Intraperitoneal administration of carcinoembryonic antigen-directed chimeric antigen receptor T cells is a robust delivery route for effective treatment of peritoneal carcinomatosis from colorectal cancer in pre-clinical study.

BACKGROUND AIMS: Peritoneal carcinomatosis (PC) from colorectal cancer (CRC) is a highly challenging disease to treat. Systemic chimeric antigen receptor (CAR) T cells have shown impressive efficacy in hematologic malignancies but have been less effective in solid tumors. We explored whether intraperitoneal (i.p.) administration of CAR T cells could provide an effective and robust route of treatment for PC from CRC. METHODS: We generated second-generation carcinoembryonic antigen (CEA)-specific CAR T cells. Various animal models of PC with i.p. and extraperitoneal metastasis were treated by i.p. or intravenous (i.v.) administration of CEA CAR T cells. RESULTS: Intraperitoneally administered CAR T cells exhibited superior anti-tumor activity compared with systemic i.v. cell infusion in an animal model of PC. In addition, i.p. administration conferred a durable effect and protection against tumor recurrence and exerted strong anti-tumor activity in an animal model of PC with metastasis in i.p. or extraperitoneal organs. Moreover, compared with systemic delivery, i.p. transfer of CAR T cells provided increased anti-tumor activity in extraperitoneal tumors without PC. This phenomenon was further confirmed in an animal model of pancreatic carcinoma after i.p. administration of our newly constructed prostate stem cell antigen-directed CAR T cells. CONCLUSIONS: Taken together, our data suggest that i.p. administration of CAR T cells may be a robust delivery route for effective treatment of cancer.

Hyperthermic chemotherapy intra-abdominal laparoscopic approach: development of a laparoscopic model using CO2 recirculation system and clinical translation in peritoneal carcinomatosis.

INTRODUCTION: Hyperthermic intraperitoneal chemotherapy (HIPEC) is an effective treatment for peritoneal carcinomatosis (PC). Laparoscopic surgery is performed in the treatment of colorectal and appendiceal cancer, and PC from diverse origin in selected patients. HIPEC management by laparoscopic approach after cytoreductive surgery (CRS) completed locoregional treatment of PC, and may be feasible and safe after appropriate patient selection. OBJECTIVE: Development of an experimental model of HIPEC by laparoscopic approach, with CO2 recirculation. Clinical translation in two patients with PC and low peritoneal cancer index. MATERIAL AND METHODS: We performed CRS in a porcine model of 5 pigs (35-38 kg) by laparoscopic approach. Laparoscopic HIPEC by CO2 recirculation system was performed; laparoscopic access was used for catheter input and output placement (Paclitaxel 175 mg/m2 for 60 min at 42 °C). The experimental variables were: blood gases, haemodynamic and intra-abdominal and central temperature. Clinical model application was performed in three cases with PC from colorectal origin. RESULTS: No statistically significant differences was found in blood gases, haemodynamic or temperature in the experimental study. In clinical study, there were no technical complications during laparoscopic-HIPEC approach, and we observed no changes in haemodynamic variables during the procedure. CONCLUSIONS: CRS and HIPEC laparoscopic model by CO2 recirculation system is safe and feasible technique in selected patients, that include low PC index, local and accessible tumour recurrences or high-risk of PC tumours.

Usefulness of thermographic analysis to control temperature homogeneity in the development and implementation of a closed recirculating CO2 chemohyperthermia model.

PURPOSE: To determine the effectiveness of thermography to control the distribution of abdominal temperature in the development of a closed chemohyperthermia model. MATERIALS AND METHODS: For thermographic analysis, we divided the abdominopelvic cavity into nine regions according to a modification of carcinomatosis peritoneal index. A difference of 2.5 °C between and within the quadrants, and thermographic colours, were used as asymmetric criteria. Preclinical study:· Rats Model: Six athymic nude rats, male, rnu/rnu. They were treated with closed technique and open technique. Porcine Model: 12 female large white pigs. Four were treated with open technique and eight with closed recirculation CO2 technique. Clinical Pilot Study, EUDRACT 2011-006319-69: 18 patients with ovarian cancer were treated with cytoreductive surgery and hyperthermia intraperitoneal chemotherapy, HIPEC, with a closed recirculating CO2 system. Thermographic control and intra-abdominal temperature assessment was performed at the baseline, when outflow temperature reached 41 °C, and at 30´. RESULTS: The thermographic images showed a higher homogeneity of the intra-abdominal temperature in the closed model respect to the open technique. The thermogram showed a temperature distribution homogeneity when starting the circulation of chemotherapy. There was correlation between the temperature thermographic map in the closed porcine model and pilot study, and reached inflow and outflow temperatures, at half time of HIPEC, of 42/41.4 °C and 42 ± 0.2/41 ± 0.8 °C, respectively. There was no significant impact to the core temperature of patients after reaching the homogeneous temperature distribution. CONCLUSIONS: To control homogeneity of temperature distribution is feasible using infra-red digital images in a closed HIPEC with CO2 recirculation.

