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.

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.

Telerobotic-assisted laparoscopic cholecystectomy: our experience on 29 patients.

BACKGROUND/PURPOSE: The role of computer-assisted surgery (CAS) is still debated and not clearly defined. METHODS: The authors report their initial experience with CAS, comparing 29 patients submitted to cholecystectomy, using a Zeus remote-controlled robot and an Aesop remote voice-activated endoscope robot, with 29 patients submitted to standard laparoscopic cholecystectomy (LC). The surgical field and the arms of the robot were under the direct and real-time control of the surgeon, who stayed at the workstation and maneuvered the Zeus, using joysticks. The workstation was in the same room as the patient. RESULTS: Twenty-nine patients underwent telerobotic-assisted cholecystectomy (TLAC); 1 procedure was converted to standard LC and 1 to open cholecystectomy. The conversions were due to choledocholithiasis and cholecystitis. During TLAC, the mean operating time and transition time (from the induction of anesthesia to incision of the skin) were, respectively, 75 min (range, 60-170 min) and 45 min (range, 25-60 min). We did not observe any complications related to TLAC. The limitations of TLAC were the lack of tactile feedback, the increase in surgical time, and the expensive cost of the procedure to reach the same result as that of LC. CONCLUSIONS: After this initial experience, we believe that TLAC could be considered only for training in CAS, but that it is without advantages in terms of its higher cost compared with LC.

Usefulness of both operative cholangiography and conversion to decrease major bile duct injuries during laparoscopic cholecystectomy.

BACKGROUND/PURPOSE: We evaluated the role of operative cholangiography and of conversion to decrease major bile duct injuries. METHODS: We report 1074 patients who underwent laparoscopic cholecystectomy, out of a total of 1195 patients who underwent laparoscopy, over an 8-year period. The planned laparoscopic operative procedure in all the patients was the standard four-port technique with the operator on the left side of the patient. Operative cholangiography was performed with Olsen's pliers. RESULTS: We performed 993 (83%) operative cholangiographies; 121 (10.1%) patients were converted from laparoscopic to open cholecystectomy. Despite a prolonged time of dissection, 54 (4.5%) patients were converted because of unclear anatomy of Calot's triangle. One hundred and ninety patients suffered acute cholecystitis and, of those, 52 (27.3% of 190 patients) were converted. Fifteen patients showed intraoperative biliary duct stones and they were converted. Seven (0.58%) bile duct injuries (one stricture and six fistulas) are reported. CONCLUSIONS: The low number of major bile duct injuries reported in our study showed the value of operative cholangiography during laparoscopic cholecystectomy. Moreover, another important factor found to reduce major bile duct injuries was conversion when, despite accurate dissection, the anatomy of Calot's triangle remained unclear.

Selection criteria for non-surgical treatment of liver injury in adult polytraumatized patients.

Conservative treatment of hepatic trauma is currently implemented in 80-90% of cases with a success rate of 92.5% and is mainly based on the haemodynamic status of the patients. We conducted a retrospective study of 71 patients with hepatic trauma from January 1993 to April 2001 and reviewed our experience with surgical and conservative treatment, also considering associated extrahepatic lesions. Fifty-three (74.6%) patients with liver trauma underwent celiotomy and 18 (25.3%) were treated conservatively. Haemodynamic instability was the most common indication for surgery (34 patients). Eighteen (52.9%) patients required an extrahepatic surgical procedure. Nineteen (35.8%) patients were haemodynamically stable and the indications for surgery in these cases were penetrating trauma in 6, large haemoperitoneum in 12, and diaphragmatic rupture in 1. The overall mortality in the operated group was 15%, but the liver-related mortality rate was 7.5%. The success rate for conservative management was 88.8%, with mortality 0% and morbidity 11%. The patients managed conservatively had grades of injury (I-III) similar to the haemodynamically stable operated patients (94.4% vs 94.7%), whereas the haemoperitoneum was larger in the operated group (63.1% vs 11.1%). Non-operative management is the preferred treatment option in haemodynamically stable patients with limited haemoperitoneum, regardless of the grade of the hepatic lesion, and without severe intra-abdominal injuries.