Resectability of Pancreatic Cancer Is in the Eye of the Observer: A Multicenter, Blinded, Prospective Assessment of Interobserver Agreement on NCCN Resectability Status Criteria.

Objectives: To determine the reproducibility of the National Comprehensive Cancer Network (NCCN) resectability status classification for pancreatic cancer. Background: The NCCN classification defines 3 resectability classes (resectable, borderline resectable, locally advanced), according to vascular invasion. It is used to recommend different approaches and stratify patients during clinical trials. Methods: Prospective, multicenter, observational study (trial ID: NCT03673423). Main outcome measure was the interobserver agreement of tumor assignment to different resectability classes and quantification of vascular invasion degrees. Agreement was measured by Fleiss' k (k = 1 perfect agreement; k = 0 agreement by chance). Sixty-nine computed tomography (CT) scans of pathologically confirmed pancreatic adenocarcinoma were independently reviewed in a blinded fashion by 22 observers from 11 hospitals (11 surgeons and 11 radiologists). Rating differences between surgeons or radiologists and between hospitals with different volumes (≥60 or <60 resections/year) were assessed. Results: Complete agreement among 22 observers was recorded in 5 CT scans (7.2%), whereas 25 CT scans (36.2%) were variously assigned to all 3 resectability classes. Interobserver agreement varied from fair to moderate (Fleiss' k range: 0.282-0.555), with the lowest agreement for borderline resectable tumors. Assessing vascular contact ≤180° had the lowest agreement for all vessels (k range: 0.196-0.362). The highest concordance was recorded for venous invasion >180° (k range: 0.619-0.756). Neither reviewers' specialty nor hospital volume influenced the agreement. Conclusions: There is high variability in the assignment to resectability categories, which may compromise the reliability of treatments recommendations and the evidence of trials stratifying patients in resectability classes. Criteria should be revised to allow a reproducible classification.

Perioperative nutrition: Recommendations from the ESPEN expert group.

BACKGROUND & AIMS: Malnutrition has been recognized as a major risk factor for adverse postoperative outcomes. The ESPEN Symposium on perioperative nutrition was held in Nottingham, UK, on 14-15 October 2018 and the aims of this document were to highlight the scientific basis for the nutritional and metabolic management of surgical patients. METHODS: This paper represents the opinion of experts in this multidisciplinary field and those of a patient and caregiver, based on current evidence. It highlights the current state of the art. RESULTS: Surgical patients may present with varying degrees of malnutrition, sarcopenia, cachexia, obesity and myosteatosis. Preoperative optimization can help improve outcomes. Perioperative fluid therapy should aim at keeping the patient in as near zero fluid and electrolyte balance as possible. Similarly, glycemic control is especially important in those patients with poorly controlled diabetes, with a stepwise increase in the risk of infectious complications and mortality per increasing HbA1c. Immobilization can induce a decline in basal energy expenditure, reduced insulin sensitivity, anabolic resistance to protein nutrition and muscle strength, all of which impair clinical outcomes. There is a role for pharmaconutrition, pre-, pro- and syn-biotics, with the evidence being stronger in those undergoing surgery for gastrointestinal cancer. CONCLUSIONS: Nutritional assessment of the surgical patient together with the appropriate interventions to restore the energy deficit, avoid weight loss, preserve the gut microbiome and improve functional performance are all necessary components of the nutritional, metabolic and functional conditioning of the surgical patient.

The 2019 ESPEN Arvid Wretlind lecture perioperative nutritional and metabolic care: Patient-tailored or organ-specific approach?