The utility of hyperthermic intra-abdominal chemotherapy with gemcitabine for the inhibition of tumor progression in an experimental model of pancreatic peritoneal carcinomatosis, in relation to their behavior with pancreatic cancer stem cells CD133+ CXCR4.

OBJECTIVE: The origin of pancreatic cancer has been identified as a population of malignant pancreatic stem cells CD133+ CXCR4+ immunophenotype. These cells have high capacity for early locoregional invasion, being responsible for early recurrence and high mortality rates of pancreatic cancer. We propose a study for decreasing tumor progression of pancreatic cancer by reducing the volume and neoplastic subpopulation of pancreatic cancer stem cells CD133+ CXCR4+. Therefore, we develop a new therapeutic model, characterized by the application of HIPEC (Hyperthermic Intraperitoneal Chemotherapy) with gemcitabine. DESIGN: Pancreatic tumor cell line: human cell line BxPC-3. The animal model involved 18 immunosuppressed rats 5 weeks weighing 150-200 gr. The implantation of 13 × 10(6) cells/mL was performed with homogeneous distribution in the 13 abdominopelvic quadrants according to the peritoneal carcinomatosis index (PCI) and were randomized into three treatment groups. Group I (4 rats) received intravenous saline. Group II (6 rats) received intravenous gemcitabine. Group III (8 rats) received HIPEC at 41 °C for 30 min with gemcitabine + gemcitabine IV. A histological study confirmed pancreatic cancer and immunohistochemical quantification of pancreatic cancer stem cells CD133+ CXCR4+ tumor cells. RESULTS: There was a population decline of pancreatic cancer stem cells CD133+ CXCR4+ in the HIPEC group with respect to the other two groups (p < 0.001). There was a decrease in PCI between treatment groups (p < 0.05). CONCLUSION: The initial results are encouraging since there is a declining population of cancer stem cells CD133+ CXCR4+ in the HIPEC group and decreased tumor volume compared to the other two treatment groups. All the conclusions are only valid for BxPC3 cell line, and the effects HIPEC on Kras-driven pancreatic tumors remain to be determined.

Intraperitoneal chemotherapy hyperthermia (HIPEC) for peritoneal carcinomatosis of ovarian cancer origin by fluid and CO2 recirculation using the closed abdomen technique (PRS-1.0 Combat): A clinical pilot study.

Background This paper reports a study of 21 patients with peritoneal carcinomatosis from ovarian cancer who underwent cytoreductive surgery and HIPEC by means of PRS-1.0 Combat®, a new model for closed abdomen HIPEC aimed at improving fluid distribution with assistance from a CO2 recirculation system. This new technology has been previously shown to be successful in an experimental study (pig model) performed by our group, and has been approved for use in our hospital. Methods Twenty-one patients with peritoneal carcinomatosis of ovarian cancer origin were included in the study. Cytoreductive surgery and HIPEC were performed by a closed abdomen fluid and CO2 recirculation technique using the PRS-1.0 Combat(®) model. We analysed the intraoperative safety tolerance and post-operative morbidity and mortality during the first 30 days. Results Between November 2011 and March 2014 21 patients with epithelial ovarian cancer, International Federation of Gynecology and Obstetrics stage II-IV, were included in the study. During the procedure there were no significant haemodynamic or analytical disturbances. Complication rates were 38.1% and 57.14% for grade III/IV and minor (grade I/II) complications, respectively. Post-operative mortality was 4.76% (one patient). Complete cytoreductive surgery and intraperitoneal chemotherapy improved overall survival and disease-free survival in women with advanced ovarian cancer. The association of intra-abdominal hyperthermia with chemotherapy (HIPEC) increased the therapeutic benefit. Conclusions This study has shown that closed abdomen intraperitoneal chemohyperthermia by a fluid and CO2 recirculation system (PRS-1.0 Combat(®)) can be a safe and feasible model for the treatment of peritoneal carcinomatosis of ovarian cancer origin.

