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.

Which video technology brings the higher cognitive burden and motion sickness in laparoscopic colorectal surgery: 3D, 2D-4 K or 3D-4 K? a propensity score study.

BACKGROUND: Technological development has offered laparoscopic colorectal surgeons new video systems to improve depth perception and perform difficult task in limited space. The aim of this study was to assess the cognitive burden and motion sickness for surgeons during 3D, 2D-4 K or 3D-4 K laparoscopic colorectal procedures and to report post-operative data with the different video systems employed. METHODS: Patients were assigned to either 3D, 2D-4 K or 3D-4 K video and two questionnaires (Simulator Sickness Questionnaire-SSQ- and NASA Task Load Index -TLX) were used during elective laparoscopic colorectal resections (October 2020-August 2022) from two operating surgeons. Short-term results of the operations performed with the three different video systems were also analyzed. RESULTS: A total of 113 consecutive patients were included: 41 (36%) in the 3D Group (A), 46 (41%) in the 3D-4 K Group and 26 (23%) in the 2D-4 K Group (C). Weighted and adjusted regression models showed no significant difference in cognitive load amongst the surgeons in the three groups of video systems when using the NASA-TLX. An increased risk for slight/moderate general discomfort and eyestrain in the 3D-4 K group compared with 2D-4 K group (OR = 3.5; p = 0.0057 and OR = 2.8; p = 0.0096, respectively) was observed. Further, slight/moderate difficulty focusing was lower in both 3D and 3D-4 K groups compared with 2D-4 K group (OR = 0.4; p = 0.0124 and OR = 0.5; p = 0.0341, respectively), and higher in the 3D-4 K group compared with 3D group (OR = 2.6; p = 0.0124). Patient population characteristics, operative time, post-operative staging, complication rate and length of stay were similar in the three groups of patients. CONCLUSIONS: 3D and 3D-4 K systems, when compared with 2D-4 K video technology, have a higher risk for slight/moderate general discomfort and eyestrain, but show lower difficulty focusing. Short post-operative outcomes do not differ, whichever imaging system is used.

Preoperative Prognostic Nutritional Index was not predictive of short-term complications after laparoscopic resection for rectal cancer.

BACKGROUND AND AIM: Prognostic Nutritional Index (PNI) is a useful tool to predict short-term results in patients undergoing surgery for gastrointestinal cancer. Few studies have addressed this issue in colorectal cancer or specifically in rectal cancer. We evaluated the prognostic relevance of preoperative PNI on morbidity of patients undergoing laparoscopic curative resection for rectal cancer (LCRRC). METHODS: PNI data and clinico-pathological characteristics of LCRRC patients (June 2005-December 2020) were evaluated. Patients with metastatic disease were excluded. Postoperative complications were evaluated using the Clavien-Dindo classification. RESULTS: A total of 182 patients were included in the analysis. Median preoperative PNI was 36.5 (IQR 32.8-41.2). Lower PNI was associated with females (p=0.02), older patients (p=0.0002), comorbidity status (p<0.0001), and those who did not receive neoadjuvant treatment (p=0.01). Post-operative complications occurred in 53 patients (29.1%), by the Clavien-Dindo classification: 40 grades I-II and 13 grades III-V. Median preoperative PNI was 35.0 (31.8-40.0) in complicated patients and 37.0 (33.0-41.5) in uncomplicated patients (p=0.09). PNI showed poor discriminative performance regarding postoperative morbidity (AUC 0.57) and was not associated with postoperative morbidity (OR 0.97) at multivariable analysis. CONCLUSIONS: Preoperative PNI was not associated with postoperative morbidity after LCRRC. Further research should focus on different nutritional indicators or hematological/immunological biomarkers.

Role of Immune Microenvironment in Pancreatic Ductal Adenocarcinoma: Could It Be Considered a Predictor of Prognosis?

