A single institution's long-term follow-up of patients with pathological complete response in locally advanced rectal adenocarcinoma following neoadjuvant chemoradiotherapy.

PURPOSE: This paper aimed to study the long term follow-up of patients with primary rectal adenocarcinoma receiving neoadjuvant chemoradiotherapy who obtained a pathological complete response (pCR) and identify factors predicting complete response. METHODS: Retrospective review of notes, histology, pre-operative full blood count and imaging of patients with primary rectal adenocarcinoma diagnosed in our institute from 2000 to 2012 from a prospectively maintained database were used. SPSS version 22.0 was used for statistical analysis. RESULTS: Three hundred eighty patients diagnosed with primary rectal adenocarcinoma were identified, 277 received neoadjuvant chemoradiotherapy followed by curative resection. Forty-six patients obtained a pCR (ypT0N0) with no local recurrence and two metastatic recurrences on follow-up. Patients with a pCR have a significantly improved overall survival and disease-free survival compared to a non-pCR (150.0 and 136.1 vs 77.5 and 84.7 months, p = 0.001). On univariate analysis, increased tumour height above anal verge, low lymph node yield, high pre-operative haemoglobin and a low neutrophil-lymphocyte ratio are significant factors identifying a pCR. Multivariable analysis of the above factors confirmed tumour height above anal verge as significant in obtaining a pCR. CONCLUSION: Patients with rectal adenocarcinoma who develop a pCR following neoadjuvant chemoradiotherapy have improved overall and disease-free survival. We have identified distance from anal verge, low lymph node yield, high pre-operative haemoglobin and low neutrophil-lymphocyte ratio as significant predictors of developing a pCR.

Management of early rectal cancer; current surgical options and future direction.

Rectal cancer is the second commonest cause of cancer death within the United Kingdom. Utilization of national screening programmes have resulted in a greater proportion of patients presenting with early-stage disease. The technique of transanal endoscopic microsurgery was first described in 1984 following which further options for local excision have emerged with transanal endoscopic operation and, more recently, transanal minimally invasive surgery. Owing to the risks of local recurrence, the current role of minimally invasive techniques for local excision in the management of rectal cancer is limited to the treatment of pre-invasive disease and low risk early-stage rectal cancer (T1N0M0 disease). The roles of chemotherapy and radiotherapy for the management of early rectal cancer are yet to be fully established. However, results of high-quality research such as the GRECCAR II, TESAR and STAR-TREC randomised control trials may highlight a wider role for local excision surgery in the future, when used in combination with oncological therapies. The aim of our review is to provide an overview in the current management of early rectal cancer, the surgical options available for local excision and the future multimodal direction of early rectal cancer treatment.

Molecular advances in pancreatic cancer: A genomic, proteomic and metabolomic approach.

Pancreatic ductal adenocarcinoma (PDAC) represents a challenging pathology with very poor outcomes and is increasing in incidence within the general population. The majority of patients are diagnosed incidentally with insidious symptoms and hence present late in the disease process. This significantly affects patient outcomes: the only cure is surgical resection but only up to 20% of patients present with resectable disease at the time of clinical presentation. The use of "omic" technology is expanding rapidly in the field of personalised medicine - using genomic, proteomic and metabolomic approaches allows researchers and clinicians to delve deep into the core molecular processes of this difficult disease. This review gives an overview of the current findings in PDAC using these "omic" approaches and summarises useful markers in aiding clinicians treating PDAC. Future strategies incorporating these findings and potential application of these methods are presented in this review article.

Proteomic Characterization of Circulating Molecular Perturbations Associated With Pancreatic Adenocarcinoma Following Intravenous ω-3 Fatty Acid and Gemcitabine Administration: A Pilot Study.

BACKGROUND: Administration of intravenous ω-3 fatty acid (ω-3FA) in advanced pancreatic adenocarcinoma patients receiving gemcitabine chemotherapy shows disease stabilization and improved progression-free survival. Using high-definition plasma proteomics, the underlying biological mechanisms responsible for these clinical effects are investigated. METHODS AND RESULTS: A pilot study involving plasma that was collected at baseline from 13 patients with histologically confirmed, unresectable pancreatic adenocarcinoma (baseline group) after 1-month treatment with intravenous gemcitabine and ω-3FA (treatment group) and intravenous gemcitabine only (control group) and was prepared for proteomic analysis. A 2-arm study comparing baseline vs treatment and treatment vs control was performed. Proteins were isolated from plasma with extensive immunodepletion, then digested and labeled with isobaric tandem mass tag peptide tags. Samples were then combined, fractionated, and injected into a QExactive-Orbitrap Mass-Spectrometer and analyzed on Proteome Discoverer and Scaffold with ensuing bioinformatics analysis. Selective reaction monitoring analysis was performed for verification. In total, 3476 proteins were identified. Anti-inflammatory markers (C-reactive protein, haptoglobin, and serum amyloid-A1) were reduced in the treatment group. Enrichment analysis showed angiogenesis downregulation, complement immune systems upregulation, and epigenetic modifications on histones. Pathway analysis identified direct action via the Pi3K-AKT pathway. Serum amyloid-A1 significantly reduced (P < .001) as a potential biomarker of efficacy for ω-3FA. CONCLUSIONS: This pilot study demonstrates administration of ω-3FA has potential anti-inflammatory, antiangiogenic, and proapoptotic effects via direct interaction with cancer-signaling pathways in patients with advanced pancreatic adenocarcinoma. Further studies in a larger sample size is required to validate the clinical correlation found in this preliminary study.

