IMMUNOREACT 7: Regular aspirin use is associated with immune surveillance activation in colorectal cancer.

BACKGROUND: Long-term daily use of aspirin reduces incidence and mortality due to colorectal cancer (CRC). This study aimed to analyze the effect of aspirin on the tumor microenvironment, systemic immunity, and on the healthy mucosa surrounding cancer. METHODS: Patients with a diagnosis of CRC operated on from 2015 to 2019 were retrospectively analyzed (METACCRE cohort). Expression of mRNA of immune surveillance-related genes (PD-L1, CD80, CD86, HLA I, and HLA II) in CRC primary cells treated with aspirin were extracted from Gene Expression Omnibus-deposited public database (GSE76583). The experiment was replicated in cell lines. The mucosal immune microenvironment of a subgroup of patients participating in the IMMUNOREACT1 (ClinicalTrials.gov NCT04915326) project was analyzed with immunohistochemistry and flow cytometry. RESULTS: In the METACCRE Cohort, 12% of 238 patients analyzed were aspirin users. Nodal metastasis was significantly less frequent (p = .008) and tumor-infiltrating lymphocyte infiltration was higher (p = .02) among aspirin users. In the CRC primary cells and selected cell lines, CD80 mRNA expression was increased following aspirin treatment (p = .001). In the healthy mucosa surrounding rectal cancer, the ratio of CD8/CD3 and epithelial cells expressing CD80 was higher in aspirin users (p = .027 and p = .034, respectively). CONCLUSIONS: These data suggested that regular aspirin use may have an active role in enhancing immunosurveillance against CRC.

IMMUNOREACT 6: weak immune surveillance characterizes early-onset rectal cancer.

BACKGROUND: Colon cancer in young patients is often associated with hereditary syndromes; however, in early-onset rectal cancer, mutations of these genes are rarely observed. The aim of this study was to analyse the features of the local immune microenvironment and the mutational pattern in early-onset rectal cancer. METHODS: Commonly mutated genes were analysed within a rectal cancer series from the University Hospital of Padova. Mutation frequency and immune gene expression in a cohort from The Cancer Genome Atlas ('TCGA') were compared and immune-cell infiltration levels in the healthy rectal mucosa adjacent to rectal cancers were evaluated in the IMMUNOlogical microenvironment in REctal AdenoCarcinoma Treatment 1 and 2 ('IMMUNOREACT') series. RESULTS: In the authors' series, the mutation frequency of BRAF, KRAS, and NRAS, as well as microsatellite instability frequency, were not different between early- and late-onset rectal cancer. In The Cancer Genome Atlas series, among the genes with the most considerable difference in mutation frequency between young and older patients, seven genes are involved in the immune response and CD69, CD3, and CD8ß expression was lower in early-onset rectal cancer. In the IMMUNOlogical microenvironment in REctal AdenoCarcinoma Treatment 1 and 2 series, young patients had a lower rate of CD4+ T cells, but higher T regulator infiltration in the rectal mucosa. CONCLUSION: Early-onset rectal cancer is rarely associated with common hereditary syndromes. The tumour microenvironment is characterized by a high frequency of mutations impairing the local immune surveillance mechanisms and low expression of immune editing-related genes. A constitutively low number of CD4 T cells associated with a high number of T regulators indicates an imbalance in the immune surveillance mechanisms.

The impact of COVID-19 pandemic on access to medical services and its consequences on emergency surgery.

Background: On March 9, 2020, the Italian Prime Minister announced the lockdown, which was officially closed on May 4. This extraordinary measure was necessary to contain the COVID-19 pandemic spread in Italy. During this phase, a significant decrease in patients' access to Emergency Department (ED) was observed. Delayed access to treatment determined a delay in the diagnosis of acute surgical conditions, as already documented in other clinical areas, with consequences on surgical outcome and survival. Aim of this study is to provide a detailed description of abdominal urgent-emergent conditions surgically treated and surgical outcomes during the lockdown in a tertiary referral Italian hospital, compared with historical data. Methods: A retrospective review of urgent-emergent patients surgically treated in our department was conducted in order to compare patients' characteristics and surgical outcomes during the period March 9th-May 4th, 2020 with the same period of the previous year. Results: 152 patients were included in our study, 79 patients in 2020 group and 77 patients in 2019. We found no significant differences between the groups regarding ASA score, age, gender, and disease prevalence. Significant differences were found in symptom duration before ER access and abdominal pain as the main symptom in non-traumatic conditions. We also performed a sub-analysis on peritonitis which showed significant differences in: hospital length of stay, presence of colostomy vs. ileostomy, and fatal events in 2020. No differences were found in the use of laparoscopy. Conclusions: While the overall number of ER accesses has decreased in 2020 group, the number of patients surgically treated in emergency-urgency conditions has not decreased. However, those patients waited significantly more before the hospital access. This diagnostic delay was associated with a more severe clinical condition and a consequent significantly worse prognosis.

