FLASH radiotherapy: A promising new method for radiotherapy

Among the treatments for malignant tumors, radiotherapy is of great significance both as a main treatment and as an adjuvant treatment. Radiation therapy damages cancer cells with ionizing radiation, leading to their death. However, radiation-induced toxicity limits the dose delivered to the tumor, thereby constraining the control effect of radiotherapy on tumor growth. In addition, the delayed toxicity caused by radiotherapy significantly harms the physical and mental health of patients. FLASH-RT, an emerging class of radiotherapy, causes a phenomenon known as the ‘FLASH effect’, which delivers radiotherapy at an ultra-high dose rate with lower toxicity to normal tissue than conventional radiotherapy to achieve local tumor control. Although its mechanism remains to be fully elucidated, this modality constitutes a potential new approach to treating malignant tumors. In the present review, the current research progress of FLASH-RT and its various particular effects are described, including the status of research on FLASH-RT and its influencing factors. The hypothetic mechanism of action of FLASH-RT is also summarized, providing insight into future tumor treatments.     

Donor complications among 500 living donor liver transplantations at a single center

Introduction

Living donor liver transplantation (LDLT) has become necessary because of the shortage of cadaveric organs. We retrospectively analyzed 500 living donor hepatectomies using the Clavien classification system for complications to grade their severity.

Materials and methods

We retrospectively identified and applied the Clavien clasification to 500 consecutive donors who underwent right for LDLT left hepatectomy between January 2007 and August 2011.

Results

The 149 complications were observed in 93 of 500 (18.6%) donors who were followed for a mean 30 months. There wan no donor mortality. Complications developed in 85 (18.6%) right 5 (35.7%) left, and 3 (10%) left lateral segment hepatectomy donors. The overall incidence of reoperations was 7.2%. Seventy-seven of 149 complications were grade I (51.6%) or 9 grade II (6%). The major complications consisted of 27 (18.1%) grade IIIa, 35 (23.4%) grade IIIb, and 1 (0.6%) grade IVa. Grade IVb and grade V complications did not occur. The most common problems were biliary complications in 14 of 181 donors (7.7%).

Conclusion

Donors for LDLT experienced a range of complications.     

Results of liver transplantation according to indications for orthotopic liver transplantation

OBJECTIVE: This study assessed the results of liver transplantation in patients with a variety of different indications. METHODS: From 1989 to April 2003, 209 orthotopic liver transplantations (OLTx) were performed on 196 patients, including 178 cases. The diagnoses were: PBC (n = 34); PSC (n = 13); elective postinflammatory cirrhosis in the course of hepatitis C (n = 29); hepatitis B (n = 16); postalcoholic cirrhosis (n = 23), autoimmune cirrhosis (n = 11); Wilson's disease (n = 6); cirrhosis of unknown etiology (n = 10); secondary biliary cirrhosis (n = 5); Budd-Chiari syndrome (n = 6); and benign liver neoplasms (n = 7). RESULTS: The 3-year survival rate in the group of patients transplanted electively was 74.1%. In other groups it was: PBC, 91.4%; PSC, 69.2%; hepatitis C, 69.6%; hepatitis B, 55.5%; postalcoholic cirrhosis, 80%; autoimmune cirrhosis, 81.8%; Wilson's disease, 57.1%; secondary biliary cirrhosis, 40%; Budd-Chiari syndrome, 66.6%; hemochromatosis, 100%; benign neoplasms of the liver, 87.5%; and liver cysts, 100%. CONCLUSIONS: Results of liver transplantation were closely related to the urgency of the procedure. Better results were achieved in patients operated upon routinely compared with in those operated upon emergently (74.1% vs 50%). The best results of liver transplantation were achieved in patients transplanted on a routine basis with a diagnosis of PBC (91.4%), autoimmunologic cirrhosis (81.1%), postalcoholic cirrhosis (80%), or hemochoromatosis (100%). Patients with liver insufficiency due to hepatitis B and Wilson's disease have an increased risk of graft destruction, and the rate of survival in these patients is significantly lower than in other patients.     

