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.

Predictive models for hepatocellular carcinoma development after sustained virological response in advanced hepatitis C / Modelos predictivos para el desarrollo de carcinoma hepatocelular tras la respuesta viral sostenida en pacientes con hepatitis C avanzada

Background & aims: Life-long hepatocellular carcinoma (HCC) surveillance is recommended after sustained virological response (SVR) in patients with advanced hepatitis C. Since the identification of patients who could be safely discontinued for surveillance is essential, we aimed to identify subsets of patients with low-risk HCC. Methods: 491 patients with advanced and compensated fibrosis (≥F3) were prospectively followed after achieving SVR with interferon-free therapies. Clinical–biological parameters and liver stiffness measurement (LSM) were performed before starting treatment (ST) and at SVR, and HCC surveillance was carried out. Results: During a median follow-up of 49.8 months, 29 (5.9%) patients developed HCC [incidence rate: 1.6/100 patient-years (PYs)]. Two predictive models based on LSM (Model-A) or FIB-4 score (Model-B) were proposed. Only SVR parameters were included in the models, because they showed a higher accuracy for predicting HCC than ST measurements. Variables independently associated with HCC were LSM (HR, 1.03; 95% CI, 1.01–1.05), age (HR, 1.04; 95% CI, 1.01–1.08) and albumin levels (HR, 0.90; 95% CI, 0.84–0.97) in Model-A, and FIB-4 (HR, 1.22; 95% CI, 1.08–1.37) and albumin (HR, 0.90; 95% CI, 0.84–0.97) in model-B. Both models allow HCC risk stratification, identifying low-risk groups with an HCC incidence rate of 0.16/100 and 0.25/100 PYs, respectively. An overall increased hazard of HCC was observed over time. (AU)

Antecedentes y objetivos: En pacientes con hepatitis C avanzada se recomienda la vigilancia del carcinoma hepatocelular (CHC) de por vida tras la respuesta viral sostenida (RVS). La identificación de pacientes que podrían interrumpir de manera segura el screening es esencial, por ello nuestro objetivo fue identificar subgrupos de pacientes con bajo riesgo de desarrollo de CHC. Métodos: Se realizó un seguimiento prospectivo de 491 pacientes con fibrosis avanzada y compensada (≥F3) tras la RVS obtenida con terapias libres de interferón. Se registraron parámetros clínico-biológicos y se midió la rigidez hepática mediante elastografía de transición (ET) antes del inicio del tratamiento y en la respuesta viral sostenida y se realizó screening para el desarrollo de CHC. Resultados: Durante una mediana de seguimiento de 49,8 meses, 29 (5,9%) pacientes desarrollaron CHC. (Tasa de incidencia: 1,6/100 pacientes-año [PA]). Se propusieron dos modelos predictivos basados en la puntuación de ET (Modelo-A) o FIB-4 (Modelo-B). Se incluyeron los parámetros en RVS en los modelos porque mostraron una mayor precisión para predecir CHC que las mediciones basales. Las variables asociadas de forma independientes con CHC fueron: ET (HR 1,03 IC; IC 95%, 1,01-1,05), edad (HR 1,04; IC 95%, 1,01-1,08) y niveles de albúmina (HR 0,90; IC 95%, 0,84-0,97) en el Modelo-A, y FIB-4 (HR 1,22; IC 95%, 1,08-1,37) y albúmina (HR 0,90; IC 95%, 0,84-0,97) en el Modelo-B. Ambos modelos permiten la estratificación del riesgo de CHC, identificando grupos de bajo riesgo con una tasa de incidencia de CHC de 0,16/100 y 0,25/100 PA, respectivamente. Se observó un aumento general del riesgo de desarrollar CHC con el tiempo. (AU)

Hepatic Artery Anomalies in Pancreaticoduodenectomy: Outcomes from a High-Volume Center.