IMMUNOREACT 5: female patients with rectal cancer have better immune editing mechanisms than male patients - a cohort study.

BACKGROUND: Studies evaluating sex differences in colorectal cancer (CRC) tumor microenvironment are limited, and no previous study has focused on rectal cancer patients' constitutive immune surveillance mechanisms. The authors aimed to assess gender-related differences in the immune microenvironment of rectal cancer patients. METHODS: A systematic review and meta-analysis were conducted up to 31 May 2021, including studies focusing on gender-related differences in the CRC tumor microenvironment. Data on the mutational profile of rectal cancer were extracted from the Cancer Genome Atlas (TCGA). A subanalysis of the two IMMUNOREACT trials (NCT04915326 and NCT04917263) was performed, aiming to detect gender-related differences in the immune microenvironment of the healthy mucosa in patients with early (IMMUNOREACT 1 cohort) and locally advanced rectal cancer following neoadjuvant therapy (IMMUNOREACT 2 cohort). In the retrospective IMMUNOREACT 1 cohort (therapy naive), the authors enrolled 442 patients (177 female and 265 male), while in the retrospective IMMUNOREACT 2 cohort (patients who had neoadjuvant therapy), we enrolled 264 patients (80 female and 184 male). In the prospective IMMUNOREACT 1 cohort (therapy naive), the authors enrolled 72 patients (26 female and 46 male), while in the prospective IMMUNOREACT 2 cohort (patients who had neoadjuvant therapy), the authors enrolled 105 patients (42 female and 63 male). RESULTS: Seven studies reported PD-L1 expression in the CRC microenvironment, but no significant difference could be identified between the sexes. In the TGCA series, mutations of SYNE1 and RYR2 were significantly more frequent in male patients with rectal cancer. In the IMMUNOREACT 1 cohort, male patients had a higher expression of epithelial cells expressing HLA class I, while female patients had a higher number of activated CD4+Th1 cells. Female patients in the IMMUNOREACT 2 cohort showed a higher infiltration of epithelial cells expressing CD86 and activated cytotoxic T cells (P=0.01). CONCLUSIONS: Male patients have more frequent oncogene mutations associated with a lower expression of T-cell activation genes. In the healthy mucosa of female patients, more Th1 cells and cytotoxic T cells suggest a potentially better immune response to the tumor. Sex should be considered when defining the treatment strategy for rectal cancer patients or designing prognostic scores.

Improved Clinical and Survival Outcomes After Esophagectomy for Cancer Over 25 Years.

BACKGROUND: In recent decades, there have been major developments in the curative treatment of esophageal cancer, such as the implementation of positron emission tomography with computed tomography, neoadjuvant chemoradiotherapy, minimally invasive surgery, and postoperative care programs. This observational study examined clinical and survival outcomes after esophagectomy for cancer over 25 years. METHODS: Consecutive patients who underwent esophagectomy for cancer at a tertiary referral center between 1993 and 2018 were selected from a prospectively maintained database. Patients were assigned to 5 periods: 1993 to 1997, 1998 to 2002, 2003 to 2007, 2008 to 2012, and 2013 to 2017. The primary outcome was 5-year overall survival by using Kaplan-Meier log-rank tests for trends. RESULTS: A total of 1616 patients were analyzed. The median follow-up of surviving patients was 91.0 months (interquartile range [IQR], 62.6-127.5 months).The 5-year overall survival improved gradually from 32.8% to 48.2% over 25 years (P < .001). Hospital length of stay decreased from 16 days (median IQR, 14-24 days) in 1993 to 1997 to 11 days (IQR, 8-18 days) in 2013 to 2017 (P < .001). No decrease in mortality was encountered over 25 years, although over the last 5 years, in-hospital and 90-day mortality dropped from 4.2% and 8.3% in 2013 to 0% in 2017 (P < .05). Anastomotic leakages decreased from 26.4% to 9.7% between 2013 and 2017 (P < .001). CONCLUSIONS: Over the last 25 years, clinical outcomes and 5-year overall survival significantly improved in patients who underwent esophagectomy for cancer at this tertiary referral center.

Prognostic value of stem cell markers in esophageal and esophagogastric junction cancer: a meta-analysis.

