Efficacy of LCMV-based cancer immunotherapies is unleashed by intratumoral injections of polyI:C.

BACKGROUND: Lymphocytic choriomeningitis virus (LCMV) belongs to the Arenavirus family known for inducing strong cytotoxic T-cell responses in both mice and humans. LCMV has been engineered for the development of cancer immunotherapies, currently undergoing evaluation in phase I/II clinical trials. Initial findings have demonstrated safety and an exceptional ability to activate and expand tumor-specific T lymphocytes. Combination strategies to maximize the antitumor effectiveness of LCMV-based immunotherapies are being explored. METHODS: We assessed the antitumor therapeutic effects of intratumoral administration of polyinosinic:polycytidylic acid (poly(I:C)) and systemic vaccination using an LCMV-vector expressing non-oncogenic versions of the E6 and E7 antigens of human papillomavirus 16 (artLCMV-E7E6) in a bilateral model engrafting TC-1/A9 cells. This cell line, derived from the parental TC-1, exhibits low MHC class I expression and is highly immune-resistant. The mechanisms underlying the combination's efficacy were investigated through bulk RNA-seq, flow cytometry analyses of the tumor microenvironment, selective depletions using antibodies and clodronate liposomes, Batf3 deficient mice, and in vivo bioluminescence experiments. Finally, we assessed the antitumor effectiveness of the combination of artLCMV-E7E6 with BO-112, a GMP-grade poly(I:C) formulated in polyethyleneimine, currently under evaluation in clinical trials. RESULTS: Intratumoral injection of poly(I:C) enhanced the antitumor efficacy of artLCMV-E7E6 in both injected and non-injected tumor lesions. The combined treatment resulted in a significant delay in tumor growth and often complete eradication of several tumor lesions, leading to significantly improved survival compared with monotherapies. While intratumoral administration of poly(I:C) did not impact LCMV vector biodistribution or transgene expression, it significantly modified leucocyte infiltrates within the tumor microenvironment and amplified systemic efficacy through proinflammatory cytokines/chemokines such as CCL3, CCL5, CXCL10, TNF, IFNα, and IL12p70. Upregulation of MHC on tumor cells and a reconfiguration of the gene expression programs related to tumor vasculature, leucocyte migration, and the activation profile of tumor-infiltrating CD8+ T lymphocytes were observed. Indeed, the antitumor effect relied on the functions of CD8+ T lymphocytes and macrophages. The synergistic efficacy of the combination was further confirmed when BO-112 was included. CONCLUSION: Intratumoral injection of poly(I:C) sensitizes MHClow tumors to the antitumor effects of artLCMV-E7E6, resulting in a potent therapeutic synergy.

Peritoneal carcinomatosis in mouse models.

Peritoneal carcinomatosis (PCa) represents a metastatic stage of a disease with unmet therapeutic options. Malignant cells from primary tumors (gastrointestinal or gynecologic malignancies) invade the peritoneal cavity and eventually seed onto peritoneal surfaces, with the omentum being the most common nest area. With a median survival of less than 6 months, PCa has a dismal prognosis that can be improved with treatments only available to a select few individuals with low tumor burden. Thus, the discovery of novel and effective therapies for this disease depends on reliable animal models. Here, we describe a method to generate syngeneic PCa mouse models based on intraperitoneal (i.p.) administration of tumor cells. This model allows to follow-up cancer progression in PCa models from ovarian and colorectal origins monitoring mice bodyweight changes, ascites development and overall survival. Moreover, luciferase-expressing tumor cells can also be used to assess tumor growth after i.p. injection through in vivo bioluminescence quantification. The establishment of reliable, easy-to-monitor and reproducible intraperitoneal syngeneic tumors models, as described here, is the first step to develop cutting-edge therapies against PCa.

Microfracture-coagulation for the real robotic liver parenchymal transection.

