Association between neutrophil-lymphocyte ratio and lymph node metastasis in gastric cancer : a meta-analysis

Introduction and Aim: The prognostic role of neutrophil to lymphocyte ratio (NLR) has been explored extensively in the literature. The aim of this meta-analysis was to evaluate the link between NLR and lymph node metastasis in gastric cancer. A method for increasing specificity and sensitivity of pre-treatment staging has implications on treatment algorithms and survival. Search Strategy: The relevant databases were searched as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart. After selection, 12 full text articles that met the inclusion criteria were included for quantitative analysis. 2 x 2 squares were generated using lymph node positive/negative, and NLR high/low data. The effect size for each study was calculated using the DerSimonian-Laird random effects model. P values were calculated using the chi-square method. Finally publication bias was evaluated. All statistics were calculated using R Studio. Results: Meta-analysis showed a 1.90 times (odds ratio, with 95% CI 1.52-2.38) increase in risk of positive lymph node status with high neutrophil to lymphocyte ratio. This has significant implications for cancer screening and staging, as NLR is a highly reproducible, cost-effective, and widely available prognostic factor for gastric cancer patients. Additionally, high or low NLR values may have implications for management pathways. Patients with lymph node metastasis can be offered neo adjuvant chemotherapy, avoiding salvage therapy in the form of adjuvant chemoradiotherapy, which is poorly tolerated. Conclusion: This meta-analysis shows an association between NLR and positive lymph node status in gastric cancer patients with implications for staging, as well as preoperative personalisation of therapy

Pancreatectomy for metastatic real cell carcinoma : twenty years of experience at a tertiary centre

Renal Cell Carcinoma (RCC) accounts for approximately 90% of primary renal malignancies, of which the clear cell subtype is most common. While metastatic disease is common at the time of diagnosis and generally confers a poor prognosis, metastatic RCC may demonstrate relatively indolent behaviour and present many years after resection of the primary tumour, including to the pancreas. The available literature suggested that surgical resection was appropriate for select patients, including those with a solitary pancreatic metastasis, minimal comorbidities and uncomplicated progress from initial treatment of their primary renal malignancy. A retrospective case series of patients presenting with RCC metastases to the pancreas, managed via surgical resection at a tertiary teaching hospital was reviewed. Analysis of patient demographics, investigations, management and outcomes were performed, with a focus on post-operative morbidity and overall survival. Between 2000 and 2020, 7 patients underwent pancreatic resection of RCC metastases at our tertiary teaching hospital with curative intent. Median age at time of resection was 66 years. No post-operative mortality or major morbidity was experienced by the 7 patients, although 4 patients developed some degree of pancreatic insufficiency. Four patients experienced recurrent metastatic RCC, with median time to recurrence of 3.5 years. This was the largest local study to describe an Australian experience of the surgical management of RCC pancreatic metastases. These patients are frequently afforded prolonged survival following pancreatic resection, but often develop other distant sites of disease and second renal tumours

Value-based care in surgery : implications in crisis and beyond

Over the past 2 years, surgeons and surgical systems have demonstrated an ability to rapidly adopt value-driven care, triage patients and make evidence-based decisions in response to crisis. Building on these successes, this paper explores a framework to expand these advances in creating a value-based approach to patient care through clinician leadership and state-wide clinical networks

Reflections on a health systems response to delivery of surgery during the COVID-19 pandemic : NSW experience

This paper presents a systems level reflection on emerging trends over the course of the pandemic to enable surgical systems to anticipate, monitor, respond and learn to support health system resilience, maintain surgical standards and mitigate workforce burnout

Management of acute appendicitis during the COVID-19 pandemic : a retrospective cohort study

Background: The Coronavirus Disease 2019 (COVID-19) pandemic profoundly impacted delivery of health care. South Western Sydney Local Health District (SWSLHD) experienced some of the highest cases, admissions and deaths during the Delta and Omicron waves in New South Wales. This study aims to determine the impact of the pandemic on emergency surgery services for adults presenting with acute appendicitis. Methods: A retrospective review of patient records was performed of adults presenting with acute appendicitis between 1st March 2021 and 31st March 2022, which was compared to a pre-COVID control period of the same dates in 2019–2020. Patients managed operatively or conservatively were included. Results: 1556 patients were included in the operative arm; 723 and 833 respectively in the study and control groups, which were comparable at baseline. 1.66% were COVID positive. During the pandemic, patients were significantly more likely to be investigated with computered tomography (CT) scan (p ≤ 0.001), present with complicated appendicitis (p = 0.03), and require caecectomy (p = 0.005). They had higher American Society of Anaesthesiology (ASA) scores (p = 0.001) and significantly lower negative appendectomy rates (p = 0.001). Fifty-two patients were included in the conservative arm; 29 and 23 respectively in the pandemic and control groups. Patients were comparable at baseline. There were two COVID positive patients. During the pandemic, there was a significant reduction in complications (p = 0.033), readmissions (0.044) and interval appendicectomy (p = 0.0044). Conclusion: We identified higher rates of complicated appendicitis, caecectomies and greater reliance on CT imaging preoperatively during the pandemic in SWSLHD