BACKGROUND & AIM: The perioperative severe changes in the nutritional and metabolic homeostasis are, by some means, proportional to the extent of tissue injury and magnitude of operative trauma. An adequate qualitative and quantitative replacement of nutritional substrates are of utmost importance to facilitate proper tissue healing and recovery and maintenance of organ function after surgery. METHODS: The present manuscript has been planned to put the most recent research of the Milano-Bicocca University surgical working group in the context of a more personalized nutritional therapy and metabolic care for surgical patients. Particular prominence has been given to major pancreatic resections because these surgeries are among the most complex and challenging operations for the degree of parenchyma resection and tissue dissection, the consequent overall injury, and the fairly high rate of major complications resulting in a catabolic response. RESULTS: Anthropometric parameters and particularly sarcopenia, visceral obesity - and their relative proportion -, are strongly associated with poor outcome after pancreatic surgery. Adequate perioperative nutritional therapy is of utmost importance in affecting morbidity. Long-term nutritional and metabolic sequelae, caused by exocrine pancreatic insufficiency, need to be promptly recognized and treated with an adequate enzyme supplementation. CONCLUSIONS: There is strong evidence sustaining the necessity of proper perioperative metabolic and nutritional care into the management of patients undergoing major pancreatic surgery.

Enhanced recovery programs in gastrointestinal surgery: Actions to promote optimal perioperative nutritional and metabolic care.

The enhanced recovery after surgery (ERAS) pathway is an evidence-based approach to the use of care elements along the patient perioperative pathway. All care elements that may impact on clinically relevant outcomes have been considered and reviewed. The combined ERAS actions allow a quicker return to bowel function, oral feeding, nutritional and metabolic equilibrium, normal activity and ultimately to achieve better outcomes. Because of the multi factorial approach and the commitment of all the professionals caring for the patient, it is necessary to have the engagement of all disciplines, such as surgery, anesthesiology, clinical nutrition, nursing, physiatry, involved. ERAS is a dynamic process and new evidence are constantly integrated into the program. The primary endpoint of this review is to give updated information on the key ERAS actions to achieve optimal perioperative nutritional and metabolic care.

Uselessness of microbiological samples in acute appendicitis with frank pus: to collect or not to collect?

INTRODUCTION: Current use of antimicrobial therapy is prophylactic, empirical and broad spectrum. But, the age-old practice of obtaining cultures still remain. The aim of this study was to evaluate bacterial etiology and adequacy of antibiotic prophylaxis in patients diagnosed with acute appendicitis to help determine the utility of intraoperative cultures in guiding clinical decision-making. MATERIALS AND METHODS: A retrospective analysis of a prospectively constructed database of all patients who underwent appendectomy from September 2013 to November 2016 was performed. RESULTS: 456 patients underwent surgery for acute appendicitis in our academic hospital. 101 patients (22.1%) had intraoperative swabs taken, and the cultures were positive in 57.4% of patients. These 101 patients comprise our study group. The most commonly recovered species were E. coli, Streptococcus spp., Bacteroides fragilis, Enterococcus faecium, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Proteus. In the comparison between positive and negative swab, there were no differences in terms of surgical site infection, deep infection, and in terms of Clavien-Dindo classification. An appropriate empiric therapy was set in 88.5% and inappropriate in 11.5%. No differences in terms of surgical site infection or in length of stay (p = 0.657) were found, with a median of 7 days in both groups. CONCLUSION: The etiological agents causing peritonitis due to acute appendicitis are predictable and empiric-targeted antibiotic therapy is effective in a high percentage of patients. The postoperative patient outcome may be dependent on the severity of the appendicitis more than on the results of the swab at the time of surgery. In this study, intraoperative culture was not associated with the choice of antibiotics, incidence of SSI, DPI or the length of stay.

Nutritional support and therapy in pancreatic surgery: A position paper of the International Study Group on Pancreatic Surgery (ISGPS).