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly immunosuppressive tumor microenvironment (TME). The aim of this study is to determine the potential significant TME immune markers of long-term survival. METHODS: We retrospectively included patients with a diagnosis of resectable PDAC having undergone upfront surgery. Immunohistochemical (IHC) staining using tissue microarray for PD-L1, CD3, CD4, CD8, FOXP3, CD20, iNOS and CD163 was performed in order to characterize the TME. The primary endpoint was long-term survival, defined as the Overall Survival > 24 months from surgery. RESULTS: A total of 38 consecutive patients were included, and 14 (36%) of them were long-term survivors. Long-term survivors showed a higher density of CD8+ lymphocytes intra- and peri-acinar (p = 0.08), and a higher CD8/FOXP3 intra- and peri-tumoral ratio (p = 0.05). A low density of intra- and peri-tumoral FOXP3 infiltration is a good predictor of long-term survival (p = 0.04). A significant association of the low density of intra- and peri-tumoral tumor-associated macrophages (TAMs) iNOS+ with long-term survival was detected (p = 0.04). CONCLUSIONS: Despite the retrospective nature and small sample size, our study showed that the high infiltration of CD8+ lymphocytes and low infiltration of FOXP3+ and TAMs iNOS+ are predictors of good prognosis. A preoperative assessment of these potential immune markers could be useful and determinant in the staging process and in PDAC management.

Skeletal Muscle Mass and Surgical Morbidity After Laparoscopic Rectal Cancer Resection.

Background: Sarcopenia is a useful tool in predicting short-term results in patients undergoing surgery for gastrointestinal cancer. However, there are few studies addressing this issue in colorectal cancer, and even less specifically focused on rectal cancer. We evaluated the prognostic relevance of preoperative skeletal mass index on postoperative morbidity in patients undergoing laparoscopic curative resection for rectal cancer. Methods: Skeletal mass index data and clinicopathological characteristics of rectal cancer patients in a 15-year period (June 2005-December 2020) were evaluated; patients with metastatic disease at surgery were excluded; postoperative complications within 30 days were evaluated using the Clavien-Dindo classification. Results: A total of 166 patients were included in the study. The overall prevalence of sarcopenia was 60%. BMI, Hb, or albumin were not associated with sarcopenia. Hospital stay was not correlated with sarcopenia. Postoperative complications occurred in 51 patients (31%); by the Clavien-Dindo classification 31 (61%) grade I, 10 (14.5%) grade II, and 10 (14.5%) grade III. Overall complications were not significantly different in sarcopenic and nonsarcopenic patients (P = .10). Considering only patients with complications, sarcopenia was found to be a predictor of more severe postoperative morbidity (odds ratio 12.7, P = .021). On multivariable analysis, sarcopenia was not associated with postoperative morbidity. Conclusions: Skeletal muscle status in rectal cancer patients undergoing curative resection was not associated with overall postoperative morbidity, although there was a correlation between sarcopenia and more severe complications. Further studies in a larger cohort of patients are needed before conclusions can be drawn on the relationship between muscular depletion and surgical outcomes in rectal cancer patients.

Prognostic effect of sarcopenia in patients undergoing laparoscopic rectal cancer resection.

BACKGROUND: The importance of body composition, in particular skeletal muscle mass, as risk factor affecting survival of cancer patients has recently gained increasing attention. The relationship between sarcopenia and oncological outcomes has become a topic of research in particular in patients with gastrointestinal cancer. However, there are few studies addressing this issue in colorectal cancer, and even less specifically focused on rectal cancer, in particular in Western countries. The aim of this study was to evaluate the prognostic relevance of preoperative skeletal mass index (SMI) on long-term outcomes in patients undergoing laparoscopic curative resection for rectal cancer. METHODS: SMI data and clinicopathological characteristics of rectal cancer patients in a 15-year period (June 2005-December 2020) were evaluated; patients with metastatic disease at surgery were excluded; overall and disease-free survival as well as recurrence were evaluated. RESULTS: Hundred and sixty-five patients were included in the study. Sarcopenia was identified in 30 (18%) patients. Multivariate analysis identified sarcopenia (HR = 3.28, CI = 1.33-8.11, P = 0.015), along with age (HR = 1.06, CI = 1.02-1.10, P = 0.002) and stage III (HR = 2.63, CI = 1.13-6.08, P < 0.03) as independent risk factors for overall survival. CONCLUSION: Long-term results of rectal cancer patients undergoing curative resection are affected by their preoperative skeletal muscle status. Larger studies including comprehensive data on muscle strength along with SMI are awaited to confirm these results on both Eastern and Western rectal cancer patient populations before strategies to reverse muscle depletion can be extensively applied.

Laparoscopic Welti's Maneuver: A Single-Center Experience.