The use of the robotic approach in liver surgery is exponentially increasing. Although technically the robot introduces several innovative features, the instruments linked with the traditional laparoscopic approach for the liver parenchymal transection are not available, which may result in multiple technical variants that may bias the comparative analysis between the different series worldwide. A real robotic approach, minimally efficient for the liver parenchymal transection, with no requirement of external tool, available for the already existing platforms, and applicable to any type of liver resection, counting on the selective use of the plugged bipolar forceps and the monopolar scissors, or "microfracture-coagulation" (MFC) transection method, is described in detail. The relevant aspects of the technique, its indications and methodological basis are discussed.

Microbial Phenolic Metabolites Are Associated with Improved Cognitive Health.

SCOPE: Diets rich in polyphenols has been associated with better cognitive performance. The aim of this study is to assess the relationship between microbial phenolic metabolites (MPM) in urine and cognition in the context of an older population at high cardiovascular risk. METHODS AND RESULTS: A cross-sectional analysis is conducted in 400 individuals of the PREDIMED-Plus study. Liquid chromatography coupled to mass spectrometry is used to identify urinary MPM. Mediterranean diet (MedDiet) adherence is estimated with a 17-item questionnaire and cognitive function is evaluated with a battery of neuropsychological tests. Multivariable-adjusted linear regression models are fitted to assess the relationship of urinary MPM with the MedDiet and cognitive tests. Protocatechuic acid and enterolactone glucuronide are associated with higher adherence to the MedDiet. Regarding cognitive function, protocatechuic acid, vanillic acid glucuronide, 3-hydroxybenzoic acid, enterodiol glucuronide, and enterolactone glucuronide are directly associated with a global composite score of all the cognitive tests. Furthermore, protocatechuic acid and enterolactone glucuronide are associated with higher scores in the Mini-Mental State Examination, whereas enterodiol glucuronide is associated with improved Clock Drawing Test scores. CONCLUSIONS: These results suggest that the MedDiet is linked to MPM associated with better cognitive performance in an older population.

Psychosocial and environmental risk factors of obesity and hypertension in children and adolescents-a literature overview.

Childhood obesity has become a worldwide epidemic in the 21st century. Its treatment is challenging and often ineffective, among others due to complex, often not obvious causes. Awareness of the existence and meaning of psychosocial and environmental risk factors seems to be an essential element in the prevention and treatment of obesity and its complications, especially arterial hypertension. In this review, we will discuss the role of that risk factors linking obesity and increased cardiovascular disorders including the role of nutritional factors (including the role of unhealthy diet, inadequate hydration), unhealthy behaviors (e.g. smoking, alcohol and drugs, sedentary behavior, low physical activity, disrupted circadian rhythms, sleep disorders, screen exposure), unfavorable social factors (such as dysfunctional family, bullying, chronic stress, mood disorders, depression, urbanization, noise, and environmental pollution), and finally differences in cardiovascular risk in girls and boys.

The significance of the omentum in locoregional immunotherapy for peritoneal carcinomatosis.

Our recent research has unveiled the potential of locoregional immunotherapy. Cytokine-armored viral vectors, such as modified vaccinia virus Ankara vector encoding single-chain interleukin-12 (MVA.scIL-12), can target the omentum and elicit a robust tumor-specific immune response, all the while minimizing toxicity.

Intraperitoneal administration of a modified vaccinia virus Ankara confers single-chain interleukin-12 expression to the omentum and achieves immune-mediated efficacy against peritoneal carcinomatosis.