Security and efficiency of a closed-system, turbulent-flow circuit for hyperthermic intraperitoneal chemotherapy after cytoreductive ovarian surgery: perioperative outputs.

OBJECTIVE: To present physiologic intraoperative data and immediate postoperative outcomes of patients diagnosed with epithelial ovarian cancer submitted to cytoreductive surgery and hyperthermic peritoneal intraoperative chemotherapy (HIPEC) with a closed-circuit, turbulent-flow system. MATERIALS AND METHODS: A closed-circuit system with CO2 turbulent flow was used for paclitaxel HIPEC during 60 min for patients diagnosed with stage II or higher and recurrent epithelial ovarian cancer. Perioperative hemodynamic and metabolic statuses were followed, as well as physiologic recovery during the first 12 postoperative hours. A non-parametric statistical analysis was performed. RESULTS: At the end of the hyperthermia phase, temperature was 37.7 ± 0.6 °C, heart rate 88 ± 19 bpm, cardiac index 2.8 ± 0.5 L min(-1) m(-2), stroke volume variation 14.6 ± 3.6 % and extravascular lung water 8.7 ± 1.9 mL kg(-1). No hyperdynamic status was recorded. The length of stay in the ICU was 2½ days, and 12.7 ± 7 days in hospital. Average postoperative intubation time was 11.7 ± 17.4 h. At the ICU admission time, glucose, lactic acid and hemoglobin were the only values out of range, but close to normal. SOFA median was 3 at admission and 0 the following day. CONCLUSION: A turbulent-flow, closed-circuit use for hyperthermic peritoneal intraoperative chemotherapy resulted in no hyperdynamic response or coagulopathy, had good tolerance and promoted early physiologic recovery.

POTEE promotes breast cancer cell malignancy by inducing invadopodia formation through the activation of SUMOylated Rac1.

The small GTPase Rac1 (Ras-related C3 botulinum toxin substrate 1) has been implicated in cancer progression and in the poor prognosis of various types of tumors. Rac1 SUMOylation occurs during epithelial-mesenchymal transition (EMT), and it is required for tumor cell migration and invasion. Here we identify POTEE (POTE Ankyrin domain family member E) as a novel Rac1-SUMO1 effector involved in breast cancer malignancy that controls invadopodium formation through the activation of Rac1-SUMO1. POTEE activates Rac1 in the invadopodium by recruiting TRIO-GEF (triple functional domain protein), and it induces tumor cell proliferation and metastasis in vitro and in vivo. We found that the co-localization of POTEE with Rac1 is correlated with more aggressive breast cancer subtypes. Given its role in tumor dissemination, the leading cause of cancer-related deaths, POTEE could represent a potential therapeutic target for these types of cancer.

Paclitaxel as HIPEC-Drug after Surgical Cytoreduction for Ovarian Peritoneal Metastases: A Randomized Phase III Clinical Trial (HIPECOVA).

Multidisciplinary strategies have transformed the management of advanced ovarian cancer. We aimed to evaluate the effectiveness of paclitaxel in hyperthermic intraperitoneal chemotherapy (HIPEC) following surgical cytoreduction for ovarian peritoneal metastases in a randomized phase III trial conducted between August 2012 and December 2019. Seventy-six patients were randomized to either the HIPEC or no HIPEC group. Although median values for the primary endpoints (recurrence-free survival (RFS) and overall survival (OS)) revealed superior outcomes for the HIPEC (RFS: 23 months, OS: 48 months) over the control group (RFS: 19 months, OS: 46 months), these differences were not statistically significant (p = 0.22 and p = 0.579). Notably, the HIPEC group demonstrated significantly higher 5-year OS and 3-year RFS rates (47.2% and 47.5%) compared to patients without HIPEC (34.5% and 21.3%). Stratification according to Peritoneal Surface Disease Severity Score (PSDSS) showed improved OS and RFS for patients with lower PSDSS (I-II) in the HIPEC-treated group (p = 0.033 and p = 0.042, respectively). The Clavien-Dindo classification of adverse event grades revealed no significant differences between HIPEC and controls (p = 0.482). While overall results were not statistically significant, our long-term follow-up emphasized the potential benefit of HIPEC-associated cytoreduction with paclitaxel, particularly in selected ovarian cancer patients with lower PSDSS indices.