INTRODUCTION: Hepatic artery anomalies (HAA) may have an impact on surgical and oncological outcomes of patients undergoing pancreaticoduodenectomy (PD). METHODS: Patients who underwent PD at our institution between July 2015 and January 2020 were retrospectively reviewed and classified into two groups: group 1, with presence of HAA, and group 2, with no HAA. A weighted logistic regression model was employed to assess the association between HAA and postoperative complications, and to assess the association between HAA and R status in patients with pancreatic cancer. RESULTS: 502 patients were considered for analysis, with 75 (15%) of them in group 1. They had either an accessory (n = 28, 40.8%) or replaced (n = 26, 36.6%) right hepatic artery. Most patients underwent surgery for a malignancy (n = 451; 90%); among them, vascular resection was performed in 69 cases (15%). The presence of a HAA was reported at preoperative imaging only in 4 cases (5%) and the aberrant vessel was preserved in 72% of patients. At weighted multivariable logistic regression analysis, HAA were not associated to higher odds of morbidity (odds ratio [OR]: 0.753, 95% confidence interval [CI]: 0.543-1.043) nor to R1 status in case of pancreatic cancer (OR: 1.583, 95% CI: 0.979-2.561). CONCLUSION: At our institution, the presence of HAA does not have an impact on postoperative outcomes or affects oncological clearance after PD. Hospitals', surgeons', volume and systematic review of preoperative imaging are all factors that help reduce possible adverse events.

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.

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.

Predictive models for hepatocellular carcinoma development after sustained virological response in advanced hepatitis C.

BACKGROUND & AIMS: Life-long hepatocellular carcinoma (HCC) surveillance is recommended after sustained virological response (SVR) in patients with advanced hepatitis C. Since the identification of patients who could be safely discontinued for surveillance is essential, we aimed to identify subsets of patients with low-risk HCC. METHODS: 491 patients with advanced and compensated fibrosis (≥F3) were prospectively followed after achieving SVR with interferon-free therapies. Clinical-biological parameters and liver stiffness measurement (LSM) were performed before starting treatment (ST) and at SVR, and HCC surveillance was carried out. RESULTS: During a median follow-up of 49.8 months, 29 (5.9%) patients developed HCC [incidence rate: 1.6/100 patient-years (PYs)]. Two predictive models based on LSM (Model-A) or FIB-4 score (Model-B) were proposed. Only SVR parameters were included in the models, because they showed a higher accuracy for predicting HCC than ST measurements. Variables independently associated with HCC were LSM (HR, 1.03; 95% CI, 1.01-1.05), age (HR, 1.04; 95% CI, 1.01-1.08) and albumin levels (HR, 0.90; 95% CI, 0.84-0.97) in Model-A, and FIB-4 (HR, 1.22; 95% CI, 1.08-1.37) and albumin (HR, 0.90; 95% CI, 0.84-0.97) in model-B. Both models allow HCC risk stratification, identifying low-risk groups with an HCC incidence rate of 0.16/100 and 0.25/100 PYs, respectively. An overall increased hazard of HCC was observed over time. CONCLUSION: Simple models based on non-invasive markers of liver fibrosis, LSM or FIB-4, together with age and albumin levels at SVR permit to identify subsets of patients with HCC risk clearly <1%/year, for whom HCC surveillance might not be cost-effective.

The CCN2 Polymorphism rs12526196 Is a Risk Factor for Ascending Thoracic Aortic Aneurysm.

Cellular communication network factor 2 (CCN2/CTGF) has been traditionally described as a downstream mediator of other profibrotic factors including transforming growth factor (TGF)-ß and angiotensin II. However, recent evidence from our group demonstrated the direct role of CCN2 in maintaining aortic wall homeostasis and acute and lethal aortic aneurysm development induced by angiotensin II in the absence of CCN2 in mice. In order to translate these findings to humans, we evaluated the potential association between three polymorphisms in the CCN2 gene and the presence of a thoracic aortic aneurysm (TAA). Patients with and without TAA retrospectively selected were genotyped for rs6918698, rs9402373 and rs12526196 polymorphisms related to the CCN2 gene. Multivariable logistic regression models were performed. In our population of 366 patients (69 with TAA), no associations were found between rs6918698 and rs9402373 and TAA. However, the presence of one C allele from rs12526196 was associated with TAA comparing with the TT genotype, independently of risk factors such as sex, age, hypertension, type of valvulopathy and the presence of a bicuspid aortic valve (OR = 3.17; 95% CI = 1.30-7.88; p = 0.011). In conclusion, we demonstrated an association between the C allele of rs12526196 in the CCN2 gene and the presence of TAA. This study extrapolates to humans the relevance of CCN2 in aortic aneurysm observed in mice and postulates, for the first time, a potential protective role to CCN2 in aortic aneurysm pathology. Our results encourage future research to explore new variants in the CCN2 gene that could be predisposed to TAA development.