BACKGROUND: The optimal nutritional therapy in the field of pancreatic surgery is still debated. METHODS: An international panel of recognized pancreatic surgeons and pancreatologists decided that the topic of nutritional support was of importance in pancreatic surgery. Thus, they reviewed the best contemporary literature and worked to develop a position paper to provide evidence supporting the integration of appropriate nutritional support into the overall management of patients undergoing pancreatic resection. Strength of recommendation and quality of evidence were based on the approach of the grading of recommendations assessment, development and evaluation Working Group. RESULTS: The measurement of nutritional status should be part of routine preoperative assessment because malnutrition is a recognized risk factor for surgery-related complications. In addition to patient's weight loss and body mass index, measurement of sarcopenia and sarcopenic obesity should be considered in the preoperative evaluation because they are strong predictors of poor short-term and long-term outcomes. The available data do not show any definitive nutritional advantages for one specific type of gastrointestinal reconstruction technique after pancreatoduodenectomy over the others. Postoperative early resumption of oral intake is safe and should be encouraged within enhanced recovery protocols, but in the case of severe postoperative complications or poor tolerance of oral food after the operation, supplementary artificial nutrition should be started at once. At present, there is not enough evidence to show the benefit of avoiding oral intake in clinically stable patients who are complicated by a clinically irrelevant postoperative pancreatic fistula (a so-called biochemical leak), while special caution should be given to feeding patients with clinically relevant postoperative pancreatic fistula orally. When an artificial nutritional support is needed, enteral nutrition is preferred whenever possible over parenteral nutrition. After the operation, regardless of the type of pancreatic resection or technique of reconstruction, patients should be monitored carefully to assess for the presence of endocrine and exocrine pancreatic insufficiency. Although fecal elastase-1 is the most readily available clinical test for detection of pancreatic exocrine insufficiency, its sensitivity and specificity are low. Pancreatic enzyme replacement therapy should be initiated routinely after pancreatoduodenectomy and in patients with locally advanced disease and continued for at least 6 months after surgery, because untreated pancreatic exocrine insufficiency may result in severe nutritional derangement. CONCLUSION: The importance of this position paper is the consensus reached on the topic. Concentrating on nutritional support and therapy is of utmost value in pancreatic surgery for both short- and long-term outcomes.

Glutamine Supplementation in Intensive Care Patients: A Meta-Analysis of Randomized Clinical Trials.

The role of glutamine (GLN) supplementation in critically ill patients is controversial. Our aim was to analyze its potential effect in patients admitted to intensive care unit (ICU).We performed a systematic literature review through Medline, Embase, Pubmed, Scopus, Ovid, ISI Web of Science, and the Cochrane-Controlled Trials Register searching for randomized clinical trials (RCTs) published from 1983 to 2014 and comparing GLN supplementation to no supplementation in patients admitted to ICU. A random-effect meta-analysis for each outcome (hospital and ICU mortality and rate of infections) of interest was carried out. The effect size was estimated by the risk ratio (RR).Thirty RCTs were analyzed with a total of 3696 patients, 1825 (49.4%) receiving GLN and 1859 (50.6%) no GLN (control groups). Hospital mortality rate was 27.6% in the GLN patients and 28.6% in controls with an RR of 0.93 (95% CI = 0.81-1.07; P = 0.325, I = 10.7%). ICU mortality was 18.0 % in the patients receiving GLN and 17.6% in controls with an RR of 1.01 (95% CI = 0.86-1.19; P = 0.932, I = 0%). The incidence of infections was 39.7% in GLN group versus 41.7% in controls. The effect of GLN was not significant (RR = 0.88; 95% CI = 0.76-1.03; P = 0.108, I = 56.1%).These results do not allow to recommend GLN supplementation in a generic population of critically ills. Further RCTs are needed to explore the effect of GLN in more specific cohort of patients.

Effect of glutamine dipeptide supplementation on primary outcomes for elective major surgery: systematic review and meta-analysis.