Nesidioblastosis. A case of hyperplasia of the islets of Langerhans in the adult.

INTRODUCTION: Nesidioblastosis is a rare disease caused by hyperplasia of pancreatic islets, developing a state of hypoglycemia due to an increase in the insulin production. It is the leading cause of hyperinsulinic hypoglycemia in childhood, whereas in adults it only represents the 0.5-5% of cases. The pathogenesis is still unknown. We have studied several genetic mutations associated with dependent potassium channel of ATP present in the beta cells of the pancreas, as well as in patients underwent bariatric surgery because of the metabolic changes involved. REPORT: Woman (38 years old) attends consultation of General Surgery derived from Endocrinology before symptoms of persistent hypoglycemia. Factitious hypoglycemia and syndromes of neuroendocrine origin were ruled out. Imaging tests failed to identify space-occupying lesions. The medical treatment failed, persisting hypoglycemia symptoms. Before the given analytical and radiological findings obtained, and the persistence of symptoms affecting the quality of life of the patient, we opted for surgical treatment performing a pancreatectomy of the 80% of the gland. The final pathologic diagnosis was nesidioblastosis. DISCUSSION: Nesidioblastosis is a rare pathology, but it must be present in the differential diagnosis of hypoglycemia symptoms with endogenous hyperinsulinism in adults, once the intake of sulfonylureas and possible pancreatic neoformations have been ruled out.

[Radiological-surgical methods to identify celiac-mesenteric anomalies of the hepatic artery before duodenopancreatectomy]. / Métodos radiológico-quirúrgicos para la identificación de anomalías celiaco-mesentéricas de la arteria hepática ante una duodenopancreatectomía.

INTRODUCTION: Up to 45% anatomical variations are found in hepatic arterial system. Identifying these anatomical anomalies before or during surgery would prevent additional morbidity in performing a duodenopancreatectomy. They are routinely identified before surgery using CT imaging, but on certain occasions they are not reported and are only discovered during the surgical operation. The initial retroperitoneal access by the superior mesenteric artery (SMA) will avoid a fairly useless intervention if there is superior mesenteric artery invasion, and will identify the anatomical variations originating in the superior mesenteric artery. These anomalies acquire importance in that their unnoticed injury could lead to severe vascular compromise and/or perioperative bleeding. OBJECTIVES: To analyse celiac-mesenteric anomalies of the hepatic artery before duodenopancreatectomy using the information from multidetector computed tomography (MDCT) using a non-standardised method, a standardised method with multidimensional reconstruction, and maximum intensity projection (MIP), after initial surgical access to the SMA. PATIENTS AND METHODS: A retrospective study of the clinical, histopathological and surgical variables was conducted on patients with an indication for duodenopancreatectomy in our Department from 2008 until April 2010. A study was performed on the reports made after image acquisition by MDCT. A blind, three-dimensional, MIP reconstruction was performed on all the patients to identify arterial anomalies. A description is given of hepatic artery anomalies after initial access to the SMA. RESULTS: A total of 61 patients were included in the study. The mean age was 65 ± 11 years, with 33 (54%) males and 28 (46%) females. Vascular anomalies, right hepatic artery (RHA) (SMA) substitute (subst), 5 (8%); RHA (SMA) accessory (acc), 4 (7%); left hepatic artery (LHA) (left gastric artery) (LGA) acc 3 (5%); common hepatic artery (CHA) (SMA) subst 3 (5%); RHA (SMA) acc+LHA (LGA) acc2 (3%); CHA (aorta) subst, 1 (2%); RHA+RGA+2 LHA (celiac trunk), 1 (2%); and CHA (SMA)+LHA (LGA) acc. CONCLUSION: On being able to identify arterial anomalies with a mixture of preoperative radiological and methodological criteria, with three-dimensional reconstruction, MIP, and initially performing a dissection of the superior mesenteric artery could avoid duodenopancreatectomies that may not benefit the patient and compromise bleeding.

Under the Hood: Understanding the Features of Mucin in Pseudomyxoma Peritonei.