BACKGROUND: Peritoneal carcinomatosis is an advanced stage of cancer in which the disease has spread to the peritoneal cavity. In order to restore antitumor immunity subverted by tumor cells in this location, we evaluated intraperitoneal administrations of modified vaccinia virus Ankara (MVA) engineered to express single-chain interleukin 12 (scIL-12) to increase antitumor immune responses. METHODS: MVA encoding scIL-12 (MVA.scIL-12) was evaluated against peritoneal carcinomatosis models based on intraperitoneal engraftment of tumor cells. CD8-mediated immune responses, elucidated antitumor efficacy, and safety were evaluated following intravenous, intratumoral, or intraperitoneal administration of the viral vector. The immune response was measured by ELISpot (enzyme-linked immunosorbent spot), RNA sequencing, flow cytometry, intravital microscopy, and depletion of lymphocyte subsets with monoclonal antibodies. Safety was assessed by body-weight follow-up and blood testing. Tissue tropism on intravenous or intraperitoneal administration was assessed by bioluminescence analysis using a reporter MVA encoding luciferase. RESULTS: Intraperitoneal or locoregional administration, but not other routes of administration, resulted in a potent immune response characterized by increased levels of tumor-specific CD8+ T lymphocytes with the ability to produce both interferon-γ and tumor necrosis factor-α. The antitumor immune response was detectable not only in the peritoneal cavity but also systemically. As a result of intraperitoneal treatment, a single administration of MVA.scIL-12 encoding scIL-12 completely eradicated MC38 tumors implanted in the peritoneal cavity and also protected cured mice from subsequent subcutaneous rechallenges. Bioluminescence imaging using an MVA encoding luciferase revealed that intraperitoneal administration targets transgene to the omentum. The omentum is considered a key tissue in immune protection of the peritoneal cavity. The safety profile of intraperitoneal administration was also better than that following intravenous administration since no weight loss or hematological toxicity was observed when the vector was locally delivered into the peritoneal cavity. CONCLUSION: Intraperitoneal administration of MVA vectors encoding scIL-12 targets the omentum, which is the tissue where peritoneal carcinomatosis usually begins. MVA.scIL-12 induces a potent tumor-specific immune response that often leads to the eradication of experimental tumors disseminated to the peritoneal cavity.

The Relationship between Depressive Symptoms, Quality of Life and miRNAs 8 Years after Bariatric Surgery.

(1) Background: There are conflicting results on whether weight loss after bariatric surgery (BS) might be associated with quality of life (QoL)/depressive symptomatology. We aim to determine whether BS outcomes are associated with QoL/depressive symptomatology in studied patients at the 8-year follow-up after BS, as well as their relationship with different serum proteins and miRNAs. (2) Methods: A total of 53 patients with class III obesity who underwent BS, and then classified into "good responders" and "non-responders" depending on the percentage of excess weight lost (%EWL) 8 years after BS (%EWL ≥ 50% and %EWL < 50%, respectively), were included. Basal serum miRNAs and different proteins were analysed, and patients completed tests to evaluate QoL/depressive symptomatology at 8 years after BS. (3) Results: The good responders group showed higher scores on SF-36 scales of physical functioning, role functioning-physical, role functioning-emotional, body pain and global general health compared with the non-responders. The expression of hsa-miR-101-3p, hsa-miR-15a-5p, hsa-miR-29c-3p, hsa-miR-144-3p and hsa-miR-19b-3p were lower in non-responders. Hsa-miR-19b-3p was the variable associated with the response to BS in a logistic regression model. (4) Conclusions: The mental health of patients after BS is limited by the success of the intervention. In addition, the expression of basal serum miRNAs related to depression/anxiety could predict the success of BS.

Morbidity and mortality of elderly patients with pancreaticobiliary disease according to age and comprehensive geriatric assessment: A prospective observational study.

BACKGROUND: This study was designed to analyze the influence of age and comprehensive geriatric evaluation on clinical results of pancreaticobiliary disease management in elderly patients. METHODS: A prospective observational study has been undertaken, including 140 elderly patients (over 75 years) with benign pancreaticobiliary disease. Patients were divided according to age in the following groups: group 1: 75-79 years old; group 2: 80-84 years old; group 3: 85 years and older. They underwent a comprehensive geriatric assessment with different scales: Barthel Index, Pfeiffer Index, Charlson Index, and Fragility scale, at admission and had been follow-up 90 days after hospital discharge to analyze its influence on morbidity and mortality. RESULTS: Overall, 140 patients have been included (group 1=51; group 2=43 and group 3=46). Most of them, 52 cases (37.8%), had acute cholecystitis, followed by 29 cases of acute cholangitis (20.2%) and acute pancreatitis with 25 cases (17.9%). Significant differences has been observed on complications in different age groups (p=0.033). Especially in patients with a Barthel Index result ≤60, which suggests that these less functional patients had more severe complications after their treatment (p=0.037). The mortality rate was 7.1% (10 patients). CONCLUSIONS: No significant differences were found between age, morbidity and mortality in elderly patients with pancreaticobiliary disease. Comprehensive geriatric scales showed some utility in their association with specific complications.