Peri-operative Variables Associated With Prolonged Intensive Care Stay Following Cytoreductive Surgery for Ovarian Cancer.

BACKGROUND: Peri-operative variables associated with prolonged Intensive Care Unit (ICU) admission following cytoreductive surgery for ovarian cancer were investigated. PATIENTS AND METHODS: A retrospective review was carried out of patients admitted to the ICU following cytoreductive surgery for ovarian cancer in a single tertiary referral centre from 2015-2019. Patients were categorized according to length of ICU stay (<48 h and ≥48 h), and peri-operative variables were compared across the two groups. RESULTS: A total of 56 patients were admitted to the ICU post-operatively, 37 for <48 h and 19 for ≥48 h (range=3-11 days). Greater duration of procedure and estimated blood loss, bowel resection, higher post-operative lactate level, lower post-operative albumin level and requirement for post-operative blood products were associated with prolonged ICU stay. Increased intraoperative fluid requirement was an independent predictor of extended ICU stay. CONCLUSION: Utilizing identified intra-operative risk factors to perform individualized risk assessments might improve planning of ICU resources. Optimizing intraoperative fluid management may improve short-term patient outcomes.

Mass spectrometric detection of KRAS protein mutations using molecular imprinting.

Cancer is a disease of cellular evolution where single base changes in the genetic code can have significant impact on the translation of proteins and their activity. Thus, in cancer research there is significant interest in methods that can determine mutations and identify the significant binding sites (epitopes) of antibodies to proteins in order to develop novel therapies. Nano molecularly imprinted polymers (nanoMIPs) provide an alternative to antibodies as reagents capable of specifically capturing target molecules depending on their structure. In this study, we used nanoMIPs to capture KRAS, a critical oncogene, to identify mutations which when present are indicative of oncological progress. Herein, coupling nanoMIPs (capture) and liquid chromatography-mass spectrometry (detection), LC-MS has allowed us to investigate mutational assignment and epitope discovery. Specifically, we have shown epitope discovery by generating nanoMIPs to a recombinant KRAS protein and identifying three regions of the protein which have been previously assigned as epitopes using much more time-consuming protocols. The mutation status of the released tryptic peptide was identified by LC-MS following capture of the conserved region of KRAS using nanoMIPS, which were tryptically digested, thus releasing the sequence of a non-conserved (mutated) region. This approach was tested in cell lines where we showed the effective genotyping of a KRAS cell line and in the plasma of cancer patients, thus demonstrating its ability to diagnose precisely the mutational status of a patient. This work provides a clear line-of-sight for the use of nanoMIPs to its translation from research into diagnostic and clinical utility.

Myeloid derived suppressor cells are reduced and T regulatory cells stabilised in patients with advanced pancreatic cancer treated with gemcitabine and intravenous omega 3.

BACKGROUND: Pancreatic adenocarcinoma (PAC) is a devastating condition, with the majority of patients presenting with metastatic or locally advanced disease. In these patients their disease is classified as advanced pancreatic cancer (APC), which is incurable and associated with survivals generally of a few months. The overall survival (OS) for pancreatic cancer has not changed significantly in the past forty years with multiple trials demonstrating disappointing results. Immune modulatory cells particularly myeloid derived suppressor cells (MDSCs) and T regulatory cells (Tregs) are important mediators in PAC. Omega 3 fatty acids (ω-3FAs) have been shown to have anti-inflammatory properties and there is now evidence demonstrating the benefit of ω-3FAs in PAC. METHODS: This was a single-center cohort study investigating intravenous ω-3FAs and gemcitabine chemotherapy versus gemcitabine therapy only in patients with APC. Here, we investigated levels of MDSCs and Tregs and examined how these changes correlated with survival. RESULTS: Eighteen trial and nine control patients were recruited. There was a significant benefit in progression-free survival (PFS) in trial compared to control patients (P=0.0003). Median survival in trial patients was 5.65 months compared to 1.8 months in control patients. There was no significant benefit in OS in trial compared to control patients (P=0.13). Median survival in trial patients was 7 months compared to 2.9 months in control patients. MDSCs were significantly decreased in trial patients (P=0.0001) but not control patients. Conversely Tregs were significantly increased in control patients (P=0.005) but not in trial patients. CONCLUSIONS: Administration of ω-3FAs with gemcitabine chemotherapy in APC results in a significant decrease of MDSCs and stability of Tregs. This may be secondary to the reduction of pro-inflammatory mediators. A phase three randomized trial is justified to further examine these effects.

