Liver transplantation for hepatocellular carcinoma in India: Are we ready for 2040?

BACKGROUND: Liver transplantation (LT) for hepatocellular carcinoma (HCC) has been widely researched and is well established worldwide. The cornerstone of this treatment lies in the various criteria formulated by expert consensus and experience. The variations among the criteria are staggering, and the short- and long-term out comes are controversial. AIM: To study the differences in the current practices of LT for HCC at different centers in India and discuss their clinical implications in the future. METHODS: We conducted a survey of major centers in India that performed LT in December 2022. A total of 23 responses were received. The centers were classified as high- and low-volume, and the current trend of care for patients und ergoing LT for HCC was noted. RESULTS: Of the 23 centers, 35% were high volume center (> 500 Liver transplants) while 52% were high-volume centers that performed more than 50 transplants/year. Approximately 39% of centers had performed > 50 LT for HCC while the percent distribution for HCC in LT patients was 5%-15% in approximately 73% of the patients. Barring a few, most centers were divided equally between University of California, San Francisco (UCSF) and center-specific criteria when choosing patients with HCC for LT, and most (65%) did not have separate transplant criteria for deceased donor LT and living donor LT (LDLT). Most centers (56%) preferred surgical resection over LT for a Child A cirrhosis patient with a resectable 4 cm HCC lesion. Positron-emission tomography-computed tomography (CT) was the modality of choice for metastatic workup in the majority of centers (74%). Downstaging was the preferred option for over 90% of the centers and included transarterial chemoembolization, transarterial radioembolization, stereotactic body radiotherapy and atezolizumab/bevacizumab with varied indications. The alpha-fetoprotein (AFP) cut-off was used by 74% of centers to decide on transplantation as well as to downstage tumors, even if they met the criteria. The criteria for successful downstaging varied, but most centers conformed to the UCSF or their center-specific criteria for LT, along with the AFP cutoff values. The wait time for LT from down staging was at least 4-6 wk in all centers. Contrast-enhanced CT was the preferred imaging modality for post-LT surveillance in 52% of the centers. Approximately 65% of the centers preferred to start everolimus between 1 and 3 months post-LT. CONCLUSION: The current predicted 5-year survival rate of HCC patients in India is less than 15%. The aim of transplantation is to achieve at least a 60% 5-year disease free survival rate, which will provide relief to the prediction of an HCC surge over the next 20 years. The current worldwide criteria (Milan/UCSF) may have a higher 5-year survival (> 70%); however, the majority of patients still do not fit these criteria and are dependent on other suboptimal modes of treatment, with much lower survival rates. To make predictions for 2040, we must prepare to arm ourselves with less stringent selection criteria to widen the pool of patients who may undergo transplantation and have a chance of a better outcome. With more advanced technology and better donor outcomes, LDLT will provide a cutting edge in the fight against liver cancer over the next two decades.

Subcutaneous Fat Obesity in a High Body Mass Index Donor Is Not a Contraindication to Living Donor Hepatectomy.

Background: Living donor liver transplantation (LDLT) has revolutionized the field of transplantation without compromising donor safety. Donor safety is of paramount concern to the transplant team. BMI >35 kg/m2 is mostly considered a contraindication to liver donation. Here, we present a successful right donor hepatectomy from a donor with a BMI of 36.5 kg/m2. Case Summary. A 39-year-old wife donated her right lobe of liver to her 43-year-old husband with nonalcoholic steatohepatitis-related chronic liver disease (CLD). His indications were refractory ascites, hepatic encephalopathy, acute kidney injury, recurrent elbow and urine infections leading to cachexia. She was initially rejected due to a high BMI but failed to lose weight over the next 2 months, and the need for a transplant in her husband was imminent. With no other potential living donors, we decided to proceed with donor evaluation as she had no other comorbidity. We were surprised to find normal liver function tests and a good liver attenuation index (LAI) of +16 on a computed tomography (CT) scan. Magnetic resonance (MR) imaging revealed a fat fraction of 3%. Volumetry confirmed a remnant of 37.9% and a potential graft-to-recipient weight ratio of 1.23. V/S ratio on CT scan (visceral fat area/subcutaneous fat area at L4-level) was <0.4 confirming subcutaneous fat obesity. Both surgeries were uneventful and both donor and recipient recovered well except recipient re-exploration on postoperative day (POD)-1 due to surgical bleeding. The donor was discharged on POD-6 and recipient was discharged on POD-15. At 3 weeks of follow-up, the donor's wound is clean and well-healed, and she is already back to doing her daily life activities without any pain with normal laboratory parameters. Conclusion: Subcutaneous fat obesity should not be considered as a contraindication to liver donation even with a BMI >35 kg/m2. A small percentage of healthy individuals will not have visceral fat obesity and may not have steatotic livers. The CT scan and MR fat fraction estimation can confirm the findings. Biopsy may be avoided if MR fat estimation is <10% in obese donors. Intraoperative visualization in these donors remains the gold standard to decide the need for biopsy. Living donor hepatectomy may be safely performed in a select group of high BMI patients (>35 kg/m2) with pure subcutaneous fat obesity in the absence of other suitable living donors.

