New Immunological Approaches in Hepatocellular Carcinoma: Glypican-3 (GPC-3) Opportunities and Challenges

Immunotherapy is one of the strategies to boost natural defenses to fight cancer. Immuno-oncology is an artificial stimulation of the human immune system to recognize and kill selectively neoplastic cells at different stage of transformation. Cancer cells have tumor antigens and the antibody of the immune system, binding them, can detect molecules on their extracellular side of cell membrane. Among these proteins, it is rising in interest and used for early detection of hepatocellular carcinoma (HCC) Glypican-3 (GPC-3) protein. It is a heparan sulfate proteoglycan (HSPG), anchored to the cell membrane of transformed hepatocytes. We investigated its function as key regulator of hepatocytes neoplastic transformation. Noteworthy, GPC-3 protein has been implicated in different pathways from cell growth to cell motility and migration. More recently, GPC-3 has been evaluated as a useful marker for HCC due to its increased expression in the liver during tumorigenesis and its absence in normal liver. Immunotherapy that targets GPC-3 domains and its connected proteins are currently under investigation. These new biomarkers may hold potential for the detection and treatment of HCC and other diseases in which GPC-3 may be overexpressed and/or play a crucial role. This review will summarize the current knowledge regarding the active immunotherapy developed to treat HCC and it will evaluate aspects of GPC-3 (structure and biology) as advantages and potential pitfalls for considering it as a valuable immunotherapeutic target. We also elaborated the current literature with the aim to better understand its biological interactions at a molecular and cellular level to identify alternative or combined targets, due to the existing gap in the literature surrounding GPC-3. The role GPC-3 plays in the hepatocellular carcinoma phenotype can be targeted for a novel immunotherapy strategy that can specify cell-mediated destruction of neoplastic cell that spares normal liver tissue, and it can be exploited as a new serum marker to trend for diagnosis and disease progression measurements. We believe further investigation of its functions and structure, including alternative cellular localizations, is necessary to evaluate GPC-3 as valuable target to cure this cancer.

Single-Step Combined Laparoscopic Management of Hepatocellular Carcinoma with Simultaneous Radio Frequency Ablation and Trans-Arterial Embolization in Unresactable Lesions

Hepatocellular carcinoma (HCC) is a cancer with increasing incidence in the USA and high mortality rate. HCC is often difficult to treat due to underlying comorbidities such as cirrhosis. However, the application of loco-regional thermal ablation using radio frequency (RF) and trans-arterial embolization with chemotherapy (TACE) or without (TAE) has shown promising results in the treatment of patients not amenable to surgical resection or liver transplantation. Conventionally, RF and TAE are performed in two separated sessions or two steps and often RF ablation is performed percutaneously. However, no consensus has been reached regarding the ideal interval between the two treatments. In this article, we discuss the feasibility and benefits of a single-step TAE in combination with laparoscopic RF ablation in one operative session. We also present a case where this procedure has been successfully performed demonstrating its feasibility. We suggest that the use of laparoscopic RF ablation in the same surgical session as TAE is feasible and potentially offers several advantages over the two-step process that is usually performed with embolization followed by percutaneous RF with a long time interval. In this article we discuss such advantages.

New approaches to increase intestinal length: Methods used for intestinal regeneration and bioengineering

Inadequate absorptive surface area poses a great challenge to the patients suffering a variety of in-testinal diseases causing short bowel syndrome. To date, these patients are managed with total parenteral nutrition or intestinal transplantation. However, these carry significant morbidity and mortality. Currently, by emergence of tissue engineering, anticipations to utilize an alternative method to increase the intestinal absorptive surface area are increasing. In this paper, we will review the improvements made over time in attempting elongating the intestine with surgical techniques as well as using intestinal bioengineering. Performing sequential intestinal lengthening was the preliminary method applied in humans. However, these methods did not reach widespread use and has limited outcome. Subsequent experimental methods were developed utilizing scaffolds to regenerate intestinal tissue and organoids unit from the intestinal epithelium. Stem cells also have been studied and applied in all types of tissue engineering. Biomaterials were utilized as a structural support for naive cells to produce bio-engineered tissue that can achieve a near-normal anatomical structure. A promising novel approach is the elongation of the intestine with an acellular biologic scaffold to generate a neoformed intestinal tissue that showed, for the first time, evidence of absorption in vivo. In the large intestine, studies are more focused on regeneration and engineering of sphincters and will be briefly reviewed. From the review of the existing literature, it can be concluded that significant progress has been achieved in these experimental methods but that these now need to be fully translated into a pre-clinical and clinical experimentation to become a future viable therapeutic option.

Long-Term Management of Post-Transplant Ureteral Stricture with Surgical Reconstruction: A Case Series and Literature Review

Introduction: Ureteral stricture is the most common complication after kidney transplant and is largely responsible for graft dysfunction. Surgical intervention is the definitive treatment if conservative management with stenting and percutaneous nephrostomy tube placement fails and has been shown to have comparable long-term survival rates and limited post-operative complications. Methods: This is a single-center retrospective study following seven patients who received a kidney or a kidney and pancreas transplant between August 2012 and January 2021. These patients underwent surgical ureteral reconstruction after failed conservative management of a ureteral stricture. The reconstruction procedures performed were native ureter to transplanted kidney ureteropyelostomy, native bladder to transplanted renal pelvis vesicopyelostomy, non-transecting side-to-side ureteroneocystostomy, and a Boari flap creation. Data collected from electronic medical records included recipient age, gender, delayed post-transplant complications, ureteral reconstruction technique, and post-reconstruction outcomes. Renal ultrasound (RUS), renogram, nephrostogram, serum creatinine (Cr), and graft biopsy were used to assess for severity of hydronephrosis, ureteral stricture, and graft dysfunction. Serum Cr and RUS were used to assess renal function after the ureteral reconstruction. Results: Six out of seven cases resulted in reduced or resolved hydronephrosis and preserved graft function without future nephrostomy or ureteral stenting. One case required immediate revision due to persistent obstruction, and this patient had concomitant rejection leading to intrarenal stricture requiring ureterocalycostomy. Conclusions: Formal ureteral reconstruction is the definitive treatment for many cases of ureteral strictures after transplant. The surgical technique chosen for these procedures must consider the physical and functional state of the bladder, ureter, and kidney. Our series outlines multiple surgical approaches that should be considered early in the management of post-transplant ureteral strictures to limit graft dysfunction.