (95% CI 75.1%-94.7%) vs 13.2% (95% CI 4.6%-25.2%), respectively P < 0.001]. IPNB identified in centers from Asia were more likely to be intrahepatic and were less frequently invasive compared with those from Western centers. Pooled estimates of absolute survival after IPNB resection were 96% (95% CI 93%-99%) at 1 year, 79% (95% CI 69%-88%) at 3 years, and 65% (95% CI 46%-76%) at 5 years. CONCLUSIONS: Early surgery is advisable for radiologically suspected IPNB as it is frequently invasive. The pathobiology of IPNB demonstrates geographic variation. Pancreaticobiliary IPNB expresses MUC1 and is more frequently associated with invasive disease than other IPNB subtypes.
\n \n\n \n \nUNLABELLED: Hepatic metastases are amenable to ablation; however, many patients are not suitable candidates for such therapy and recurrence is common. The tumor microenvironment is known to be essential for metastatic growth, yet identification of plausible targets for cancer therapy in the microenvironment has proven elusive. We found that human colorectal cancer liver metastases and murine gastrointestinal experimental liver metastases are infiltrated by neutrophils. Plasticity in neutrophils has recently been shown to lead to both protumor and antitumor effects. Here, neutrophils promoted the growth of hepatic metastases, given that depletion of neutrophils in already established, experimental, murine liver metastases led to diminished metastatic growth. Decreased growth was associated with reductions in vascular density and branching suggestive of vessel normalization. Metastasis-associated neutrophils expressed substantially more fibroblast growth factor 2 (FGF2) than na\u00efve neutrophils, indicating neutrophil polarization by the tumor microenvironment. Administration of FGF2 neutralizing antibody to mice bearing experimental liver metastases phenocopied neutrophil depletion by reducing liver metastatic colony growth, vascular density, and branching. CONCLUSION: Here, we show, using FGF2 as an example, that identification of factors responsible for the protumoral effects of infiltrating myeloid cells can be used to target established liver metastases. Such therapies could be utilized to limit disease progression and potentiate the effects of standard ablative therapies. (Hepatology 2017;65:1920-1935).
\n \n\n \n \nMacrophage migration inhibitory factor (MIF) was one of the first cytokines to be discovered, over 40 years ago. Since that time a burgeoning interest has developed in the role that MIF plays in both the regulation of normal physiology and the response to pathology. MIF is a pleotropic cytokine that functions to promote inflammation, drive cellular proliferation, inhibit apoptosis and regulate the migration and activation state of immune cells. These functions are particularly relevant for the development of cancer and it is notable that various solid tumours over express MIF. This includes tumours of the gastrointestinal tract and MIF appears to play a particularly prominent role in the development and progression of colonic adenocarcinoma. Here we review the role that MIF plays in colonic carcinogenesis through the promotion of colonic inflammation, as well as the progression of primary and metastatic colon cancer. The recent development of various antagonists and antibodies that inhibit MIF activity indicates that we may soon be able to classify MIF as a therapeutic target in colon cancer patients.
\n \n\n \n \nBACKGROUND: Individualised risk prediction is crucial if targeted pre-operative risk reduction strategies are to be deployed effectively. Radiologically determined sarcopenia has been shown to predict outcomes across a range of intra-abdominal pathologies. Access to pre-operative cross-sectional imaging has resulted in a number of studies investigating the predictive value of radiologically assessed sarcopenia over recent years. This systematic review and meta-analysis aimed to determine whether radiologically determined sarcopenia predicts post-operative morbidity and mortality following abdominal surgery. METHOD: CENTRAL, EMBASE and MEDLINE databases were searched using terms to capture the concept of radiologically assessed sarcopenia used to predict post-operative complications in abdominal surgery. Outcomes included 30\u00a0day post-operative morbidity and mortality, 1-, 3- and 5-year overall and disease-free survival and length of stay. Data were extracted and meta-analysed using either random or fixed effects model (Revman \u00ae 5.3). RESULTS: A total of 24 studies involving 5267 patients were included in the review. The presence of sarcopenia was associated with a significant increase in major post-operative complications (RR 1.61 95% CI 1.24-4.15 p\u00a0=\u00a0<0.00001) and 30-day mortality (RR 2.06 95% CI 1.02-4.17 p\u00a0=\u00a00.04). In addition, sarcopenia predicted 1-, 3- and 5-year survival (RR 1.61 95% CI 1.36-1.91 p\u00a0=\u00a0<0.0001, RR 1.45 95% CI 1.33-1.58 p\u00a0=\u00a0<0.0001, RR 1.25 95% CI 1.11-1.42 p\u00a0=\u00a00.0003, respectively) and 1- and 3-year disease-free survival (RR 1.30 95% CI 1.12-1.52 p\u00a0=\u00a00.0008). CONCLUSION: Peri-operative cross-sectional imaging may be utilised in order to predict those at risk of complications following abdominal surgery. These findings should be interpreted in the context of retrospectively collected data and no universal sarcopenic threshold. Targeted prehabilitation strategies aiming to reverse sarcopenia may benefit patients undergoing abdominal surgery.
\n \n\n \n \nBACKGROUND: CXCL12 (SDF1) is reported to promote cancer progression in several preclinical models and this is corroborated by the analysis of human tissue specimens. However, the relationship between CXCL12 expression and cancer survival has not been systematically assessed. METHODS: We conducted a systematic review and meta-analysis of studies that evaluated the association between CXCL12 expression and cancer survival. RESULTS: Thirty-eight studies inclusive of 5807 patients were included in the analysis of overall, recurrence-free or cancer-specific survival, the majority of which were retrospective. The pooled hazard ratios (HRs) for overall and recurrence-free survival in patients with high CXCL12 expression were 1.39 (95% CI: 1.17-1.65, P=0.0002) and 1.12 (95% CI: 0.82-1.53, P=0.48) respectively, but with significant heterogeneity between studies. On subgroup analysis by cancer type, high CXCL12 expression was associated with reduced overall survival in patients with oesophagogastric (HR 2.08; 95% CI: 1.31-3.33, P=0.002), pancreatic (HR 1.54; 95% CI: 1.21-1.97, P=0.0005) and lung cancer (HR 1.37; 95% CI: 1.08-1.75, P=0.01), whereas in breast cancer patients high CXCL12 expression conferred an overall survival advantage (HR 0.5; 95% CI: 0.38-0.66, P<0.00001). CONCLUSIONS: Determination of CXCL12 expression has the potential to be of use as a cancer biomarker and adds prognostic information in various cancer types. Prospective or prospective-retrospective analyses of CXCL12 expression in clearly defined cancer cohorts are now required to advance our understanding of the relationship between CXCL12 expression and cancer outcome.
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