Intratumoral injection of IL-12-encoding mRNA targeted to CSFR1 and PD-L1 exerts potent anti-tumor effects without substantial systemic exposure.

IL-12 is a potent cytokine for cancer immunotherapy. However, its systemic delivery as a recombinant protein has shown unacceptable toxicity in the clinic. Currently, the intratumoral injection of IL-12-encoding mRNA or DNA to avoid such side effects is being evaluated in clinical trials. In this study, we aimed to improve this strategy by further favoring IL-12 tethering to the tumor. We generated in vitro transcribed mRNAs encoding murine single-chain IL-12 fused to diabodies binding to CSF1R and/or PD-L1. These targeted molecules are expressed in the tumor microenvironment, especially on myeloid cells. The binding capacity of chimeric constructs and the bioactivity of IL-12 were demonstrated in vitro and in vivo. Doses as low as 0.5 µg IL-12-encoding mRNA achieved potent antitumor effects in subcutaneously injected B16-OVA and MC38 tumors. Treatment delivery was associated with increases in IL-12p70 and IFN-γ levels in circulation. Fusion of IL-12 to the diabodies exerted comparable efficacy against bilateral tumor models. However, it achieved tethering to myeloid cells infiltrating the tumor, resulting in nearly undetectable systemic levels of IL-12 and IFN-γ. Overall, tethering IL-12 to intratumoral myeloid cells in the mRNA-transferred tumors achieves similar efficacy while reducing the dangerous systemic bioavailability of IL-12.

Development of gambling disorder after bariatric surgery: a call for research.

The relationship between bariatric surgery and alcohol use disorder (AUD) suggests that there may be a parallel connection between bariatric surgery and gambling disorder (GD), although this has never been researched before. Here, we describe observations suggesting that patients undergoing bariatric surgery may develop gambling disorders after surgery. Obese, older adults, and women may be at particular risk of developing GD because of their higher susceptibility to somatic comorbidities. We call for research addressing factors affecting the development of GD in patients undergoing bariatric surgery and how this could be prevented.

Robotic liver surgery: A new reality. Descriptive analysis of 220 cases of minimally invasive liver surgery in 182 patients.

INTRODUCTION: The level of recommendation of the robotic approach in liver surgery is controversial. The objective of the study is to carry out a single-center retrospective descriptive analysis of the short-term results of the robotic and laparoscopic approach in liver surgery during the same period. METHODS: Descriptive analysis of the short-term results of the robotic and laparoscopic approach on 220 resections in 182 patients undergoing minimally invasive liver surgery. RESULTS: Between April 2018 and June 2022, a total of 92 robotic liver resections (RLR) were performed in 83 patients and 128 laparoscopic (LLR) in 99 patients. The LLR group showed a higher proportion of major surgery (P < .001) and multiple resections (P = .002). The two groups were similar in anatomical resections (RLR 64.1% vs. LLR 56.3%). In the LLS group, the average operating time was 212 min (SD 52.1). Blood loss was 276.5 mL (100-1000) and conversion 12.1%. Mean hospital stay was 5.7 (SD 4.9) days. Morbidity was 27.3% and 2% mortality. In the RLS group, the mean operative time was 217 min (SD 53.6), blood loss 169.5 mL (100.900), and conversion 2.5%. Mean hospital stay was 4.1 (SD 2.1) days. Morbidity was 15%, with no mortality. CONCLUSION: Minimally invasive liver surgery is a safe technique, and in particular, RLS allows liver resections to be performed safely and reproducibly; it appears to be a non-inferior technique to LLS, but randomized studies are needed to determine the minimally invasive approach of choice in liver surgery.

Laparoscopic and robotic distal pancreatectomy: the choice and the future.

