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.

Applicability of 3D-printed models in hepatobiliary surgey: results from "LIV3DPRINT" multicenter study.

BACKGROUND: Hepatobiliary resections are challenging due to the complex liver anatomy. Three-dimensional printing (3DP) has gained popularity due to its ability to produce anatomical models based on the characteristics of each patient. METHODS: A multicenter study was conducted on complex hepatobiliary tumours. The endpoint was to validate 3DP model accuracy from original image sources for application in the teaching, patient-communication, and planning of hepatobiliary surgery. RESULTS: Thirty-five patients from eight centers were included. Process testing between 3DP and CT/MRI presented a considerable degree of similarity in vascular calibers (0.22 ± 1.8 mm), and distances between the tumour and vessel (0.31 ± 0.24 mm). The Dice Similarity Coefficient was 0.92, with a variation of 2%. Bland-Altman plots also demonstrated an agreement between 3DP and the surgical specimen with the distance of the resection margin (1.15 ± 1.52 mm). Professionals considered 3DP at a positive rate of 0.89 (95%CI; 0.73-0.95). According to student's distribution a higher success rate was reached with 3DP (median:0.9, IQR: 0.8-1) compared with CT/MRI or 3D digital imaging (P = 0.01). CONCLUSION: 3DP hepatic models present a good correlation compared with CT/MRI and surgical pathology and they are useful for education, understanding, and surgical planning, but does not necessarily affect the surgical outcome.

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.

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.

Liver transplantation using uncontrolled non-heart-beating donors under normothermic extracorporeal membrane oxygenation.

Because of the organ shortage, non-heart-beating donors have been proposed as a possible source of grafts for orthotopic liver transplantation (OLT). Despite the widespread use of controlled non-heart-beating donors, there are only a few published studies reporting the outcomes with uncontrolled non-heart-beating donors (UNHBDs). A prospective case-control study on adult patients undergoing OLT was designed. We used normothermic extracorporeal membrane oxygenation (NECMO) in all UNHBDs. Matching 2:1 ratio comparison was performed between a study group (UNHBDs) and a brain death donor (BDD) control group. Between January 2006 and March 2008, a total of 60 patients were included: 20 in the UNHBD group and 40 in the control group. The incidence of ischemic cholangiopathy was 5% (n = 1) for the UNHBD group and 0% for the BDD group (P = 0.15). The rate of primary nonfunction was 10% (n = 2) in UNHBD recipients and 2.5% (n = 1) in BDD recipients (P = 0.21), with graft loss in all of them. Three patients were retransplanted in the UNHBD group (15%), 2 of them because of primary nonfunction and 1 because of ischemic cholangiopathy; no patient was retransplanted in the control group (P = 0.012). After a mean follow-up of 330.4 +/- 224.9 days, 1-year cumulative patient survival was 85.5% for the UNHBD group and 87.5% for the BDD group (P = 0.768). One-year cumulative graft survival was 80% in the UNHBD group and 87.5% in the BDD group (P = 0.774). In conclusion, UNHBDs under NECMO are a potential source of organs for OLT with encouraging outcomes potentially comparable to those obtained with BDDs.

[How can the number of liver transplantations be increased?]. / ¿Cómo incrementar el número de trasplantes hepáticos?

The number of patients suitable for liver transplantation is progressively increasing due to the excellent results achieved with this procedure, giving rise to a growing imbalance in the number of candidates on the waiting list and the number of donors. This situation has prompted transplant teams to search for alternatives to increase the number of liver grafts. On the one hand, the criteria for donation have been broadened to include donors with advanced age, liver steatosis, hepatitis B and C viruses, neoplasms, and benign underlying diseases. On the other hand, new transplant techniques have been used with grafts from split livers, living donors, sequential or domino transplants and non-heart-beating donors. Other options such as xenotransplantation and hepatocyte transplants currently lack clinical applicability.