Validation of a Nomogram to Predict Long Term Outcomes After Curative Surgery for Gastric Cancer in an Italian Cohort of Patients.

AIM OF THE STUDY: Nomograms have been proposed to assess prognosis following curative surgery for gastric cancer. The objective of the current study was to evaluate the performance of the Gastric Cancer Collaborative Group nomograms developed in 2014 by Kim et al., using a cohort of patients from a 10-year single institution experience in gastric cancer management. PATIENTS AND METHODS: We retrospectively reviewed patients who underwent curative-intent surgery for histologically confirmed gastric cancer at First Surgical Clinic of Padua University Hospital (Italy) from January 2010 to May 2020. Univariable and multivariable Cox proportional hazard models were employed to assess the effect of the variables of interest on mortality and recurrence. Multivariable analysis was performed by considering the variables included in the Gastric Cancer Collaborative Group nomograms in order to validate them. The performance of the nomograms was evaluated using Harrell's C-index and calibration plots. RESULTS: Overall, 168 patients were included, with a median follow-up of 20.1 months. On multivariable analysis, tumor location, lymph node ratio, and pathological T stage were associated with recurrence; age, tumor location, lymph node ratio, and pT stage were associated with OS (overall survival). The nomograms had good discriminatory capability to classify both OS (C-index: 0.75) and DFS (disease-free survival) (C-index 0.72). The corrected C-Index for DFS based on the AJCC staging system revealed better prediction (C-Index 0.75), while the corrected C-Index for OS had worse discrimination ability compared with the current nomogram (C-Index 0.72). CONCLUSIONS: The Gastric Cancer Collaborative Group nomograms demonstrated good performances in terms of prediction of both OS and DFS on external validation. The two nomograms are easy to apply, and variables included are widely available to most facilities.

Intratumor morphologic and transcriptomic heterogeneity in V600EBRAF-mutated metastatic colorectal adenocarcinomas.

BACKGROUND: Intratumor heterogeneity (ITH) is described as the presence of various clones within one tumor, each with their own unique features in terms of morphology, inflammation, genetics or transcriptomics. Heterogeneity provides the fuel for drug resistance; therefore, an accurate assessment of tumor heterogeneity is essential for the development of effective therapies. The purpose of this study was to dissect morphologic and molecular ITH in colorectal adenocarcinoma. MATERIALS AND METHODS: A series of 120 V600EBRAF-mutated (V600EBRAFmt) consecutive metastatic colorectal adenocarcinomas was assessed for morphologic heterogeneity. The two heterogeneous components of each specimen underwent a histopathological, immunohistochemical and molecular characterization to evaluate: histologic variant, grading, tumor-infiltrating lymphocytes (TILs), mismatch repair proteins' expression, KRAS/BRAF/NRAS mutations, microsatellite instability (MSI) status and consensus molecular subtype (CMS). RESULTS: Thirty-one out of 120 (25.8%) V600EBRAFmt primary colorectal adenocarcinomas presented a heterogeneous morphology. Among these, eight cases had adequate material for molecular profiling. Five out of the eight (62.5%) cases resulted instable at MSI testing. The majority (62.5%) of the samples showed a CMS4 phenotype based on gene expression profiling. Heterogeneity in CMS classification was observed in four out of eight cases. One out of eight cases presented significant heterogeneity in the number of TILs between the two components of the tumor. CONCLUSIONS: Although the distribution of the immune infiltrate appears relatively conserved among heterogeneous areas of the same tumor, changes in gene expression profile and CMS occur in 50% of V600EBRAFmt adenocarcinoma cases in our small series and might contribute to variability in response to anticancer therapy and clinical outcomes. Assessment of morphological and molecular ITH is needed to improve colorectal cancer classification and to tailor anticancer treatments and should be included in the pathology report.

T2-weighted, apparent diffusion coefficient and 18F-FDG PET histogram analysis of rectal cancer after preoperative chemoradiotherapy.