Purpose: Left hemicolectomy is the standard surgical operation for a variety of colonic diseases, both benign and malignant. When colonic resection is extended, relocation of the small bowel loops can be difficult. Several techniques have been described to reposition the small intestine. Welti's technique consists in the passage of the entire small bowel to the left side of the abdomen, below the descending colon that is positioned on the right side. Methods: We retrospectively evaluated 23 patients who underwent extended left hemicolectomy and reconstruction according to the Welti's technique at our hospital. We assessed the recovery of intestinal function and the length of hospital stay; in the mid-term follow-up we searched for episodes of acute or chronic intestinal obstruction. Results: Median operative time was 215 minutes; median resumption of gas and stool emission were, respectively, 3 days (interquartile range [IQR]: 2-6) and 4 days (IQR: 2-9) after surgery. Median hospital stay was 8 (IQR: 5-37) day. After a median follow-up of 15 months (IQR: 3-132) we did not observe any episode of acute or chronic bowel obstruction. Conclusions: Welti's technique is safe and does not cause a delay in resumption of bowel functions or a delayed hospital discharge; it is a useful technique that the colorectal surgeon can use when needed.

Reminder for the clinician: abdominal manifestations of type 1 neurofibromatosis are not so uncommon.

We describe the case of a woman in her 50s with abdominal pelvic masses suspected to be an ovarian lesion with metastases. At laparoscopy, it appeared as a possible abdominal location of neurofibromatosis type 1 (NF-1). A 50 cm of small bowel was resected to remove multiple nodular lesions. On histopathology, small bowel lesions (n=14) were all classified as GISTs. Clinicians should recognise and consider gastrointestinal manifestations of NF-1 in the diagnostic flow chart. Surgical treatment may resolve symptomatic cases and prevent local infiltration or malignant degeneration of abdominal neoplasms occurring in patients with NF-1.

Fully Laparoscopic Pancreas-Preserving Resection of the Third and Fourth Portion of the Duodenum for Adenocarcinomas and Gastrointestinal Stromal Tumors: Technical Report on a Case Series.

Background: Infra-ampullary duodenal lesions are rare and surgical management is controversial. The commonly accepted treatment, which allows radical resection, is pancreaticoduodenectomy, but segmental duodenal resection has been considered as alternative. Aim of the study was to describe the effectiveness of minimally invasive resection of the third/fourth portion of the duodenum for both benign and malignant lesions, with pancreas preservation and reconstruction through end-to-side duodenojejunostomy. Methods: Data from patients undergoing elective laparoscopic curative duodenal resection with pancreas preservation between June 2005 and June 2019 were prospectively collected. Results: A total of 5 patients were identified (3M/2F), median age 73 years (range: 54-83). Lesions were all located in the third or fourth portion of the duodenum and were adenocarcinoma in 2 patients (pT2N0 and pT3N2, both 3 cm in diameter) and gastrointestinal stromal tumor in 3 patients (two pT1N0 and one pT2N0, low-risk according to Miettinen, of 3, 2, and 5 cm in diameter, respectively). The operations lasted a median of 225 minutes (range: 180-300). Digestive continuity was restored with fully laparoscopic side-to-side duodenojejunostomy in all cases. One patient developed pneumonia after surgery (20%) and required also postoperative blood transfusions. Reoperation and mortality rate was nil. Median postoperative stay was 11 days (range: 10-13). The median follow-up was 30 months. Conclusions: Fully laparoscopic pancreas-preserving duodenal resection with duodenojejunal reconstruction can be a safe and feasible option for both benign and malignant lesions of the third and fourth portion of the duodenum. It brings good oncological results, but it needs to be validated with larger number of patients.

Internal hernia following laparoscopic anterior resection for cancer: higher prevalence than expected of an under-reported complication.