To evaluate if glutamine (GLN) supplementation may affect primary outcomes in patients undergoing major elective abdominal operations, we performed a systematic literature review of randomized clinical trials (RCTs) published from 1983 to 2013 and comparing intravenous glutamine dipeptide supplementation to no supplementation in elective surgical abdominal procedures. A meta-analysis for each outcome (overall and infectious morbidity and length of stay) of interest was carried out. The effect size was estimated by the risk ratio (RR) or by the weighted mean difference (WMD). Nineteen RCTs were identified with a total of 1243 patients (640 receiving GLN and 603 controls). In general, the studies were underpowered and of medium or low quality. GLN supplementation did not affect overall morbidity (RR = 0.84, 95% CI 0.51 to 1.36; p = 0.473) and infectious morbidity (RR = 0.64; 95% CI = 0.38 to 1.07; p = 0.087). Patients treated with glutamine had a significant reduction in length of hospital stay (WMD = -2.67; 95% CI = -3.83 to -1.50; p < 0.0001). In conclusion, GLN supplementation appears to reduce hospital stay without affecting the rate of complications. The positive effect of GLN on time of hospitalization is difficult to interpret due to the lack of significant effects on surgery-related morbidity.

Perioperative intravenous glutamine supplemetation in major abdominal surgery for cancer: a randomized multicenter trial.

OBJECTIVE: To investigate whether perioperative intravenous glutamine supplementation may affect surgical morbidity. SUMMARY BACKGROUND DATA: Small-sized randomized trials showed a trend toward a reduction of postoperative infections in surgical patients receiving glutamine. METHODS: : A randomized, multicentre trial was carried out in 428 subjects who were candidates for elective major gastrointestinal surgery. Inclusion criteria were: documented gastrointestinal cancer, weight loss <10% in previous 6 months, and age >18 years. Patients received either intravenous infusion of L-alanine-L-glutamine dipeptide (0.40 g/kg/d; equal to 0.25 g of free glutamine) (Ala-Glu group, n = 212), or no supplementation (control group, n = 216). Glutamine infusion began the day before operation and continued postoperatively for at least 5 days. No postoperative artificial nutrition was allowed unless patients could not adequately eat by day 7. Postoperative morbidity was assessed by independent observers according to a priori definition. RESULTS: Patients were homogenous for baseline and surgical characteristics. Mean percent of weight loss was 1.4 (2.7) in controls and 1.4 (2.4) in Ala-Glu group. Overall postoperative complication rate was 34.9% (74/212) in Ala-Glu and 32.9% (71/216) in control group (P = 0.65). Infectious morbidity was 19.3% (41/212) in Ala-Glu group and 17.1% (37/216) in controls (P = 0.55). The rate of major complications was 7.5% (16/212) in Ala-Glu group and 7.9% (17/216) in controls (P = 0.90). Mean length of hospitalization was 10.2 days (4.8) in Ala-Glu group versus 9.9 days (3.9) in controls (P = 0.90). The rate of patients requiring postoperative artificial nutrition was 13.2% (28/212) in Ala-Glu group and 12.0% (26/216) in controls (P = 0.71). CONCLUSIONS: Perioperative glutamine does not affect outcome in well-nourished GI cancer patients.

Nutrition and infections.

BACKGROUND: Patients with cancer suffer alterations of their metabolic state and nutritional depletion. This review was designed to evaluate the effect of different nutritional regimens on surgical outcomes. METHOD: Review of the literature on parenteral and enteral nutrition and immunonutrition in patients with gastrointestinal cancer undergoing major surgery. The outcome measures were postoperative complication rate and length of hospital stay. RESULTS: Postoperative enteral nutrition reduced significantly the rate of postoperative complications compared with parenteral feeding only in malnourished subjects. Several metaanalyses and randomized trials showed that preoperative and perioperative use of an enteral formula containing arginine and omega-3 fatty acids has a significant beneficial effect on surgical outcome in both well-nourished and malnourished patients. CONCLUSIONS: Enteral immunonutrition should represent the first choice to nourish surgical subjects.

Hospital resources consumed for surgical morbidity: effects of preoperative arginine and omega-3 fatty acid supplementation on costs.