Pseudomyxoma peritonei (PMP) is a rare malignant growth characterized by the production of mucin and the potential for peritoneal relapse. This study aimed to investigate the immunohistochemical and biological characteristics of mucin in patients with cellular and acellular PMP. We prospectively analyzed mucin specimens obtained from our patient cohort and described the composition and type of mucin present in each sample. A metagenomic analysis of the samples was performed to investigate the bacterial composition of the PMP microbiome. Secreted mucins 2 and 5AC and membrane-associated mucin-1 were the primary components of mucin in both cellular and acellular tumor specimens. The metagenomic study revealed a predominance of the phylum Proteobacteria and the genus Pseudomonas. Notably, Pseudomonas plecoglossicida, a species not previously reported in the human microbiome, was found to be the most abundant organism in the mucin of pseudomyxoma peritonei. Our findings suggest that the presence of MUC-2 and mucin colonization by Pseudomonas are characteristic features of both cellular and acellular disease. These results may have significant implications for the diagnosis and treatment of this rare entity.

Understanding CAR T cell therapy and its role in ovarian cancer and peritoneal carcinomatosis from ovarian cancer.

Ovarian cancer is the seventh most common cancer worldwide in women and the most lethal gynecologic malignancy due to the lack of accurate screening tools for early detection and late symptom onset. The absence of early-onset symptoms often delays diagnosis until the disease has progressed to advanced stages, frequently when there is peritoneal involvement. Although ovarian cancer is a heterogeneous malignancy with different histopathologic types, treatment for advanced tumors is usually based on chemotherapy and cytoreduction surgery. CAR T cells have shown promise for the treatment of hematological malignancies, though their role in treating solid tumors remains unclear. Outcomes are less favorable owing to the low capacity of CAR T cells to migrate to the tumor site, the influence of the protective tumor microenvironment, and the heterogeneity of surface antigens on tumor cells. Despite these results, CAR T cells have been proposed as a treatment approach for peritoneal carcinomatosis from colorectal and gastric origin. Local intraperitoneal administration of CAR T cells has been found to be superior to systemic administration, as this route is associated with increased tumor reduction, a more durable effect, protection against local relapse and distant metastases, and fewer systemic adverse effects. In this article we review the application of CAR T cells for the treatment of ovarian cancer and peritoneal carcinomatosis from ovarian cancer.

Efficacy and Safety of Intraoperative Hyperthermic Intraperitoneal Chemotherapy for Locally Advanced Colon Cancer: A Phase 3 Randomized Clinical Trial.

Importance: Peritoneal metastasis in patients with locally advanced colon cancer (T4 stage) is estimated to recur at a rate of approximately 25% at 3 years from surgical resection and is associated with poor prognosis. There is controversy regarding the clinical benefit of prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) in these patients. Objective: To assess the efficacy and safety of intraoperative HIPEC in patients with locally advanced colon cancer. Design, Setting, and Participants: This open-label, phase 3 randomized clinical trial was conducted in 17 Spanish centers from November 15, 2015, to March 9, 2021. Enrolled patients were aged 18 to 75 years with locally advanced primary colon cancer diagnosed preoperatively (cT4N02M0). Interventions: Patients were randomly assigned 1:1 to receive cytoreduction plus HIPEC with mitomycin C (30 mg/m2 over 60 minutes; investigational group) or cytoreduction alone (comparator group), both followed by systemic adjuvant chemotherapy. Randomization of the intention-to-treat population was done via a web-based system, with stratification by treatment center and sex. Main Outcomes and Measures: The primary outcome was 3-year locoregional control (LC) rate, defined as the proportion of patients without peritoneal disease recurrence analyzed by intention to treat. Secondary end points were disease-free survival, overall survival, morbidity, and rate of toxic effects. Results: A total of 184 patients were recruited and randomized (investigational group, n = 89; comparator group, n = 95). The mean (SD) age was 61.5 (9.2) years, and 111 (60.3%) were male. Median duration of follow-up was 36 months (IQR, 27-36 months). Demographic and clinical characteristics were similar between groups. The 3-year LC rate was higher in the investigational group (97.6%) than in the comparator group (87.6%) (log-rank P = .03; hazard ratio [HR], 0.21; 95% CI, 0.05-0.95). No differences were observed in disease-free survival (investigational, 81.2%; comparator, 78.0%; log-rank P = .22; HR, 0.71; 95% CI, 0.41-1.22) or overall survival (investigational, 91.7%; comparator, 92.9%; log-rank P = .68; HR, 0.79; 95% CI, 0.26-2.37). The definitive subgroup with pT4 disease showed a pronounced benefit in 3-year LC rate after investigational treatment (investigational: 98.3%; comparator: 82.1%; log-rank P = .003; HR, 0.09; 95% CI, 0.01-0.70). No differences in morbidity or toxic effects between groups were observed. Conclusions and Relevance: In this randomized clinical trial, the addition of HIPEC to complete surgical resection for locally advanced colon cancer improved the 3-year LC rate compared with surgery alone. This approach should be considered for patients with locally advanced colorectal cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT02614534.