BACKGROUND: Internal hernia (IH) after laparoscopic colorectal surgery is a potentially severe complication. It may go undiagnosed in patients having their abdominal CT scan during oncologic follow-up. We evaluated the occurrence of IH on CT scans after laparoscopic curative resection for rectal cancer (LRRC) and routine closure of the mesenteric defect. METHODS: Data from 189 consecutive patients undergoing elective curative LRRC in a 14-year period (June 2005-june 2019) were prospectively collected. Only patients with abdominal CT scans, performed as routine oncologic follow-up, between 3 months and 7 years post-operatively were included in the study and reviewed by a surgeon and a radiologist. RESULTS: A total of 161 patients were eligible for the study with a median age of 69 years (IQR: 59-77) at surgery. They had abdominal follow-up CT scans at a median of 39.5 months (IQR: 12.8-62.7) after surgery. The prevalence of IH was 11.2% (18/161 patients). Of the 18 patients, 15 (83.3%) were fully asymptomatic, 2 (11.1%) reported chronic abdominal discomfort (including mostly nausea and colicky pain) during their oncologic follow-up (however, IH was not suspected neither prompted additional investigations), and 1 (5.6%) was reoperated elsewhere for IH and acute small bowel obstruction. CONCLUSIONS: IH following LRRC is not uncommon, with a prevalence > 10% in our experience. Most of these patients remain fully asymptomatic, but in a few patients, IH might be responsible for some symptoms or require reoperation. Awareness of this complication is important, given the potential risk of acute small bowel obstruction.

Prevalence of internal hernia following laparoscopic colorectal surgery: single-center report on 1300 patients.

BACKGROUND: Internal hernia (IH) is an infrequent complication following colorectal resection with minimally invasive technique. The real prevalence is difficult to define and there are only few large series reporting data on this complication, often focusing only on left-sided resections. Aim of the study was to evaluate the occurrence of IH following laparoscopic colorectal resection (LCR), reporting clinical presentation and treatment. METHODS: Data from 1297 patients undergoing elective LCR for cancer or benign disease in a 15-year period (June 2005-March 2020) were prospectively collected. A database query was performed to search for small bowel obstructions requiring reintervention. RESULTS: Five patients presented symptomatic IH (prevalence = 0.38%) and required reintervention. The preceding surgical procedure was left hemicolectomy for diverticular disease in all patients. The mesenteric defect had been originally closed in 4/5 patients. The median time interval between initial surgery and the occurrence of IH was 1 (range: 0.3-10) month. In all cases a small bowel loop was found herniating through the mesocolic defect. Small bowel resection was required in one patient only. The median hospital stay following reintervention was 7 (range: 4-17) days. CONCLUSIONS: IH following LCR is a rare but severe complication, potentially leading to death, if not promptly diagnosed and treated. Awareness of this complication, early recognition, and proper diagnostic and therapeutic management is mandatory allowing laparoscopic approach and often avoiding small bowel resection.

Oligometastatic Pancreatic Cancer to the Liver in the Era of Neoadjuvant Chemotherapy: Which Role for Conversion Surgery? A Systematic Review and Meta-Analysis.

Background: the improved survival rates achieved using new polychemotherapy regimens in patients with metastatic pancreatic cancer (mPDAC) have suggested a potential role for surgery following a favorable response to initial chemotherapy (IC). The purpose of this systematic review is to summarize the available evidence on the role of surgery following IC in mPDAC, focusing on oligometastatic disease to the liver (lmPDAC). Methods: studies reporting on patients with lmPDAC undergoing surgery after IC were included. The main outcome was overall survival (OS). Results: six observational retrospective studies were included in the qualitative analysis. Data were retrieved on 2087 patients. The most common IC regimen in patients undergoing surgery was FOLFIRINOX (N 84, 73%). Only three studies reported survival comparison among patients treated with IC+surgery vs. IC alone. Median OS varied from 23 to 56 months after conversion surgery vs. 11 to 16.4 months after IC alone. Conclusions: despite wide heterogeneity of chemotherapy regimens, different downstaging criteria and potential selection biases, patients with oligometastatic lmPDAC undergoing surgery after IC have significantly higher survival rates compared to patients treated with IC alone. Future trials are needed for definition of univocal criteria of downstaging, oligometastatic definition and indications for surgery.

Impact of Age on Short- and Long-Term Outcomes after Pancreatoduodenectomy for Periampullary Neoplasms.