INTRODUCTION: Distal pancreatectomy (DP) is currently well established as a minimally invasive surgery (MIS) procedure, using either a laparoscopic (LDP) or robotic (RDP) approach. METHODS: Out of 83 DP performed between January 2018 and March 2022, 57 cases (68.7%) were performed using MIS: 35 LDP and 22 RDP (da Vinci Xi). We have assessed the experience with the two techniques and analyzed the value of the robotic approach. Cases of conversion have been examined in detail. RESULTS: The mean operative times for LDP and RDP were 201.2 (SD 47.8) and 247.54 (SD 35.8) minutes, respectively (P = NS). No differences were observed in length of hospital stay or conversion rate: 6 (5-34) vs. 5.6 (5-22) days, and 4 (11.4%) vs. 3 (13.6%) cases, respectively (P = NS). The readmission rate was 3/35 patients (11.4%) treated with LDP and 6/22 (27.3%) cases of RDP (P = NS). There were no differences in morbidity (Dindo-Clavien ≥ III) between the two groups. Mortality was one case in the robotic group (a patient with early conversion due to vascular involvement). The rate of R0 resection was greater and statistically significant in the RDP group (77.1% vs. 90.9%) (P = .04). CONCLUSION: Minimally invasive distal pancreatectomy (MIDP) is a safe and feasible procedure in selected patients. Surgical planning and stepwise implementation based on prior experience help surgeons successfully perform technically demanding procedures. RDP could be the approach of choice in distal pancreatectomy, and it is not inferior to LDP.

Dose and administration time of indocyanine green in near-infrared fluorescence cholangiography during laparoscopic cholecystectomy (DOTIG): study protocol for a randomised clinical trial.

BACKGROUND: One of the most severe complications in laparoscopic cholecystectomy (LC) is intraoperative bile duct injury (BDI). Despite its low incidence, the medical implications for the patient can be serious. Besides, BDI can also generate significant legal issues in healthcare. Different techniques have been described to reduce the incidence of this complication, and near-infrared fluorescence cholangiography with indocyanine green (NIRFC-ICG) is one of the latest additions. In spite of the great interest aroused by this procedure, there are currently great disparities in the usage or administration protocols of ICG. METHODS AND ANALYSIS: This is a randomised, multicentre, per-protocol analysis, open clinical trial with four arms. The estimated duration of the trial is 12 months. The aim of the study is to analyse whether there are differences between the dose and administration ICG intervals to obtain good-quality NIRFC during LC. The primary outcome is the degree of identification of critical biliary structures during LC. In addition, different factors will be analysed that may have an influence on the results of this technique. ETHICS AND DISSEMINATION: The trial will be conducted according to the recommendations for Clinical Trials in the Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects and the recommendations of the Spanish Agency of Medicines and Medical Devices (AEMPs) for clinical trials. This trial was approved by the local institutional Ethics Committee and the AEMPs. The results of the study will be presented to the scientific community through publications, conferences or other means. EUDRACT NUMBER: 2022-000904-36. PROTOCOL VERSION: V.1.4, 2 June 2022 TRIAL REGISTRATION NUMBER: NCT05419947.

Augmented reality in hepatobiliary-pancreatic surgery: a technology at your fingertips.

Augmented reality is a technology that opens new possibilities in surgery. We present our experience in a hepatobiliary-pancreatic surgery unit in terms of preoperative planning, intraoperative support and teaching. For surgical planning, we have used 3D CT and MRI reconstructions to evaluate complex cases, which has made the interpretation of the anatomy more precise and the planning of the technique simpler. At an intraoperative level, it provides for remote holographic connection between specialists, the substitution of physical elements for virtual elements, and the use of virtual consultation models and surgical guides. In teaching, new lessons include sharing live video of surgery with the support of virtual elements for a better student understanding. As the experience has been satisfactory, augmented reality could be applied in the future to improve the results of hepatobiliary-pancreatic surgery.

Venous resection in pancreatic oncologic surgery: Different techniques for different situations.