Obesity may not be related to pathologic response in locally advanced rectal cancer following neoadjuvant chemoradiotherapy.

Background: The aim of this study is to evaluate the correlation between body mass index (BMI) and body fat composition (measured with radiological fat parameters (RFP)) and pathological response after neoadjuvant chemoradiotherapy for locally advanced rectal cancer patients. The secondary aim of the study was to assess the role of BMI and RFP on major surgical complications, overall survival (OS), and disease-free survival (DFS). Methods: All patients who underwent surgical resection following nCRT between 2005 and 2017 for mid-low rectal cancer were retrospectively collected. Visceral fat area (VFA), superficial fat area (SFA), visceral/superficial fat area ratio (V/S), perinephric fat thickness (PNF), and waist circumference (WC) were estimated by baseline CT scan. Predictors of pathologic response and postoperative complications were investigated using logistic regression analysis. The correlations between BMI and radiologic fat parameters and survival were investigated using the Kaplan-Meier method and log-rank test. Results: Out of 144 patients included, a complete (TRG1) and major (TRG1+2) pathologic response was reported in 32 (22%) and 60 (45.5%) cases, respectively. A statistically significant correlation between BMI and all the RFP was found. At a median follow-up of 60 (35-103) months, no differences in terms of OS and DFS were found considering BMI and radiologic fat parameters. At univariable analysis, neither BMI nor radiologic fat parameters were predictors of complete or major pathologic response; nevertheless, VFA, V/S>1, and BMI were predictors of postoperative major complications. Conclusions: We found no associations between BMI and body fat composition and pathological response to nCRT, although VFA, V/S, and BMI were predictors of major complications. BMI and RFP are not related to worse long-term OS and DFS.

A SuperLearner Approach to Predict Run-In Selection in Clinical Trials.

A critical early step in a clinical trial is defining the study sample that appropriately represents the target population from which the sample will be drawn. Envisaging a "run-in" process in study design may accomplish this task; however, the traditional run-in requires additional patients, increasing times, and costs. The possible use of the available a-priori data could skip the run-in period. In this regard, ML (machine learning) techniques, which have recently shown considerable promising usage in clinical research, can be used to construct individual predictions of therapy response probability conditional on patient characteristics. An ensemble model of ML techniques was trained and validated on twin randomized clinical trials to mimic a run-in process within this framework. An ensemble ML model composed of 26 algorithms was trained on the twin clinical trials. SuperLearner (SL) performance for the Verum (Treatment) arm is above 70% sensitivity. The Positive Predictive Value (PPP) achieves a value of 80%. Results show good performance in the direction of being useful in the simulation of the run-in period; the trials conducted in similar settings can train an optimal patient selection algorithm minimizing the run-in time and costs of conduction.

Prognostic significance of additional histologic features for subclassification of pathological T3 colon cancer.

BACKGROUND: Additional histologic features of T3 colon cancer, such as tumour depth invasion beyond muscularis propria and elastic lamina invasion (ELI), have taken interest for a more accurate staging. METHODS: Patients with pT3 and pT4a (control group) colon adenocarcinoma were retrospectively collected from our institutional database. The study group was divided according to depth of tumour invasion < 5 mm and ≥ 5 mm, and into ELI - and ELI + . Chi-square test was used to compare the clinicopathological characteristics. OS and DFS were estimated using Kaplan-Meier method and compared with the log-rank test. Univariable and multivariable Cox proportional hazard models were employed to assess the effect on OS and DFS. RESULTS: Out of 290 pT3 tumours, 168 (58%) had a depth of tumour invasion < 5 mm and 122 (42%) ≥ 5 mm. The 5-year OS and DFS were 85.2, 68.7 and 60.9%, and 81.4, 73.9 and 60.1% in pT3 < 5 mm, pT3 ≥ 5 mm, and pT4a respectively (p = 0.001, p = 0.072). Considering ELI - (n = 157, 54%) and ELI + (n = 133, 46%), the 5-year OS and DFS were 78.9, 76.7, and 60.9%, and 75.5, 81.5, and 60.1% in ELI - , ELI + and pT4a respectively (p = 0.955, p = 0.462). At multivariable analysis, the depth of invasion was found to be an independent predictive factor for OS (HR 2.04, 95%CI 1.28-3.24, p = 0.003) and DFS (HR 1.98, 95%CI 1.24-3.18, p = 0.004), while ELI did not result a prognostic factor for OS nor DFS. CONCLUSION: In pT3 colon cancer, depth of tumour invasion ≥ 5 mm is an independent risk factor for OS and DFS, whereas ELI did not result a prognostic factor affecting OS nor DFS.