BACKGROUND: Although mortality and morbidity of pancreatoduodenectomy (PD) have improved significantly over the past years, the impact of age for patients undergoing PD is still debated. This study is aimed at analyzing short- and long-term outcomes of PD in elderly patients. METHODS: 124 consecutive patients who have undergone PD for pancreas neoplasms in our center between 2012 and 2017 were analyzed. Patients were divided into two groups: group I (<75 years) and group II (≥75 years). Demographic features and intraoperative and clinical-pathological data were collected. Primary endpoints were perioperative morbidity and mortality; complications were classified according to the Clavien-Dindo Score. Secondary endpoints included feasibility of adjuvant treatment and overall survival rates. RESULTS: A total of 106 patients were included in this study. There were 73 (68.9%) patients in group I and 33 (31.1%) in group II. Perioperative deceases were 4 (3.6%), and postoperative pancreatic fistulas were 34 (32.1%). Significant difference between two groups was demonstrated for the ASA Score (p = 0.004), Karnofsky Score (p = 0.025), preoperative jaundice (p = 0.004), and pulmonary complications (p = 0.034). No significance was shown for diabetes, radicality of resection, stage of disease, operative time, length of stay, postoperative complications according to the Clavien-Dindo Score, postoperative mortality, pancreatic fistula, and reoperation rates. 69.9% of the patients in group I underwent adjuvant treatment vs. 39.4% of the older ones (p = 0.012). Mean overall survival was 28.5 months in group I vs. 22 months in group II (p = 0.909). CONCLUSION: PD can be performed safely in elderly patients. Advanced age should not be an absolute contraindication for PD, even if greater frailty should be considered. The outcome of elderly patients who have undergone PD is similar to that of younger patients, even though adjuvant treatment administration is significantly lower, demonstrating that surgery remains the main therapeutic option.

Perioperative albumin ratio is associated with post-operative pancreatic fistula.

BACKGROUND: Despite improvements in surgical techniques and perioperative management, post-operative pancreatic fistula (POPF) remains a serious complication after pancreaticoduodenectomy (PD). The aim of this study was to evaluate the role of perioperative clinical variables of patients, including albumin level, in predicting pancreatic fistula. METHODS: A total of 86 patients underwent PD for pancreas cancer between 2011 and 2017 at our institution. We prospectively investigated the relation between patient's characteristics and the incidence of clinically relevant (CR)-POPF. Perioperative albumin ratio was defined as post-operative day 1 (POD1) albumin level/preoperative albumin level. RESULTS: A total of 23 patients (26.7%) developed CR-POPF. At univariate analysis POPF correlated with soft pancreas (P = 0.045), low POD1 albumin (P = 0.02), POD1 and POD3 amylase levels in drainage fluid (P = 0.003 and P = 0.014, respectively) and perioperative albumin ratio (0.58 ± 0.10 versus 0.69 ± 0.12 in patients without POPF; P = 0.003). No significant correlations with POPF were demonstrated for surgical time, serum amylase levels and preoperative albumin levels. At multivariate analysis POD3 amylase level in drainage fluid and perioperative albumin ratio were the only significant independent parameters (P = 0.027 and P = 0.047, respectively). CONCLUSIONS: Perioperative albumin ratio can predict POPF after PD.

Gastrin: from pathophysiology to cancer prevention and treatment.

Gastrin has been identified as the principal effector of gastric secretion, but several studies have demonstrated its role as a biomarker of cancer risk and as a growth factor for colorectal, stomach, liver, and pancreatic cancer. Hypergastrinemia characterizes autoimmune gastritis, with body and fundic gland atrophy and increased risk for both gastric adenocarcinoma and neuroendocrine tumors. Gastric type I carcinoids develop in the context of autoimmune gastritis because of the stimulus exerted by gastrin on enterochromaffin-like cells and remain gastrin-sensitive for long durations because the removal of hypergastrinemia leads to tumor regression. The treatment of gastric carcinoid is still open to debate, but when the disease frequently relapses, or is multicentric or infiltrating, surgery is advocated or, in the alternative, a costly and long-lasting treatment with long-acting somatostatin analogues is prescribed. A technology allowing the preparation of an immunogen eliciting an immune system response with generation of antibodies against G17 has been developed. This vaccine has been tested in patients with colorectal, pancreatic or advanced gastric cancer. The vaccine has also been used in the treatment of gastric type I carcinoids, and the administration of G17DT in patients harboring these lesions leads to carcinoid regression. Antigastrin vaccination in the treatment of gastrointestinal cancer obviously needs validation, but this immunotherapy may well represent a simple, inexpensive, and active 'adjuvant' treatment.