BACKGROUND: The aim of our study was to investigate the correlation among T2-weighted (T2w) images, apparent diffusion coefficient (ADC) maps, 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) images, histogram analysis and the pathological response in locally advanced rectal cancer (LARC) after preoperative chemoradiotherapy (pCRT). METHODS: Patients with LARC were prospectively enrolled between February 2015 and August 2018 and underwent PET/magnetic resonance imaging (MRI). MRI included T2w and diffusion-weighted imaging (DWI)-sequences. ADC maps and PET images were matched to the T2w images. Voxel-based standardized uptake values (SUVs,) ADC and T2w-signal-intensity values were collected from the volumes of interest (VOIs) and mean, skewness and kurtosis were calculated. Spearman's correlation coefficient was applied to evaluate the correlation among the variables and tumor regression grade (TRG), T stage, N stage and fibrosis. RESULTS: Twenty-two patients with biopsy-proven LARC in the low or mid rectum were enrolled [17 males, mean age was 69 years (range 49-85 years)]. Seven patients experienced complete regression (TRG1). A significant positive correlation was found between SUV mean values (ρ = 0.480; p = 0.037) and TRG. No other significant correlations were found. CONCLUSIONS: Histogram analysis of SUV values is a predictor of TRG in LARC.

Cognitive load in 3d and 2d minimally invasive colorectal surgery.

BACKGROUND: Three-dimensional (3d) laparoscopy has been introduced to enhance depth perception and facilitate surgical operations. The aim of this study was to compare cognitive load during 3d and 2d laparoscopic procedures. METHODS: Two subjective questionnaires (the Simulator Sickness Questionnaire and the NASA task load index) were used to prospectively collect data regarding cognitive load in surgeons performing 2d and 3d laparoscopic colorectal resections. Moreover, the perioperative results of 3d and 2d laparoscopic operations were analyzed. RESULTS: A total of 313 patients were included: 82 in the 2d group and 231 in the 3d group. The NASA TLX results did not reveal significantly major cognitive load differences in the 3d group compared with the 2d group; the SSQ results were better in the 3d group than in the 2d group in terms of general discomfort, whereas difficulty concentrating, difficulty focusing, and fatigue were more frequent in 3d operations than in 2d operations (p = 0.001-0.038). The results of age, sex, and ASA score were comparable between the two groups (p = 0.299-0.374). The median operative time showed no statistically significant difference between the 3d and 2d groups (median, IQR, 2d 150 min [120-180]-3d 160 min [130-190] p = 0.611). There was no statistically significant difference in the risk of severe complications between patients in the 3d group and in the 2d group (2d 7 [8.54%] vs 3d 21 [9.1%], p = 0.271). The median hospitalization time and the reoperation rate showed no difference between the 2d and 3d operations (p = 0.417-0.843). CONCLUSION: The NASA TLX did not reveal a significant difference in cognitive load between the 2d and 3d groups, whereas data reported by the SSQ showed a mild risk of cognitive load in the 3d group. Furthermore, 3d laparoscopic surgery revealed the same postoperative results as 2d standard laparoscopy.

Local excision in rectal cancer patients with major or complete clinical response after neoadjuvant therapy: a case-matched study.

PURPOSE: To assess the long-term oncological outcomes in patients with locally advanced rectal cancer who underwent neoadjuvant therapy followed by local or total mesorectal excision. METHODS: Patients with locally advanced rectal adenocarcinoma who received neoadjuvant therapy from 2005 to 2017 were evaluated. Those with major or complete clinical response underwent a full-thickness local excision. Kaplan-Meier estimates were used to evaluate overall, disease-free, and local recurrence-free survival of patients who underwent local excision (LE group) and were compared with a matched cohort of patients who underwent total mesorectal excision (TME group). RESULTS: Among 252 patients who received neoadjuvant therapy for rectal cancer, 51 (20.2%) underwent a local excision. At a median follow-up of 61 months, patients who underwent local excision were stoma-free in 88.2% of cases and with rectum preserved in 78.5% of cases, respectively. The estimated 5-year local, disease-free, and overall survival was 91.8% vs 97.6% (95% CI: 79.5-96.8 vs 84.6-99.6), 86.7% vs 86.4% (95% CI: 72.5-93.9 vs 70.1-94.1), and 85% vs 90% (95% CI: 69.0-93.0% vs 75.3-96.2), in the study and matched control group, respectively. None of the differences was statistically significant. CONCLUSIONS: One-fifth of patients with locally advanced rectal cancer are manageable with a rectum-sparing approach after neoadjuvant therapy. With this strategy, about 80% patients will have their rectum preserved and 90% will be without stoma at long term.