Oncological outcomes after major vascular resections for primary retroperitoneal liposarcoma.

BACKGROUND: The surgical management of retroperitoneal sarcomas frequently involves complex multivisceral resections, however retroperitoneal liposarcoma (LPS) rarely invade major abdominal vessels. The aim of the study was to assess association of major vascular resections with outcome of primary LPS. METHODS: All consecutive patients who underwent resection at our institutions for primary LPS between 2002 and 2019 were included. A propensity matched analysis was performed, adjusting the groups for the variables of Sarculator, to assess the effect of vascular resection on oncological outcomes. RESULTS: Overall 425 patients were identified. Twenty-four (5%) patients had vascular resection. At final pathology 18 patients had vascular infiltration, 2 vascular encasement and 4 involvement without infiltration. Vascular resection was associated with longer operative time (480' vs. 330'; p < 0.001) and greater need for transfusions (4 vs. 0 units; p < 0.001), and was burdened by a higher rate of major complications (54% vs. 25%; p = 0.002). After propensity matched analysis, patients undergoing vascular resection had a lower 5-year OS (60% vs. 81%; p = 0.05), and a higher incidence of local and distant recurrence at 5 years (local: 45% vs. 24%, p = 0.05; distant: 20% vs. 0%, p = 0.04). CONCLUSIONS: Vascular resection is feasible and safe even in the context of multivisceral resection for primary retroperitoneal liposarcomas, although associated to a higher complication rate. However, the independent association between vascular involvement and a higher risk of local recurrence, distant metastases and death may imply a more aggressive biology, which should be factored in the initial management of this complex disease.

Biological versus mechanical aortic valve replacement in non-elderly patients: a single-centre analysis of clinical outcomes and quality of life.

OBJECTIVES: The aim of this study was to evaluate short- and long-term clinical outcomes, including the perceived health-related quality of life, in patients younger than 65 years having undergone aortic valve replacement either with biological or mechanical valve prostheses. METHODS: Between 2002 and 2013, 242 consecutive patients <65 years of age underwent isolated aortic valve replacement at our institution, either with biological (n = 134, 55.4%) or mechanical (n = 108, 44.6%) prostheses. Survival, health-related quality of life, short- and long-term clinical outcomes and echocardiographic data were analysed with a retrospective, single-centre study. Propensity matching was performed. RESULTS: No significant difference in survival was found between the 2 groups (mechanical versus biological: 100% vs 96.6% at 1 year, 98.2% vs 93.1% at 5 years and 92.3% vs 83.4% at 10 years after surgery, P = 0.091). For all the interviewed patients (n = 161, 66.5%), perceived quality of life at the latest follow-up was excellent. Need for reoperation was higher in the bioprosthetic group (8% vs 0%, P = 0.995), whereas the rate of major bleedings was higher in the mechanical valve group (3% vs 20%, P = 0.094). The mean and maximum transvalvular pressure gradients were 20.5 ± 9.7 and 37.4 ± 17.5 mmHg in the biological group and 14.8 ± 4.8 and 26.6 ± 9.2 mmHg in the mechanical group (P = 0.014). CONCLUSIONS: No significant differences were found between biological and mechanical valves in terms of patients' survival, clinical outcomes and quality of life. Mean and maximum transvalvular pressure gradients were significantly higher in the biological group. The majority of patients would opt for the same prosthesis type, if asked to choose again.