Background: Esophageal cancer is an aggressive tumor, with poor prognosis and low survival rates. Although diagnosis and treatment have improved considerably, more efficient prognostic factors are urgently needed to prevent postoperative recurrence and metastasis. Cancer stem cells are key players in tumor progression and several studies have investigated the association between the expression of stemness genes and clinical outcome. However, the prognostic value of stemness markers in esophageal cancer remains controversial. We identified six factors involved in angiogenesis, anti-apoptosis and self-renewal that have been associated to poor prognosis in other types of cancer. We conducted a review of the literature and a meta-analysis to assess their potential prognostic role in this malignancy. Material and Methods: The database of PMC, PubMed, Web of Science, Embase and The Cochrane Library were searched to investigate the association between CD34, CD133, Nucleostemin, OCT-4, NANOG and CD90, and the survival of patients affected by esophageal squamous cell carcinoma or esophageal adenocarcinoma. Among the 615 eligible studies, a total of 19 articles (including 1586 patients) met the inclusion criteria for the meta-analysis, and the pooled hazard ratio and 95% confidence intervals were calculated. Results: Data showed that high expression of CD34 (HR 2.10; 95%CI 1.41-3.14; I2=56%; p=0.0003), CD133 (HR 1.91; 95%CI 1.15-3.19; I2=55%; p=0.01) and Nucleostemin (HR 2.97; 95%CI 1.11-7.98; I2=0%; p=0.03) were associated with poor prognosis in patients affected by esophageal cancer. The expression of NANOG and OCT-4 showed no significant association with survival of patients, whereas no study involving CD90 was included in this meta-analysis. Conclusion: CD34, CD133 and Nucleostemin might represent useful prognostic markers in patients affected by esophageal cancer.

Comparison of autofluorescence and white-light bronchoscopies performed with the Evis Lucera Spectrum for the detection of bronchial cancers: a meta-analysis.

BACKGROUND: Many recent studies have reported that autofluorescence bronchoscopy (AFB) has a superior sensitivity and decreased specificity in the diagnosis of bronchial cancers when compared with white-light bronchoscopy (WLB). We specifically analyzed the diagnostic performances of autofluorescence imaging video bronchoscopy (AFI) performed with the Evis Lucera Spectrum from Olympus, which is a relatively novel approach in detecting and delineating bronchial cancers, and compared it to the older WLB method. METHODS: We searched the PubMed, Embase, Web of Science, and CNKI databases from inception to July 12th, 2018 for trials in which patients were diagnosed with lung cancer via concurrent or combined use of AFI and WLB. The included studies were required to have a histologic diagnosis as the gold standard comparison, and a sufficient amount of data was extracted to assess the diagnostic capacity. A 2×2 table was constructed, and the area under the receiver-operating characteristic curve (AUC) of AFI and WLB was estimated by using a stochastic model for diagnostic meta-analysis using STATA software. RESULTS: A total of 10 articles were eligible for the meta analysis, comprising 1,830 patients with complete data included in the analysis. AFI showed a superior sensitivity of 0.92 (95% CI, 0.88-0.95) over WLB's 0.70 (95% CI, 0.58-0.80) with P<0.01, and a comparable specificity of 0.67 (95% CI, 0.51-0.80) compared with WLB's 0.78 (95% CI, 0.68-0.86) with P=0.056. Egger's test P value (0.225) demonstrated that there was no publication bias. CONCLUSIONS: Our research showed that in the evaluation of bronchial cancers, AFI was superior to conventional WLB. With its higher sensitivity, AFI could be valuable for avoiding misdiagnosis.

Neutrophil-to-lymphocyte ratio as prognostic marker in esophageal cancer: a systematic review and meta-analysis.

A high preoperative neutrophil-lymphocyte ratio (NLR) has been shown in several studies as a predictor of worse survival in many solid neoplasms, including esophageal cancer, but its impact remains unclear. The goal of this systematic review was to gain all the evidence about NLR in order to analyse its potential in predicting survival in esophageal cancer. Therefore, we conducted a systematic literature search of all relevant studies reporting data on NLR as prognostic marker in esophageal cancer patients. We considered overall survival (OS) as primary outcome, disease-free survival (DFS) and progression-free survival (PFS) as secondary outcomes. We included studies with a directly or indirectly available hazard ratio (HR), furthermore we used both fixed effect model and random effect model depending on heterogeneity. We included a total of 20 studies, published between 2011 and 2017, consisting of 6,457 patients. The NLR cut-off value ranges from 1.7 to 5. The HR for OS of all included studies was 1.60. The HR for DFS and PFS was 1.75 and 1.66 respectively. The survival sub-analysis about tumor characteristics, treatment modality, blood sample timing also confirmed NLR prognostic relevance with statistically significant results. The meta-analysis showed that high preoperative NLR is associated with worse survival in esophageal cancer, as shown in several solid tumors, but its use in the clinical practice is still underestimated. High-quality studies are needed to assess the most effective cut-off in survival prognostication and NLR relevance on postoperative complications.