Preoperative successful thrombectomy and thrombolysis of acute extensive splanchnic venous system and TIPSS thrombosis in a child with Budd-Chiari syndrome-Creating a window to enable living donor liver transplantation.

Preoperative extensive PV thrombosis can pose a technical challenge during liver transplantation surgery. Several strategies adopted to mitigate this problem include creation of a superior mesenteric vein-PV jump graft, use of a polytetrafluoroethylene graft, renoportal anastomosis, or cavoportal hemitransposition. Extensive and diffuse thrombosis of the splanchnic venous system may even necessitate multivisceral transplantation. We describe the case of a pediatric patient with Budd-Chiari syndrome and decompensated cirrhosis, who developed extensive thrombosis of the porto-spleno-mesenteric venous system prior to liver transplantation. We used a combination technique of thrombus aspiration by a novel trans-TIPPS approach followed by thrombolysis. Complete preoperative resolution of the extensive thrombosis was achieved. This allowed the creation of a brief window to enable planned LDLT. In prudently selected patients, performing an early mechanical and chemical thrombolysis of an extensive acute splanchnic venous thrombosis can thus help expedite a planned LDLT.

Intragastric balloon as a novel modality for weight loss in patients with cirrhosis and morbid obesity awaiting liver transplantation.

INTRODUCTION: In extreme obesity, bariatric surgery or weight loss by lifestyle modification is often not possible because of presence of decompensated cirrhosis. Endoscopic intragastric balloon placement may be used as minimal invasive technique to promote weight loss and make them better candidates for liver transplantation surgery; however, there is no literature in this regard. METHODS: Patients with body mass index (BMI) >40 kg/m(2) or BMI between 35 and 40 (with a low graft to recipient weight ratio) were considered for weight reduction modalities including dietary counseling and intragastric balloon placement when feasible. RESULTS: Intragastric balloon placement was done in six males and two females, age 46 ± 5 years, BMI 43.5 ± 6.9 kg/m(2). All patients (except one with hepatocellular carcinoma) had decompensated liver disease, mean Child score was 8.5 ± 1.6. Five of them had successful liver transplantation (three deceased and two living donor liver transplantation) after weight loss, while three are waiting. All these five patients had uneventful post-transplant course. All patients had transient vomiting except one, in whom volume of balloon was decreased due to persistent vomiting. All patients except one had weight loss. None of patients had any serious complications. Three of five patients maintained weight loss post-transplant also. CONCLUSION: Intragastric balloon placement is a useful modality for promoting short-term weight loss and thereby making morbidly obese recipients fit for liver transplantation surgery.

Laparoscopic left lateral resection is the gold standard for benign liver lesions: a case-control study.

INTRODUCTION: A left lateral section is the first choice for a laparoscopic anatomic liver resection. The objective of this case-control study was to assess the surgical outcome after a laparoscopic left lateral resection for benign liver lesions compared with the open approach. METHODS: From January 2004 to April 2011, 31 laparoscopic left lateral resections were matched with 31 open left lateral resections by selection based on pathology of the lesion, size of the lesion, American Society of Anesthesiologists (ASA) grade, body mass index (BMI), age and gender of the patient. RESULTS: Duration of the operation (laparoscopic: 182 ± 71 versus open: 244 ± 105 min; P = 0.04), blood loss (223 ± 281 versus 455 ± 593 ml; P = 0.03), duration of hospital stay (4.1 ± 1.7 versus 8.1 ± 4.4 days; P < 0.001) and total cost of hospitalization (7475 ± 2679 versus 11504 ± 7776 Euros; P < 0.001) were significantly lower in the laparoscopic group. CONCLUSIONS: This matched case-control study demonstrated procedural safety, excellent post-operative outcomes and economic benefits for a laparoscopic liver resection. A laparoscopic left lateral liver sectionectomy is recommended as a gold standard for benign liver lesions.

Review of the surgical approach to prevent small-for-size syndrome in recipients after left lobe adult LDLT.