Update for Advance CAR-T Therapy in Solid Tumors, Clinical Application in Peritoneal Carcinomatosis From Colorectal Cancer and Future Prospects.

Latest advances in the field of cancer immunotherapy have developed the (Chimeric Antigen Receptor) CAR-T cell therapy. This therapy was first used in hematological malignancies which obtained promising results; therefore, the use of CAR-T cells has become a popular approach for treating non-solid tumors. CAR-T cells consist of T-lymphocytes that are engineered to express an artificial receptor against any surface antigen of our choice giving us the capacity of offering precise and personalized treatment. This leaded to the development of CAR-T cells for treating solid tumors with the hope of obtaining the same result; however, their use in solid tumor and their efficacy have not achieved the expected results. The reason of these results is because solid tumors have some peculiarities that are not present in hematological malignancies. In this review we explain how CAR-T cells are made, their mechanism of action, adverse effect and how solid tumors can evade their action, and also we summarize their use in colorectal cancer and peritoneal carcinomatosis.

TRIB1 regulates tumor growth via controlling tumor-associated macrophage phenotypes and is associated with breast cancer survival and treatment response.

Molecular mechanisms that regulate tumor-associated macrophage (TAM) phenotype and function are incompletely understood. The pseudokinase TRIB1 has been reported as a regulator of macrophage phenotypes, both in mouse and human systems. Methods: Bioinformatic analysis was used to investigate the link between TRIB1 expression in breast cancer and therapeutic response to chemotherapy. In vivo models of breast cancer included immune-competent mice to characterize the consequences of altered (reduced or elevated) myeloid Trib1 expression on tumor growth and composition of stromal immune cell populations. Results: TRIB1 was highly expressed by TAMs in breast cancer and high TRIB1 expression correlated with response to chemotherapy and patient survival. Both overexpression and knockout of myeloid Trib1 promote mouse breast tumor growth, albeit through different molecular mechanisms. Myeloid Trib1 deficiency led to an early acceleration of tumor growth, paired with a selective reduction in perivascular macrophage numbers in vivo and enhanced oncogenic cytokine expression in vitro. In contrast, elevated levels of Trib1 in myeloid cells led to an increased late-stage mammary tumor volume, coupled with a reduction of NOS2 expressing macrophages and an overall reduction of macrophages in hypoxic tumor regions. In addition, we show that myeloid Trib1 is a previously unknown, negative regulator of the anti-tumor cytokine IL-15, and that increased myeloid Trib1 expression leads to reduced IL-15 levels in mammary tumors, with a consequent reduction in the number of T-cells that are key to anti-tumor immune responses. Conclusions: Together, these results define a key role for TRIB1 in chemotherapy responses for human breast cancer and provide a mechanistic understanding for the importance of the control of myeloid TRIB1 expression in the development of this disease.

Chemical Scalpel: An Experimental Collagenase-Based Treatment for Peritoneal Adhesions.

(1) Background: Abdominal adhesions are a common disease appearing after any type of abdominal surgery and may prolong surgical time and cause intestinal obstruction, infertility, or chronic pain. We propose the use of intraperitoneal collagenase to perform chemical adhesiolysis based on the pathophysiology and histology of adhesions. (2) Methods: We generated an adhesion model with intraperitoneal polypropylene meshes. Four months later, we evaluated the efficacy of the treatment in blinded form, i.e., 0.05% collagenase vs. placebo at 37 °C for 20 min. Protocol 1: Ten rats with ten mesh fragments, in which an attempt was made to remove the maximum number of meshes in a 5-min period. Protocol 2: Six rats with four mesh fragments in the sides of the abdominal cavity in which adhesiolysis was performed using a device that measures burst pressure. (3) Results: Protocol 1: 42% efficacy in the collagenase group versus 8% in the control group (p < 0.013). Protocol 2: 188.25 mmHg (SD 69.65) in the collagenase group vs. 325.76 mmHg (SD 50.25) in the control group (p < 0.001). (4) Conclusions: Collagenase allows for the safe and effective chemical adhesiolysis in this experimental model of adhesions.