Ex vivo normothermic porcine pancreas: A physiological model for preservation and transplant study.

INTRODUCTION: An ex vivo normothermic porcine pancreas perfusion (ENPPP) model was established to investigate effects of machine perfusion pressures on graft preservation. METHODOLOGY: Nine porcine pancreata were perfused with autologous blood at 50 mmHg (control) pressure. Graft viability was compared against four ex-vivo porcine pancreata perfused at 20 mmHg ('low') pressure. Arterio-venous oxygen gas differentials, biochemistry, and graft insulin responses to glucose stimulation were compared. Immunohistochemistry stains compared the cellular viability. RESULTS: Control pancreata were perfused for a median of 3 h (range 2-4 h) with a mean pressure 50 mmHg and graft flow 141 mL min-1. In comparison, all of the 'low' pressure models were perfused for 4 h, with mean perfusion pressure 20 mmHg and graft flow 40 mL.min-1. All pancreata demonstrated cellular viability with evidence of oxygen consumption with preserved endocrine and exocrine function. However, following statistical analysis, the 'low' pressure perfusion of porcine pancreata compared favourably in important biochemical and immunohistochemistry cellular profiles; potentially arguing for an improved method for graft preservation. CONCLUSION: ENPPP will facilitate whole organ preservation to be studied in further detail and avoids use of expensive live animals. ENPPP is reproducible and mimics a "donation after circulatory death" scenario.

Intravenous ω-3 Fatty Acids Plus Gemcitabine.

BACKGROUND: Marine-derived ω-3 fatty acids (ω-3FAs) have proven antitumor activity in vivo and in vitro and improve quality of life (QOL) in clinical cancer studies. These changes may be mediated by reduction in circulating proangiogenic and proinflammatory factors. In this first study of intravenous ω-3FAs as a therapy in cancer patients, we aimed to assess if it could augment the antitumor activity of gemcitabine in patients with advanced pancreatic cancer and improve QOL. MATERIALS AND METHODS: Patients were administered gemcitabine 1000 mg/m3 weekly followed by up to 100 g (200 mg/mL) of ω-3 rich lipid emulsion for 3 weeks followed by a rest week. This was continued for up to 6 cycles, progression, unacceptable toxicity, patient request, or death. The primary outcome measure was objective response rate, with secondary outcome measures of overall and progression free survival, QOL scores, and adverse events. RESULTS: Fifty patients were recruited. Response rate was 14.3% and disease control rate was 85.7%. Overall and progression free survival were 5.9 and 4.8 months, respectively. Increase in global health of > 10% over baseline was seen in 47.2% of patients. More than 50% of patients had > 10% increase in QOL scores in generic symptom scores and both disease-specific domains. Grade 3/4 adverse events were thrombocytopenia (8%), neutropenia (12%), nausea or vomiting (4%), and chills (6%). CONCLUSION: Intravenous ω-3FAs in combination with gemcitabine shows evidence of improved activity and benefit to QOL in patients with advanced pancreas cancer and is worthy of investigation in a randomized phase III trial.

Potential for proteomic approaches in determining efficacy biomarkers following administration of fish oils rich in omega-3 fatty acids: application in pancreatic cancers.

Pancreatic cancer is a disease with a significantly poor prognosis. Despite modern advances in other medical, surgical, and oncologic therapy, the outcome from pancreatic cancer has improved little over the last 40 years. To improve the management of this difficult disease, trials investigating the use of dietary and parenteral fish oils rich in omega-3 (ω-3) fatty acids, exhibiting proven anti-inflammatory and anticarcinogenic properties, have revealed favorable results in pancreatic cancers. Proteomics is the large-scale study of proteins that attempts to characterize the complete set of proteins encoded by the genome of an organism and that, with the use of sensitive mass spectrometric-based techniques, has allowed high-throughput analysis of the proteome to aid identification of putative biomarkers pertinent to given disease states. These biomarkers provide useful insight into potentially discovering new markers for early detection or elucidating the efficacy of treatment on pancreatic cancers. Here, our review identifies potential proteomic-based biomarkers in pancreatic cancer relating to apoptosis, cell proliferation, angiogenesis, and metabolic regulation in clinical studies. We also reviewed proteomic biomarkers from the administration of ω-3 fatty acids that act on similar anticarcinogenic pathways as above and reflect that proteomic studies on the effect of ω-3 fatty acids in pancreatic cancer will yield favorable results.