INTRODUCTION: To report the clinical results of patients with malignant pancreatic lesions who underwent oncological surgery with vascular resection. The type of intervention performed, types of vascular reconstruction, the pathological anatomy results, postoperative morbidity and mortality, and survival at 3 and 5 years were analyzed. METHODS: Retrospective, cross-sectional and comparative analysis. We include 41 patients with malignant pancreatic lesions who underwent surgery with vascular resection due to vascular involvement, from 2013 to 2021. RESULTS: The most performed surgery was pancreaticoduodenectomy (Whipple procedure) using median laparotomy, in 35 out of the 41 patients (85%). One of the cases in the series was performed laparoscopically. Type 1 reconstruction (simple suture) was performed in 11 (27%) patients, type 2 in 4 (10%) cases, type 3 (end-to-end) in 23 (56%) cases, and type 4 reconstruction by autologous graft in 3 (7%) cases. The mean length of the resected venous segment was 21 (11-46) mm, and mean surgical time was 290 (220-360) minutes. 90% (37/41) were pancreatic adenocarcinoma. 83% were considered R0, and there was involvement in the resected vascular section in 41% of the cases. Four patients had Clavien Dindo morbidity >3, and there were no cases of postoperative mortality. Survival at 3 years was 48% and at 5 years 20%. CONCLUSIONS: The aggressive surgical treatment with venous resection in pancreatic malignant lesions to ensure R0 and its vascular reconstruction is a feasible technique, with an acceptable morbid-mortality rate and overall survival.

Indocyanine green (ICG) fluorescent cholangiography in laparoscopic cholecystectomy: Simplifying time and dose.

BACKGROUND: This article aims to analyze and to simplify the optimal dose and time of intravenous indocyanine green (ICG) administration to achieve the identification of the cystic duct and the common bile duct (CBD). METHODS: A consecutive series of 146 patients was prospectively analyzed and divided into three groups according to the time of ICG administration: at induction of anesthesia group (20-30 min); hours before group (between 2 and 6 h); and the day before group (≥6 h); and two groups according to the dose of ICG: 1 cc (2.5 mg) or weight-based dose (0.05 mg/kg). RESULTS: The CBD was better visualized in the at induction of anesthesia group (85.4%), in the hours before group (97.1%) (p = 0.002) and in the 1cc group (p = 0.011). When we analyzed the 1 cc group (n = 126) a greater visualization of the CBD was observed in the at induction of anesthesia group (86.7%) and in the hours before group (97.1%) (p = 0.027). CONCLUSION: Due to its simplicity and reproducibility, we suggest a dose of 2.5 mg administered 2-6 h before the procedure is the optimal. However, ICG administered 30 min prior to the surgery is enough for adequate visualization of biliary structures.

Long-term results of liver-first approach strategy in patients with advanced synchronous liver metastases from colorectal cancer.

BACKGROUND: The "liver-first" approach (LFA) is a strategy indicated for advanced synchronous liver metastases (ASLM) from colorectal cancer (CRC). Includes neoadjuvant chemotherapy, resection of the ASLM followed by CRC resection. METHODS: Retrospective descriptive analysis from a prospective database of hepatectomies from liver metastases (LM) from CRC in two centers. Between 2007-2019, 88 patients with CRC-ASLM were included in a LFA scheme. Bilobar (LM) was present in 65.9%, the mean number of lesions was 5.5 and mean size 42.7 mm. Response to treatment was assessed by RECIST criteria. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier survival curves. RESULTS: Seventy-five of 88 patients (85.2%) completed the LFA. RECIST evaluation showed partial response in 75.7% and stable disease in 22.8%. Severe morbidity rate (Clavien-Dindo ≥ IIIA) after liver and colorectal surgery was present in 29.4% and 9.3%, respectively. There was no 90-day postoperative mortality in both liver and colorectal surgeries. Recurrence rate was 76%, being the liver the most frequent site, followed by the pulmonary. From the total number of recurrences (106) in 56 patients, surgical with chemotherapy rescue treatment was accomplished in 34 of them (32.1%). The mean PFS was 8.5 and 5-year OS was 53%. CONCLUSIONS: In patients with CRC-ASLM the LFA allows control of the liver disease beforehand and an assessment of the tumor response to neoadjuvant chemotherapy, optimising the chance of potentially curative liver resection, which influences long-term survival.