A Novel PiRNA Enhances CA19-9 Sensitivity for Pancreatic Cancer Identification by Liquid Biopsy.

Pancreatic cancer is one of the deadliest tumours worldwide, and its poor prognosis is due to an inability to detect the disease at the early stages, thereby creating an urgent need to develop non-invasive biomarkers. P-element-induced wimpy testis (PIWI) proteins work together with piwi-interacting RNAs (piRNAs) to perform epigenetic regulation and as such hold great potential as biomarkers for pancreatic cancer. PIWIL2 and PIWIL4 are associated with better prognosis, while PIWIL1 and PIWIL3 involvement appears to be associated with carcinogenesis. We aimed to discover PIWIL3- and PIWIL4-modulated piRNAs and determine their potential mechanisms in pancreatic cancer and the clinical implications. PIWIL3 or PIWIL4 was downregulated in pancreatic cancer-derived cell lines or in a non-tumour cell line. Differentially expressed piRNAs were analysed by next generation sequencing of small RNA. Nine fresh-frozen samples from solid human pancreases (three healthy pancreases, three intraductal papillary mucinous neoplasms, and three early-stage pancreatic cancers) were included in the sequencing analysis. Two piRNAs associated with PIWIL3 (piR-168112 and piR-162725) were identified in the neoplastic cells; in untransformed samples, we identified one piRNA associated with PIWIL4 (pir-366845). After validation in pancreatic cancer-derived cell lines and one untransformed pancreatic cell line, these piRNAs were evaluated in plasma samples from healthy donors (n = 27) or patients with pancreatic cancer (n = 45). Interestingly, piR-162725 expression identified pancreatic cancer patients versus healthy donors in liquid biopsies. Moreover, the potential of the serum carbohydrate antigen 19-9 (CA19-9) biomarker to identify pancreatic cancer patients was greatly enhanced when combined with piR-162725 detection. The enhanced diagnostic potential for the early detection of pancreatic cancer in liquid biopsies of these new small non-coding RNAs will likely improve the prognosis and management of this deadly cancer.

The Role of CAR-T Cells in Peritoneal Carcinomatosis from Gastric Cancer: Rationale, Experimental Work, and Clinical Applications.

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have shown poor effectiveness in treating peritoneal carcinomatosis (PC) of gastric origin with a high tumor burden (high peritoneal cancer index), though there are scarce therapy alternatives that are able to improve survival. In experimental studies, chimeric antigen receptor-T (CAR-T) cell therapy has shown encouraging results in gastric cancer and is currently being evaluated in several clinical trials. Regarding PC, CAR-T cell therapy has also proven useful in experimental studies, especially when administered intraperitoneally, as this route improves cell distribution and lifespan. Although these results need to be supported by ongoing clinical trials, CAR-T cells are a promising new therapeutic approach to peritoneal metastases from gastric cancer. In this review, we summarize the current evidence of the use of CAR-T cells in gastric cancer and PC of gastric origin.

[Single port laparoscopic cholecystectomy in major ambulatory surgery (MAS)]. / Colecistectomía laparoscópica de puerto único en un programa de CMA.

INTRODUCTION: Natural orifice endoscopic surgery is a new surgical procedure still in the development phase. The most natural entry for surgeons is to use an already existing scar, such as the navel. The recent introduction of trocars designed for this purpose has made it possible to put this into practice. MATERIAL AND METHODS: We present our preliminary experience in single trans-umbilical incision laparoscopic cholecystectomy, by means of a prospective study which included 26 patients operated on between January 2009 and January 2010. We also attempt to find out whether it can be performed in a MAS programme. RESULTS: All patients had uncomplicated cholelithiasis, although in 5 of them cholecystitis was identified during the surgery. The mean surgical time was 51.2 min. The mean hospital stay was 25.7h, and 76.92% of patients were admitted for less than 24h. There were no re-admissions or significant intra-operative or post-operative complications. CONCLUSIONS: On looking at our results, single port laparoscopic cholecystectomy could be included in a major ambulatory surgery programme.