Multicentre randomized clinical trial of colonic J pouch or straight stapled colorectal reconstruction after low anterior resection for rectal cancer.

BACKGROUND: Colonic J pouch reconstruction has been found to be associated with a lower incidence of anastomotic leakage than straight anastomosis. However, studies on this topic are underpowered and retrospective. This randomized trial evaluated whether the incidence of anastomotic leakage was reduced after colonic J pouch reconstruction compared with straight colorectal anastomosis following anterior resection for rectal cancer. METHODS: This multicentre RCT included patients with rectal carcinoma who underwent low anterior resection followed by colorectal anastomosis. Patients were assigned randomly to receive a colonic J pouch or straight colorectal anastomosis. The main outcome measure was the occurrence of major anastomotic leakage. The incidence of global (major plus minor) anastomotic leakage and general complications were secondary outcomes. Risk factors for anastomotic leakage were identified by regression analysis. RESULTS: Of 457 patients enrolled, 379 were evaluable (colonic J pouch arm 190, straight colorectal arm 189). The incidence of major and global anastomotic leakage, and general complications was 14·2, 19·5 and 34·2 per cent respectively in the colonic J pouch group, and 12·2, 19·0 and 27·0 per cent in the straight colorectal anastomosis group. No statistically significant differences were observed between the two arms. In multivariable logistic regression analysis, male sex (odds ratio 1·79, 95 per cent c.i. 1·02 to 3·15; P = 0·042) and high ASA fitness grade (odds ratio 2·06, 1·15 to 3·71; P = 0·015) were independently associated with the occurrence of anastomotic leakage. CONCLUSION: Colonic J pouch reconstruction does not reduce the incidence of anastomotic leakage and postoperative complications compared with conventional straight colorectal anastomosis. Registration number NCT01110798 (http://www.clinicaltrials.gov).

Metastatic pattern and new primary tumours after neoadjuvant therapy and surgery in rectal cancer.

AIM: Current follow-up guidelines for distant tumour recurrence after rectal cancer surgery are not defined or agreed. The aim was to elucidate the pattern of recurrence over time and provide information that could help direct a strategy for surveillance. METHOD: In all, 378 patients with locally advanced rectal cancer were treated with preoperative chemoradiotherapy and surgery with curative intent. Patients were followed up with a standard protocol, and data were prospectively collected in a dedicated database. Disease-free survival and overall survival were calculated. RESULTS: Within a median follow-up time of 75 months, rates of local and distant recurrence were 2.6% and 21.7%, respectively. Risk factors for recurrence were a baseline carcinoembryonic antigen > 5.0 ng/ml, a distance from the anal verge ≤ 5 cm, R1 resection margins, G3 grading, ypT staging > 2, positive lymph node status and a tumour regression grade of 3-5. Disease-free survival did not vary significantly between patients with lung and extra-pulmonary metastases (P = 0.59). The only factor associated with increased risk of lung metastases was a distance of the tumour from the anal verge of ≤ 5 cm (P = 0.01). Most recurrences occurred within the first 3 years after surgery (74.4%). The first site of recurrence was most frequently the lung (52.0%). The most frequent new primary malignancy was lung cancer (22.5%). CONCLUSIONS: Patients undergoing curative therapy for rectal cancer often experience distant recurrence; the majority of recurrences occur within the first 3 years after surgery and lung metastases are the most common. A predictive factor for pulmonary recurrence is a tumour in the lower rectum.

C-Reactive Protein and Procalcitonin as Predictors of Postoperative Inflammatory Complications After Pancreatic Surgery.