Left lobe liver grafts increase the donor safety in adult-to-adult living-donor liver transplantation (ALDLT). However, the left lobe graft provides about 30-50 % of the required liver volume to adult recipients, which is insufficient to sustain their metabolic demands, which can lead to small-for-size syndrome (SFSS). Transient portal hypertension and microcirculatory hemodynamic derangement, apart from outflow obstruction, during the first week after reperfusion are the critical events associated with small-for-size graft transplantation. The incidence of SFSS in left lobe ALDLT can be decreased by increasing the left lobe graft volume by effective utilization of the caudate lobe with preserved vascular supply, by modulating the portal pressure with splenectomy or a porto-systemic shunt or by hepatic venous outflow reconstruction to prevent the development of venous congestion. In this review, we discuss the pathophysiology of SFSS and the various surgical strategies that can be performed to prevent SFSS in an effort to enhance the donor safety during living-donor liver transplantation.

Upregulated microRNA-92b regulates the differentiation and proliferation of EpCAM-positive fetal liver cells by targeting C/EBPß.

microRNAs (miRNAs) are short noncoding RNAs that negatively regulate gene expression. Although recent evidences have been indicated that their aberrant expression may play an important role in cancer stem cells, the mechanism of their deregulation in neoplastic transformation of liver cancer stem cells (LCSCs) has not been explored. In our study, the HCC model was established in F344 rats by DEN induction. The EpCAM(+) cells were sorted out from unfractionated fetal liver cells and liver cancer cells using the FACS analysis and miRNA expression profiles of two groups were screened through microarray platform. Gain-of-function studies were performed in vitro and in vivo to determine the role of miR-92b on proliferation and differentiation of the hepatic progenitors. In addition, luciferase reporter system and gene function analysis were used to predict miR-92b target. we found that miR-92b was highly downregulated in EpCAM(+) fetal liver cells in expression profiling studies. RT-PCR analysis demonstrated reverse correlation between miR-92b expression and differentiation degree in human HCC samples. Overexpression of miR-92b in EpCAM(+) fetal liver cells significantly increased proliferation and inhibited differentiation as well as in vitro and in vivo studies. Moreover, we verified that C/EBPß is a direct target of miR-92b and contributes to its effects on proliferation and differentiation. We conclude that aberrant expression of miR-92b can result in proliferation increase and differentiation arrest of hepatic progenitors by targeting C/EBPß.

Comprehensive application of modern technologies in precise liver resection.

BACKGROUND: Liver surgery has gone through the phases of wedge liver resection, regular resection of hepatic lobes, irregular and local resection, extracorporeal hepatectomy, hemi-extracorporeal hepatectomy and Da Vinci surgical system-assisted hepatectomy. Taking advantage of modern technologies, liver surgery is stepping into an age of precise liver resection. This review aimed to analyze the comprehensive application of modern technologies in precise liver resection. DATA SOURCE: PubMed search was carried out for English-language articles relevant to precise liver resection, liver anatomy, hepatic blood inflow blockage, parenchyma transection, and down-staging treatment. RESULTS: The 3D image system can imitate the liver operation procedures, conduct risk assessment, help to identify the operation feasibility and confirm the operation scheme. In addition, some techniques including puncture and injection of methylene blue into the target Glisson sheath help to precisely determine the resection. Alternative methods such as Pringle maneuver are helpful for hepatic blood inflow blockage in precise liver resection. Moreover, the use of exquisite equipment for liver parenchyma transection, such as cavitron ultrasonic surgical aspirator, ultrasonic scalpel, Ligasure and Tissue Link is also helpful to reduce hemorrhage in liver resection, or even operate exsanguinous liver resection without blocking hepatic blood flow. Furthermore, various down-staging therapies including transcatheter arterial chemoembolization and radio-frequency ablation were appropriate for unresectable cancer, which reverse the advanced tumor back to early phase by local or systemic treatment so that hepatectomy or liver transplantation is possible. CONCLUSIONS: Modern technologies mentioned in this paper are the key tool for achieving precise liver resection and can effectively lead to maximum preservation of anatomical structural integrity and functions of the remnant liver. In addition, large randomized trials are needed to evaluate the usefulness of these technologies in patients with hepatocellular carcinoma who have undergone precise liver resection.

"Inherent limitations" in donors: control matched study of consequences following a right hepatectomy for living donation and benign liver lesions.