Colic and rectal tumors with peritoneal metastases treated with cytoreductive surgery and HIPEC: One homogeneous condition or two different diseases? A systematic review and meta-analysis.

Colorectal cancer (CRC) peritoneal metastasis (PM) is one of the most important cause of cancer-related death in world. CRC PM is considered as a homogeneous disease without differentiating colonic or rectal origin. Aim of this study is to analyze survival of patients treated with cytoreductive surgery and HIPEC, according to the origin of PM. Literature search was performed to identify relevant articles. All meta-analysis were performed using mean difference and log of HR, when appropriate. The I2 statistic was used to determine the heterogeneity of included studies. Out of 349 selected records, 9 articles (1308 patients, 1153 colon PM and 155 rectal PM) have been included. OS and DFS is higher in patients affected by colon PM (OS mean difference: 24,49 months [95% CI: 14,70-34,28 months, p < 0,000001]; DFS mean difference: 7,75 months [95% CI: 1,37-14,13 months, p: 0,02]) and pooled Hazard Ratio for disease-related death in rectal PM is 1.62 [95% CI: 1,01-2,59, p: 0,05] compared to colon PM). Heterogeneity among selected studies is high in two subgroups and low in one (OS subgroup A I2: 98%, p < 0,000001; DFS subgroup I2: 91%, p < 0,000001; OS subgroup B I2: 25%, p: 0,26). Our analysis, with all the limitations related to included studies, suggests that peritoneal metastasis of rectal tumors treated with CRS and HIPEC have a worst prognosis of colon tumors PM. Larger studies are required to confirm those results and therefore we invite all Authors in considering also tumor localization when reporting data on CRC peritoneal metastasis treatment.

Long term recurrence in primary liver neuroendocrine tumor: Report of a single case and review of literature.

Primary liver neuroendocrine tumors (PLNETs) are rare tumors of the liver. They share some common characteristics with neuroendocrine tumors (NETs) of the extrahepatic bile ducts, such as slow rise, hormonal, and histological features. Nevertheless, they possess some peculiarities and the major feature is the difference in the metastatic potential between PLNETs and NETs. PLNETs have less metastatic potential compared with NETs, which is the main factor based on which differential diagnosis between the two groups is achieved. There exists few reports disease's long-term outcome, especially about the recurrences management. We report the case of a 52-year-old woman admitted to hospital for jaundice and presence of liver mass. She underwent extended right hepatectomy and subsequently, PLNET was revealed. After 9 years, a new mass was discovered in the remnant liver, far from the resection line, and was surgically removed. Histological examination confirmed a PLNET recurrence. The patient is alive and doing well after a year of surgery. We conducted a review of the literature on recurrent PLNETS. Five papers followed our inclusion criteria and included 10 patients. Clinical presentation was mostly nonspecific in included cases and no carcinoid syndrome was reported. Median overall survival and median disease-free survival periods were 22 and 5 months, respectively. The primary disease was treated with surgical resection in all the included cases and recurrent diseases were mostly treated with non-surgical techniques (mainly transarterial chemoembolization). In conclusion, more studies should be conducted in order to have significant data about this uncommon neoplasm. Finally, considering the lack of data on long-term outcome, a long and accurate follow-up should be considered.

Cost analysis of incisional hernia repair with synthetic mesh and biological mesh: an Italian study.

Repair of an incisional hernia (IH) generates costs on several levels and domains of society. The aim of this study was to make a complete cost analysis of incisional hernia repair (IHR) with synthetic and biological mesh and to compare it with financial reimbursement. Patients were grouped into three levels to determine the complexity of their care, and hence, the costs involved. Group 1 included patients without comorbidities, who underwent a "standard" incisional hernia repair (SIHR), with synthetic mesh. Group 2 included patients with comorbidities, who underwent the same surgical procedure. Group 3 included all patients who underwent a "complex" IHR (CIHR) with biological mesh. Total costs were divided into direct (including preoperative and operative phases) and indirect costs (medications and working days loss). Reimbursement was calculated according to Diagnosis-Related Group (DRG). From 2012 to 2014, 76 patients underwent prosthetic IHR: group 1 (35 pts); group 2 (30 pts); and group 3 (11 pts). The direct costs of preoperative and operative phases for groups 1 and 2 were €5544.25 and €5020.65, respectively, and €16,397.17 in group 3. The total reimbursement in the three groups was €68,292.37 for group 1, €80,014.14 for group 2, and €72,173.79 for group 3, with a total loss of €124,658.43, €69,675.36, and €100,620.04, respectively. All DRGs underestimate the costs related to IHR and CIHR, thus resulting in an important economic loss for the hospital. The cost analysis shows that patient-related risk factors do not alter the overall costs. To provide a correct "cost-based" reimbursement, different DRGs should be created for different types of hernias and prostheses.