BACKGROUND: The association between postoperative inflammatory markers and risk of complications after pancreaticoduodenectomy (PD) is controversial. We sought to assess the diagnostic value of perioperative C-reactive protein (CRP) and procalcitonin (PCT) levels in the early identification of patients at risk for complications after PD. METHODS: In 2014, 84 patients undergoing elective PD were enrolled in a prospective database. Clinicopathological characteristics, CRP and PCT, as well as short-term outcomes, such as complications and pancreatic fistula, were analyzed. Complications and pancreatic fistula were defined based on the Clavien-Dindo classification and the International Study Group on Pancreatic Fistula (ISGPF) classification, respectively. High CRP and PCT were classified using cut-off values based on ROC curve analysis. RESULTS: The majority (73.8 %) of patients had pancreatic adenocarcinoma. CRP and PCT levels over the first 5 postoperative days (POD) were higher among patients who experienced a complication versus those who did not (p < 0.001). Postoperative CRP and PCT levels were also higher among patients who developed a grade B or C pancreatic fistula (p < 0.05). A CRP concentration >84 mg/l on POD 1 (AUC 0.77) and >127 mg/l on POD 3 (AUC 0.79) was associated with the highest risk of overall complications (OR 6.86 and 9.0, respectively; both p < 0.001). Similarly patients with PCT >0.7 mg/dl on POD 1 (AUC 0.67) were at higher risk of developing a postoperative complication (OR 3.33; p = 0.024). On POD 1, a CRP >92 mg/l (AUC 0.72) and a PCT >0.4 mg/dl (AUC 0.70) were associated with the highest risk of pancreatic fistula (OR 5.63 and 5.62, respectively; both p < 0.05). CONCLUSIONS: CRP and PCT concentration were associated with an increased risk of developing complications and clinical relevant pancreatic fistula after PD. Use of these biomarkers may help identify those patients at highest risk for perioperative morbidity and help guide postoperative management of patients undergoing PD.

Neutrophil-lymphocyte and platelet-lymphocyte ratio in patients after resection for hepato-pancreatico-biliary malignancies.

BACKGROUND AND OBJECTIVES: We sought to determine whether Neutrophil-lymphocyte ratio (NLR) or platelet-lymphocyte ratio (PLR) were associated with outcomes of patients undergoing surgery for a hepatopancreatico-biliary (HPB) malignancy. METHOD: Between 2000 and 2013, 452 patients who underwent an HPB procedure for a malignant indication were identified. Clinicopathological characteristics, NLR, and PLR, as well as short- and long-term outcomes were analyzed. High NLR and PLR were classified using a cut-off value of 5 and 190, respectively, based on ROC curve analysis. RESULTS: Patients with low versus high NLR and PLR had similar baseline characteristics with regard to performance status and tumor stage (all P > 0.05). Elevated PLR (HR = 1.40) tends to be association with shorter recurrence-free survival (RFS) (P = 0.05), whereas NLR was not a predictor of shorter RFS. Differently, both elevated NLR (HR = 1.94) and PLR (HR = 1.79) were associated with worse overall survival (OS) (both P < 0.05). Patients with NLR ≥5 and those with PLR ≥190 had a significantly shorter OS compared to patients with NLR <5 and PLR <190, respectively (log-rank test, both P < 0.05). Moreover, patients who had both NLR and PLR elevated had worse OS compared to patients with either one or none inflammatory markers elevated (log-rank P = 0.02). CONCLUSION: Elevated NLR and PLR were predictors of worse long-term outcome among patients with HPB malignancy undergoing resection.

Synchronous colorectal liver metastasis: a network meta-analysis review comparing classical, combined, and liver-first surgical strategies.

BACKGROUND: In recent years, the management of synchronous colorectal liver metastasis has changed significantly. Alternative surgical strategies to the classical colorectal-first approach have been proposed. These include the liver-first and combined resections approaches. The objectives of this review were to compare the short- and long-term outcomes for all three approaches. METHODS: A systematic review of comparative studies was performed. Evaluated endpoints included surgical outcomes (5-year overall survival, 30-day mortality, and post-operative complications). Pair-wise and network meta-analysis (NMA) were performed to compare survival outcomes. RESULTS: Eighteen studies were included in this review, reporting on 3,605 patients. NMA and pair-wise meta-analysis of the 5-year overall survival did not show significant difference between the three surgical approaches: combined versus colorectal-first, mean odds ratio (OR) 1.02 (95% CI 0.8-1.28, P = 0.93); liver-first versus colorectal-first, mean OR 0.81 (95% CI 0.53-1.26, P = 0.37); liver-first versus combined, mean OR 0.80 (95% CI 0.52-1.24, P = 0.41). In addition NMA of the 30-day mortality among the three approaches also did not observe statistical difference. Analysis of variance showed that mean post-operative complications of all approaches were comparable (P = 0.51). CONCLUSION: There are considerable differences in the peri-operative management of synchronous CLM patients. This meta-analysis demonstrated no clear statistical surgical outcome or survival advantage towards any of the three approaches.