OBJECTIVE: Costs related to postoperative complications continue to be a major burden on any health care system. The aim of the present study was to calculate hospital costs for postoperative complications and to evaluate whether preoperative supplementation with omega-3 fatty acids and arginine (specialized diet) might lead to cost savings in patient care. METHODS: Blind analysis of costs performed on data gathered from a randomized clinical trial carried out on 305 patients with gastrointestinal cancer showed that an oral preoperative specialized diet decreased postoperative morbidity compared with conventional treatment (no supplementation). Estimates of complication costs were based on resources used for treatment and on additional length of hospital stay. Cost-comparison and cost-effectiveness analyses were then carried out. RESULTS: The mean cost of postoperative complications was 4492 pounds sterlings. The greatest amount of resources was consumed by 19 anastomotic leaks (159,803 pounds sterlings), 18 abdominal abscesses (112,921 pounds sterlings), and 18 pancreatic fistulae (106,516 pounds sterlings). The mean costs per complication were 6178 pounds sterlings in the conventional group and 4639 pounds sterlings in the preoperative group (P = 0.05). The mean total costs of patients with complications were 10,494 pounds sterlings in the conventional group and 8793 pounds sterlings in the preoperative group. The mean cost per randomized patient was 3122 pounds sterlings in the conventional group versus 1872 pounds sterlings in the preoperative group (P = 0.04). Effectiveness values were 50.0% in the conventional group and 62.8% in the preoperative group (P = 0.03). Total costs consumed 93% of the diagnosis-related group reimbursement rate in the conventional group and 78% in the preoperative group. CONCLUSIONS: The costs of postoperative morbidity consumed a large amount of the diagnosis-related group reimbursement rate. Preoperative supplementation with the specialized diet appears to be a cost-effective treatment.

Preoperative immunonutrition: cost-benefit analysis.

BACKGROUND: To evaluate whether preoperative immunonutrition might lead to a savings in patient care. Data on resources consumed to treat postoperative complications are scanty, but morbidity costs continue to be a major burden for any health care system. A recent randomized clinical trial carried out in well-nourished patients with gastrointestinal cancer showed that a 5-day preoperative oral immunonutrition reduced postoperative morbidity compared with conventional treatment (no supplementation). METHODS: The abovementioned trial was the basis for the economic evaluation. In-hospital related costs of routine surgical care and costs of nutrition were calculated. Estimates of complication costs were based on both resources used for treatment and additional length of hospital stay. Cost comparison and cost-effectiveness analysis were then carried out. RESULTS: Total cost of nutrition was 3407 euro in the conventional group and 14,729 euro in the preoperative group. In patients without complication, the cost of in-hospital routine care was similar in both groups. The mean cost of complication was 6178 euro in the conventional group and 4639 euro in the preoperative group (p = .05). Total cost of patients with complications was 535,236 euro in the conventional group and 334,148 euro in the preoperative group. Total costs consumed 93% of the diagnosis-related-group (DRG) reimbursement rate in the conventional group and 78% in the preoperative group. Cost-effectiveness was 6245 euro for the conventional group and 2985 euro for the preoperative group. CONCLUSIONS: The costs of postoperative morbidity consumed a large amount of the DRG reimbursement rate. Preoperative immunonutrition was cost-effective in our series.

Preoperative oral arginine and n-3 fatty acid supplementation improves the immunometabolic host response and outcome after colorectal resection for cancer.

BACKGROUND: Previous trials showed that perioperative immunonutrition improved outcome in patients with gastrointestinal cancer. This study was designed to appraise the impact of the simple preoperative oral arginine and n-3 fatty acids supplementation on immune response, gut oxygenation, and postoperative infections. METHODS: Two hundred patients with colorectal neoplasm were randomized to: (a) oral intake for 5 days before surgery of a formula enriched with arginine and n-3 fatty acids (pre-op group; n = 50); (b) same preoperative treatment prolonged after surgery by jejunal infusion (peri-op group; n = 50); (c) oral intake for 5 days before surgery of a standard isoenergetic, isonitrogenous formula (control group; n = 50); and (d) no supplementation before and after operation (conventional group; n = 50). The immune response was measured by phagocytosis ability of polymorphonuclear cells and delayed hypersensitivity response to skin tests. Gut oxygenation and microperfusion were assessed by polarographic probes and laser Doppler flowmetry, respectively. RESULTS: The 4 groups were comparable for demographics, comorbidity, and surgical variables. The 2 groups receiving immunoutrients (pre-op and peri-op) had a significantly better immune response, gut oxygenation, and microperfusion than the other 2 groups. Intent-to-treat analysis showed an overall infection rate of 12% in pre-op, 10% in peri-op, 32% in control, and 30% in conventional groups (P <.04 pre-op and peri-op vs control and conventional). CONCLUSION: Preoperative oral arginine and n-fatty acids improves the immunometabolic response and decreases the infection rate. Postoperative prolongation with such supplemented formula has no additional benefit.