OBJECTIVE: The aim of this study was to identify "inherent limitations" in healthy donors who are responsible for donor morbidity after right hepatectomy (RH) for adult-to-adult living donor liver transplantation (ALDLT). BACKGROUND: Right hepatectomy for ALDLT remains a challenging procedure without significant improvement in morbidity over time. This suggests some "inherent limitations" in healthy individuals, which are beyond the recent improvements in the donor evaluation and selection process and refinements in surgical technique during the learning curve. METHODS: To identify response of RH in ALDLT, we prospectively studied 32 patients requiring an RH for benign liver lesions (BL), matched with 32 living donors (LD) operated by same team. All patients underwent liver volume evaluation by computed tomographic (CT) volumetry preoperatively and 1 week after RH, postoperative complications graded with Clavien's system. RESULTS: The comparison (LD vs BL) showed that remnant liver volume (RLV) on preoperative CT volumetry was higher in the BL group (450 ± 150 vs 646 ± 200 mL, P < 0.001) representing 31% ± 7% in LD group versus 36% ± 7% of the total liver volume in BL group (P = 0.03). On postoperative day 7, the RLV was similar in the 2 groups (866 ± 162 vs 941 ± 153 mL) resulting from a significantly higher regeneration rate in the LD group (89% vs 55%, P = 0.009). Overall complications rate was lower in the BL group (46% vs 21%, P = 0.035). CONCLUSIONS: Right hepatectomy in LDLT induces a more severe deprivation of liver volume than in BL, which induce an accelerated regeneration. Accelerated regeneration could represent "inherent limitation" in healthy donors that makes them more vulnerable for postoperative complications.

Management of ABO-incompatible living-donor liver transplantation: past and present trends.

Based on the concept that the liver is a "privileged organ," which resists acute rejection, Thomas Starzl introduced liver transplantation across the ABO blood group. However, with improved survival after liver transplantation came reports of an increased incidence of acute rejection, biliary and vascular complications, and decreased survival after ABO-incompatible liver transplantation. As a result, ABO-incompatible liver transplantations are performed only in emergencies when ABO-compatible grafts are unavailable. In living-donor liver transplantation (LDLT), donors are restricted to family members; therefore, breaking ABO blood group barriers becomes inevitable. This inevitable situation has forced liver transplant surgeons to exploit many innovative techniques to overcome the challenges of ABO-incompatible liver transplantation. This review looks at the history and current practices of ABO-incompatible LDLT to provide insight so that the protocol can be improved further.

Sinisan, a traditional Chinese medicine, attenuates experimental chronic pancreatitis induced by trinitrobenzene sulfonic acid in rats.

BACKGROUND/PURPOSE: Sinisan, a traditional Chinese medicine, is effective for the treatment of gastrointestinal disorders. In this study, we investigated the potential protective role of Sinisan against chronic pancreatitis (CP) in rats. METHODS: CP was induced in rats by intrapancreatic injection of trinitrobenzene sulfonic acid (TNBS). Rats were randomly divided into a sham group, a TNBS-induced CP group and a Sinisan-treated group. Serum amylase and histological score were used to evaluate the severity of disease. The levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), cyclooxygenase-2 (COX-2), interleukin-10 (IL-10) and α-smooth muscle actin (α-SMA) were also measured in the three groups. Mechanical allodynia was measured with von Frey filaments. In addition, the protein levels of nerve growth factor (NGF) were measured in pancreatic tissues. RESULTS: Administration of Sinisan significantly decreased the severity of CP. In the Sinisan-treated group, serum amylase, TNF-α, IL-1ß, COX-2 and α-SMA levels were lower and the level of IL-10 was upregulated compared with the TNBS-induced CP group. Furthermore, treatment with Sinisan significantly, though not completely, attenuated the allodynia. Simultaneously NGF expression was also significantly downregulated in the Sinisan-treated group compared with the TNBS-induced CP group. CONCLUSIONS: Sinisan could be an effective treatment modality for CP via its anti-inflammatory, anti-fibrotic and analgesic properties. It may be a promising drug candidate for the treatment of patients with CP.

Optimal tissue tension for secure laparoscopic knots.

Security and strength of a knot are main concerns of the surgeon since last 4000 years. The advancement of endoscopic and minimally invasive surgery in last few decades had a significant influence on a knot tying. The most difficult methods of a knot tying are performed during endoscopic procedures, in which the surgeon execute instrumentation from outside the body without palpation of organs and three-dimensional vision. In addition, laparoscopic instruments due to friction in transmission mechanism have very poor force feedback. This results into difficulty in applying the appropriate grasping force to the tissue, resulting in slippage or damage to the tissue. Our hypothesis highlights the need of tissue approximation at the 'optimum tissue tension' sufficient to resist the slippage of suture/clip without strangulation. The purpose of suture is to maintain an approximation of the tissue until healing progresses to the point where artificial support is no longer necessary for the wound to resist normal stress. When the approximation is too tight, tension in tissue leads to diminished blood supply resulting into the necrosis. Various tissues need different blood supply and different tissue pressure for optimum healings. Proposed hypothesis helps to improve the feedback of current knot pushers or clip applicators used in laparoscopic surgery using optimum tissue tension. Tissue approximation at an optimal tissue tension translates into the secure laparoscopic knot/clip application resulting in prevention of wound dehiscence, anastomosis leak, and secondary haemorrhages.