Il monastero benedettino di S. Giorgio in Braida a Verona: nuove prospettive di ricerca sulla rifabbrica romanica (sec. XII)

L’attuale aspetto rinascimentale della chiesa di San Giorgio in Braida è frutto di una serie di interventi promossi dai canonici veneziani di San Giorgio in Alga a partire dalla fine del XV secolo. Il monastero benedettino, tuttavia, fu fondato nella metà dell’XI secolo e completamente ricostruito fra il terzo e il quarto decennio del secolo successivo per volere del vescovo Bernardo. L’articolo ripercorre le vicende storiche dell’istituzione in età medievale e rende nota l’esistenza di alcune parti della compagine romanica tuttora inedite, che permettono d’inserire il cantiere di San Giorgio in Braida nel contesto delle coeve manifestazioni architettoniche veronesi

Targeting the undruggable in pancreatic cancer using nano-based gene silencing drugs

Pancreatic cancer is predicted to be the second leading cause of cancer-related death by 2025. The best chemotherapy only extends survival by an average of 18 weeks. The extensive fibrotic stroma surrounding the tumor curbs therapeutic options as chemotherapy drugs cannot freely penetrate the tumor. RNA interference (RNAi) has emerged as a promising approach to revolutionize cancer treatment. Small interfering RNA (siRNA) can be designed to inhibit the expression of any gene which is important given the high degree of genetic heterogeneity present in pancreatic tumors. Despite the potential of siRNA therapies, there are hurdles limiting their clinical application such as poor transport across biological barriers, limited cellular uptake, degradation, and rapid clearance. Nanotechnology can address these challenges. In fact, the past few decades have seen the conceptualization, design, pre-clinical testing and recent clinical approval of a RNAi nanodrug to treat disease. In this review, we comment on the current state of play of clinical trials evaluating siRNA nanodrugs and review pre-clinical studies investigating the efficacy of siRNA therapeutics in pancreatic cancer. We assess the physiological barriers unique to pancreatic cancer that need to be considered when designing and testing new nanomedicines for this disease

Association of biomarkers for human papillomavirus with survival among adults with Barrett high-grade dysplasia and esophageal adenocarcinoma

Importance: The presence of high-risk human papillomavirus (HPV) has been associated with a favorable outcome in Barrett high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). Nevertheless, the prognostic significance of other HPV-related biomarkers (ie, retinoblastoma protein [pRb], cyclin D1 [CD1], minichromosome maintenance protein [MCM2] and Ki-67) is unknown. Objective: To examine the association between HPV-related biomarkers and survival in adult patients with Barrett HGD and EAC. Design, Setting, and Participants: This retrospective case-control study examined the hypothesis that the HPV-related cell cycle markers (pRb, CD1, and Ki-67) and the viral surrogate marker (MCM2) may be associated with a favorable prognosis in Barrett HGD and EAC. Pretreatment biopsies were used for HPV DNA determination via polymerase chain reaction and immunohistochemistry for the HPV-related biomarkers. Recruitment of patients occurred in secondary and tertiary referral centers, with 151 patients assessed for eligibility. The study period was from December 1, 2002, to November 28, 2017, and the dates of analysis were from September 9, 2011, to November 28, 2017. Main Outcomes and Measures: Disease-free survival and overall survival. Results: Of 151 patients assessed for eligibility, 9 were excluded. Among the 142 patients with Barrett HGD or EAC (126 [88.7%] men; mean [SD] age, 66.0 [12.1] years; 142 [100%] white), 37 were HPV positive and 105 were HPV negative. No association with disease-free survival was noted for pRb, CD1, Ki-67, and MCM2. In regard to overall survival, only low expression of CD1 had a favorable prognosis (hazard ratio [HR], 0.53; 95% CI, 0.30-0.95; adjusted P = .03). All the biomarkers stratified by HPV status showed significant associations with survival. Patients with HPV-positive, low-expression pRb esophageal tumors were associated with a significantly improved disease-free survival compared with the HPV-negative, high-expression Rb tumors (HR, 0.33; 95% CI, 0.12-0.93; adjusted P = .04). Similarly, HPV-positive, low-expression CD1 was associated with a significantly favorable disease-free survival (HR, 0.26; 95% CI, 0.09-0.76; adjusted P = .01), as was HPV-positive, high-expression MCM2 (HR, 0.27; 95% CI, 0.09-0.78; adjusted P = .02). In regard to overall survival, HPV was significantly associated only with low CD1 (HR, 0.38; 95% CI, 0.15-0.94; adjusted P = .04). Conclusions and Relevance: This study's findings suggest that low expression of CD1 appears to be an independent prognostic marker in Barrett HGD and EAC. Human papillomavirus positivity in combination with pRb, CD1, MCM2, and Ki-67 was associated with a survival benefit in esophageal tumors. These findings suggest the possibility of personalization of therapy for Barrett HGD and EAC based on viral status