Variation in triggers and use of perioperative blood transfusion in major gastrointestinal surgery.

BACKGROUND: The decision to perform intraoperative blood transfusion is subject to a variety of clinical and laboratory factors. This study examined variation in haemoglobin (Hb) triggers and overall utilization of intraoperative blood transfusion, as well the impact of transfusion on perioperative outcomes. METHODS: The study included all patients who underwent pancreatic, hepatic or colorectal resection between 2010 and 2013 at Johns Hopkins Hospital, Baltimore, Maryland. Data on Hb levels that triggered an intraoperative or postoperative transfusion and overall perioperative blood utilization were obtained and analysed. RESULTS: Intraoperative transfusion was employed in 437 (15·6 per cent) of the 2806 patients identified. Older patients (odds ratio (OR) 1·68), patients with multiple co-morbidities (Charlson co-morbidity score 4 or above; OR 1·66) and those with a lower preoperative Hb level (OR 4·95) were at increased risk of intraoperative blood transfusion (all P < 0·001). The Hb level employed to trigger transfusion varied by sex, race and service (all P < 0·001). A total of 105 patients (24·0 per cent of patients transfused) had an intraoperative transfusion with a liberal Hb trigger (10 g/dl or more); the majority of these patients (78; 74·3 per cent) did not require any additional postoperative transfusion. Patients who received an intraoperative transfusion were at greater risk of perioperative complications (OR 1·55; P = 0·002), although patients transfused with a restrictive Hb trigger (less than 10 g/dl) showed no increased risk of perioperative morbidity compared with those transfused with a liberal Hb trigger (OR 1·22; P = 0·514). CONCLUSION: Use of perioperative blood transfusion varies among surgeons and type of operation. Nearly one in four patients received a blood transfusion with a liberal intraoperative transfusion Hb trigger of 10 g/dl or more. Intraoperative blood transfusion was associated with higher risk of perioperative morbidity.

Failure to rescue as a source of variation in hospital mortality after hepatic surgery.

BACKGROUND: The mechanisms that underlie the association between high surgical volume and improved outcomes remain uncertain. This study examined the impact of complications and failure to rescue patients from these complications on mortality following hepatic resection. METHODS: The Nationwide Inpatient Sample was used to identify patients who had liver surgery between 2000 and 2010. Hospital volume was stratified into tertiles (low, intermediate and high). Rates of major complications, failure to rescue and mortality following hepatic surgery were compared. RESULTS: Some 9874 patients were identified. The major complication rate was 19.6 per cent in low-volume, 19.3 per cent in intermediate-volume and 16.6 per cent in high-volume hospitals (P < 0.001). Most common major complications included respiratory insufficiency or failure (8.8 per cent), acute renal failure (4.2 per cent) and gastrointestinal bleeding (3.9 per cent), with each of these complications being less common in high-volume hospitals (P < 0.050). The incidence of major morbidity following hepatectomy remained the same over the past decade, but failure to rescue patients from these complications decreased (P = 0.011). The overall inpatient mortality rate following liver surgery was 3.2 per cent (3.8, 3.6 and 2.3 per cent for low-, intermediate- and high-volume hospitals respectively; P < 0.001). The rate of failure to rescue (death after a complication) was higher at low- and intermediate-volume hospitals (16.8 and 16.1 per cent respectively) compared with high-volume hospitals (11.8 per cent) (P = 0.032). After accounting for patient and hospital characteristics, patients treated at low-volume hospitals who had a complication were 40 per cent more likely to die than patients with a complication in a high-volume hospital (odds ratio 1.40, 95 per cent confidence interval 1.02 to 1.93). CONCLUSION: The risk of death following hepatic surgery is lower at high-volume hospitals. The reduction in mortality appears to be the result of both lower complication rates and a better ability in high-volume hospitals to rescue patients with major complications.