Arterialization of the portal vein improves hepatic microcirculation and tissue oxygenation in experimental cirrhosis

BACKGROUND: Arterialization of the portal vein (APV) has shown beneficial effects on liver regeneration and function in selected patients undergoing liver resection and transplantation. Whether APV improves liver perfusion and function in cirrhosis is unclear. This study investigated the effect of APV on hepatic haemodynamics and liver function in a rat model of cirrhosis. METHODS: Male Sprague-Dawley rats (250-300 g) were divided into three groups: normal controls (n = 7), cirrhosis with sham laparotomy (sham; n = 7) and cirrhosis with APV (APV; n = 9). Portal venous blood flow, portal vein pressure and hepatic parenchymal microcirculation (HPM) were measured before and after APV. Hepatic parenchymal oxygenation was assessed by near-infrared spectroscopy and hepatocellular injury by standard liver function tests. Measurements were taken at baseline, after APV and 7 days after surgery. RESULTS: APV increased portal blood flow and pressure in cirrhotic rats without altering intrahepatic portal resistance. APV increased the HPM in cirrhotic rats by a mean(s.e.m.) of 28.5(0.1) per cent on day 0 and 54.6(0.1) per cent by day 7 (P = 0.001). Liver tissue oxygenation was increased by APV and the plasma gamma-glutamyltranspeptidase level was reduced (mean(s.e.m.) 6.0(0.5) versus 3.8(0.3) units/l before and after APV respectively; P = 0.006) at day 7. CONCLUSION: APV increases portal blood flow, tissue perfusion and oxygenation in cirrhosis.     

Procalcitonin and macrophage inflammatory protein-1 beta (MIP-1β) in serum and peritoneal fluid of patients with decompensated cirrhosis and spontaneous bacterial peritonitis

PurposeSpontaneous bacterial peritonitis (SBP) is the most frequent infection in patients with cirrhosis causing significant mortality which requires rapid recognition for effective antibiotic therapy, whereas ascitic fluid cultures are frequently negative. The aim of this study was to evaluate the SBP diagnostic efficacy of procalcitonin (PCT) and macrophage inflammatory protein-1 beta (MIP-1β) measured in serum and peritoneal fluid.Material/methodsThirty-two participants with liver cirrhosis and ascites were included into the study (11 females and 21 males, mean age 49.5 ± 11.9 years). The peritoneal fluid and venous blood were collected for routine laboratory examinations and measurements of PCT and MIP-1β. Patients were divided into two groups according to the ascitic absolute polymorphonuclear leukocytes count (≥250 mm⁻³ and <250 mm^–3).ResultsAscites was sterile in 22 participants and SBP was diagnosed in 10 patients. Serum and ascitic levels of PCT and MIP-1β did not correlate with clinical and routine laboratory parameters. MIP-1β in the ascitic fluid was significantly higher in patients with SBP (213 ± 279 pg/ml vs. 66.3 ± 49.8 pg/ml; p = 0.01). The sensitivity and specificity for diagnosis of SBP with ascitic MIP-1β were 80% and 72.7%, respectively (cut-off value 69.4 pg/ml) with AUROC 0.77 (95%CI 0.58–0.96). Serum levels of MIP-1β showed lower diagnostic yield. Serum and ascitic PCT levels were not different in patients with and without SBP.ConclusionsMIP-1β concentration in ascitic fluid may distinguish patients with and without SBP with satisfactory sensitivity and specificity. Chemokines should be further explored for diagnostic use.     

Monitoring of viral load by quantitative plasma PCR during active cytomegalovirus infection of individual liver transplant patients

A quantitative PCR test, the Cobas Amplicor CMV Monitor, was used for the monitoring of viral load in the peripheral blood of 27 individual liver transplant patients and correlated with cytomegalovirus (CMV) pp65 antigenemia. Altogether, 243 specimens were analyzed. During the first 3 months, 20 patients showed PCR positivity which correlated with pp65 antigenemia. Of those, 13 patients developed symptomatic CMV infection 27 to 52 days after transplantation, with a significantly higher peak viral load in PCR and in pp65 assay compared with the seven asymptomatic infections (median 10,200 versus 2,240 copies/ml, P < 0.05, and median 100 versus 30 pp65-positive cells/50,000 leukocytes, P < 0.01). Five were primary infections of D+/R- cases (donor CMV seropositive and recipient seronegative) and demonstrated, except in one case, a high peak viral load (>10,000 copies/ml; range, 10,200 to 21,600 copies, and > or =50 positive cells, range, 50 to 800 cells). The peak viral loads of the six D+/R+ patients with symptomatic infection varied widely (range, 2,290 to 126,000 copies and 50 to 300 positive cells). Two D-/R+ patients developed symptomatic infection with a lower viral load (range, 1,120 to 6,510 copies and 25 to 100 positive cells). All symptomatic infections were successfully treated with ganciclovir. The asymptomatic infections all in D+/R+ patients with low copy numbers (<5,500 copies) were monitored until CMV disappeared. One of the seven PCR-negative patients had one sample with low antigenemia, but the subsequent specimens were all negative. The time-related correlation of the two methods was also good. In summary, quantitative PCR could equally well be used as the CMV pp65 assay for the monitoring of viral load in individual transplant patients.     