Mitochondrial mutations and metabolic adaptation in pancreatic cancer.

BACKGROUND: Pancreatic cancer has a five-year survival rate of ~8%, with characteristic molecular heterogeneity and restricted treatment options. Targeting metabolism has emerged as a potentially effective therapeutic strategy for cancers such as pancreatic cancer, which are driven by genetic alterations that are not tractable drug targets. Although somatic mitochondrial genome (mtDNA) mutations have been observed in various tumors types, understanding of metabolic genotype-phenotype relationships is limited. METHODS: We deployed an integrated approach combining genomics, metabolomics, and phenotypic analysis on a unique cohort of patient-derived pancreatic cancer cell lines (PDCLs). Genome analysis was performed via targeted sequencing of the mitochondrial genome (mtDNA) and nuclear genes encoding mitochondrial components and metabolic genes. Phenotypic characterization of PDCLs included measurement of cellular oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using a Seahorse XF extracellular flux analyser, targeted metabolomics and pathway profiling, and radiolabelled glutamine tracing. RESULTS: We identified 24 somatic mutations in the mtDNA of 12 patient-derived pancreatic cancer cell lines (PDCLs). A further 18 mutations were identified in a targeted study of ~1000 nuclear genes important for mitochondrial function and metabolism. Comparison with reference datasets indicated a strong selection bias for non-synonymous mutants with predicted functional effects. Phenotypic analysis showed metabolic changes consistent with mitochondrial dysfunction, including reduced oxygen consumption and increased glycolysis. Metabolomics and radiolabeled substrate tracing indicated the initiation of reductive glutamine metabolism and lipid synthesis in tumours. CONCLUSIONS: The heterogeneous genomic landscape of pancreatic tumours may converge on a common metabolic phenotype, with individual tumours adapting to increased anabolic demands via different genetic mechanisms. Targeting resulting metabolic phenotypes may be a productive therapeutic strategy

ROR1 and ROR2 expression in pancreatic cancer

Background: The Wnt receptors ROR1 and ROR2 are generating increased interest as cancer therapeutic targets but remain understudied in pancreatic ductal adenocarcinoma (PDAC). Compared to canonical Wnt/ β-catenin signalling, the role of noncanonical Wnt signalling in PDAC remains largely unknown. Only one study has investigated the prognostic significance of the noncanonical Wnt signalling receptor, ROR2 in PDAC. No studies have investigated the prognostic role of ROR1 in PDAC. Methods: Here, we performed analysis of ROR1 and ROR2 mRNA expression in three publicly available datasets ICGC-PACA-AU (n = 81), TCGA-PAAD (n = 150) and CPTAC-PDAC (n = 137). ROR1 and ROR2 protein expression from the CPTAC-PDAC discovery cohort were also analysed. Immunohistochemistry (IHC) using the validated anti ROR1 monoclonal antibody (4A5) was performed on the Australian Pancreatic Cancer Genome Initiative (APGI) cohort of PDAC samples (n = 152). Association between ROR1 cytoplasmic staining intensity and clinicopathological parameters including stage, grade and overall survival (OS) was investigated. Results: High ROR1 mRNA expression levels correlated with a favourable OS outcome in all of the ICGC-PACA-AU, TCGA-PAAD and CPTAC-PDAC cohorts. ROR1 protein expression was not associated with stage, grade or OS in the APGI cohort. Conclusion: ROR1 and ROR2 have potential as prognostic markers when measured at the mRNA level in PDAC. Our IHC cohort did not support ROR1 protein expression in predicting OS, and highlighted the discrepancy of prognostic biomarkers when measured by MS, IHC and RNAseq