A randomized controlled trial of preoperative oral supplementation with a specialized diet in patients with gastrointestinal cancer.

BACKGROUND & AIMS: Perioperative nutrition with specialized enteral diets improves outcome when compared with standard formulas. A post-hoc analysis suggested preoperative administration as the most important period. Thus, we designed a study to understand prospectively whether preoperative supplementation could be as efficacious as the perioperative approach and superior to a conventional treatment (no artificial nutrition) in reducing postoperative infections and length of hospital stay. METHODS: A total of 305 patients with preoperative weight loss <10% and cancer of the gastrointestinal tract were randomized to receive the following: (1) oral supplementation for 5 days before surgery with 1 L/day of a formula enriched with arginine, omega-3 fatty acids, and RNA, with no nutritional support given after surgery (preoperative group, n = 102); (2) the same preoperative treatment plus postoperative jejunal infusion with the same enriched formula (perioperative group, n = 101); and (3) no artificial nutrition before and after surgery (conventional group; n = 102). RESULTS: The 3 groups were comparable for all baseline and surgical characteristics. Intention-to-treat analysis showed a 13.7% incidence of postoperative infections in the preoperative group, 15.8% in the perioperative group, and 30.4% in the conventional group (P = 0.006 vs. preoperative; P = 0.02 vs. perioperative). Length of hospital stay was 11.6 +/- 4.7 days in the preoperative group, 12.2 +/- 4.1 days in the perioperative group, and 14.0 +/- 7.7 days in the conventional group (P = 0.008 vs. preoperative and P = 0.03 vs. perioperative). CONCLUSIONS: Preoperative supplementation is as effective as perioperative administration in improving outcome. Both strategies seem superior to the conventional approach.

Nutritional approach in malnourished surgical patients: a prospective randomized study.

HYPOTHESIS: Perioperative administration of a supplemented enteral formula may decrease postoperative morbidity. DESIGN: Randomized clinical trial. SETTING: Department of surgery at a university hospital. PATIENTS: One hundred ninety-six registered malnourished patients (weight loss > or = 10%) who were candidates for major elective surgery for malignancy of the gastrointestinal tract. INTERVENTION: After randomization (n = 150), one group received postoperative enteral feeding with a standard diet within 12 hours of surgery (control group; n = 50). Another group orally received 1 L/d for 7 consecutive days of a liquid diet enriched with arginine, omega-3 fatty acids, and RNA (preoperative group; n = 50). After surgery, patients were given the same standard enteral formula as the control group. A third group orally received 1 L/d for 7 consecutive days of the enriched liquid diet. After surgery, patients were given enteral feeding with the same enriched formula (perioperative group; n = 50). MAIN OUTCOME MEASURES: Postoperative complications and length of hospital stay. RESULTS: The 3 groups were comparable for baseline demographics, biochemical markers, comorbidity factors, and surgical variables. The intent-to-treat analysis showed that the total number of patients with complications was 24 in the control group, 14 in the preoperative group, and 9 in the perioperative group (P =.02, control group vs perioperative group). Postoperative length of stay was significantly shorter in the preoperative (13.2 days) and perioperative (12.0 days) groups than in the control group (15.3 days) (P =.01 and P =.001, respectively, vs the control group). CONCLUSION: Perioperative immunonutrition seems to be the best approach to support malnourished patients with cancer.