A simplified experimental model of large-for-size liver transplantation in pigs

OBJECTIVE:

The ideal ratio between liver graft mass and recipient body weight for liver transplantation in small infants is unknown; however, if this ratio is over 4%, a condition called large-for-size may occur. Experimental models of large-for-size liver transplants have not been described in the literature. In addition, orthotopic liver transplantation is marked by high morbidity and mortality rates in animals due to the clamping of the venous splanchnic system. Therefore, the objective of this study was to create a porcine model of large-for-size liver transplantation with clamping of the supraceliac aorta during the anhepatic phase as an alternative to venovenous bypass.

METHOD:

Fourteen pigs underwent liver transplantation with whole-liver grafts without venovenous bypass and were divided into two experimental groups: the control group, in which the weights of the donors were similar to the weights of the recipients; and the large-for-size group, in which the weights of the donors were nearly 2 times the weights of the recipients. Hemodynamic data, the results of serum biochemical analyses and histological examination of the transplanted livers were collected.

RESULTS:

The mortality rate in both groups was 16.5% (1/7). The animals in the large-for-size group had increased serum levels of potassium, sodium, aspartate aminotransferase and alanine aminotransferase after graft reperfusion. The histological analyses revealed that there were no significant differences between the groups.

CONCLUSION:

This transplant method is a feasible experimental model of large-for-size liver transplantation.     

Serum hepatitis B surface antigen is correlated with intrahepatic total HBV DNA and cccDNA in treatment‐naïve patients with chronic hepatitis B but not in patients with HBV related hepatocellular carcinoma

The aim of the study was to investigate correlations between intrahepatic hepatitis B virus total DNA, covalently closed circular DNA (cccDNA), and serum HBsAg in treatment‐naïve chronic hepatitis B and HBV related hepatocellular carcinoma (HCC). Liver tissues were taken from 42 HBV related HCC and 36 patients with chronic hepatitis B. A fraction of DNA extracted from liver tissue was digested with a plasmid‐safe ATP‐dependent DNase and used for HBV cccDNA detection. The remaining DNA was used for the detection of HBV total DNA and β‐globin, the latter of which is a housekeeping gene and quantified for normalization by real‐time PCR. Quantitation of serum HBsAg was performed by a chemiluminescence assay. Serum HBsAg had positive correlations with serum HBV DNA (r = 0.636, P < 0.001), intrahepatic HBV total DNA (r = 0.519, P = 0.001) and cccDNA (r = 0.733, P < 0.001) in 36 treatment‐naïve chronic hepatitis B, while HBsAg correlated poorly with DNA (r = 0.224, P = 0.210), intrahepatic total DNA and cccDNA in the tumor (r = 0.351, P = 0.031; r = 0.164, P = 0.324, respectively) and non‐tumor (r = 0.237, P = 0.152; r = 0.072, P = 0.667, respectively) liver tissues of 42 HCC. HBV cccDNA and total DNA were significantly higher in liver tissue from chronic hepatitis B than in tumor and non‐tumor of HCC (P < 0.001). Serum HBsAg and HBV DNA were also higher in chronic hepatitis B than in HCC (P < 0.001). It was concluded that levels of serum HBsAg and intrahepatic cccDNA and total DNA were significantly higher in chronic hepatitis B than in HCC, and significant correlations among them were observed in treatment‐naïve chronic hepatitis B but not in HCC. J. Med. Virol. 85:219–227, 2013. © 2012 Wiley Periodicals, Inc.