Kazuaki Shimada

Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial

BACKGROUND Postsurgical recurrence of hepatocellular carcinoma (HCC) is frequent and fatal. Adoptive immunotherapy is active against HCC. We assessed whether postoperative immunotherapy could lower the frequency of recurrence. METHODS Between 1992 and 1995, we did a randomised trial in which 150 patients who had undergone curative resection for HCC were assigned adoptive immunotherapy (n=76) or no adjuvant treatment (n=74). Autologous lymphocytes activated vitro with recombinant interleukin-2 and antibody to CD3 were infused five times during the first 6 months. Primary endpoints were time to first recurrence and recurrence-free survival and analyses were by intention to treat. FINDINGS 76 patients received 370 (97%) of 380 scheduled lymphocyte infusions (mean cell number per patient 7.1x10(10) [SD 2.1]; CD3 and HLA-DR cells 78% [16]), and none had grade 3 or 4 adverse events. After a median follow-up of 4.4 years (range 0.2-6.7), adoptive immunotherapy decreased the frequency of recurrence by 18% compared with controls (45 [59%] vs 57 [77%]) [corrected] patients. Time to first recurrence in the immunotherapy group was significantly longer than that in the control group (48% [37-59] vs 33% [22-43] at 3 years, 38% [22-54] vs 22% [11-34] at 5 years; p=0.008). The immunotherapy group had significantly longer recurrence-free survival (p=0.01) and disease-specific survival (p=0.04) than the control group. Overall survival did not differ significantly between groups (p=0.09). INTERPRETATION Adoptive immunotherapy is a safe, feasible treatment that can lower recurrence and improve recurrence-free outcomes after surgery for HCC.

Plasma (1→3)-β-D-glucan measurement in diagnosis of invasive deep mycosis and fungal febrile episodes

(1-->3)-beta-D-glucan is a characteristic fungal cell-wall constituent. To assess the clinical usefulness of this glucan in screening for invasive fungal infection or fungal febrile episodes, we measured the plasma concentration at the time of routine blood culture in 202 febrile episodes by means of factor G, a horseshoe-crab coagulation enzyme that is extremely sensitive to this polysaccharide. With a plasma cut-off value of 20 pg/mL, 37 of 41 episodes of definite fungal infections (confirmed at necropsy or by microbiology) had positive results (sensitivity 90%). All of 59 episodes of non-fungal infections, tumour fever, or collagen diseases had concentrations below the cut-off value (specificity 100%). Of 102 episodes of fever of unknown origin, 26 had plasma glucan concentrations of more than 20 pg/mL. With those 102 cases taken as non-fungal infections, the positive predictive value of the test was estimated as 59% (37/63), the negative predictive value as 97% (135/139), and the efficiency as 85% (172/202). The positive predictive value should improve if there were a sensitive gold standard that could discriminate fungal from non-fungal infections. Causative fungi included candida, aspergillus, cryptococcus, and trichosporon. Determination of plasma (1-->3)-beta-D-glucan with factor G is a highly sensitive and specific test for invasive deep mycosis and fungal febrile episodes, and will substantially benefit immunocompromised patients.

Ocean acidification reduces sperm flagellar motility in broadcast spawning reef invertebrates.

Ocean acidification is now recognized as a threat to marine ecosystems; however, the effect of ocean acidification on fertilization in marine organisms is still largely unknown. In this study, we focused on sperm flagellar motility in broadcast spawning reef invertebrates (a coral and a sea cucumber). Below pH 7.7, the pH predicted to occur within the next 100 years, sperm flagellar motility was seriously impaired in these organisms. Considering that sperm flagellar motility is indispensable for transporting the paternal haploid genome for fertilization, fertilization taking place in seawater may decline in the not too distant future. Urgent surveys are necessary for a better understanding of the physiological consequences of ocean acidification on sperm flagellar motility in a wide range of marine invertebrates.

Effects of acidified seawater on early life stages of scleractinian corals (Genus Acropora)

Ocean acidification, caused by increased atmospheric carbon dioxide (CO2) concentrations, is currently an important environmental problem. It is therefore necessary to investigate the effects of ocean acidification on all life stages of a wide range of marine organisms. However, few studies have examined the effects of increased CO2 on early life stages of organisms, including corals. Using a range of pH values (pH 7.3, 7.6, and 8.0) in manipulative duplicate aquarium experiments, we have evaluated the effects of increased CO2 on early life stages (larval and polyp stages) of Acropora spp. with the aim of estimating CO2 tolerance thresholds at these stages. Larval survival rates did not differ significantly between the reduced pH and control conditions. In contrast, polyp growth and algal infection rates were significantly decreased at reduced pH levels compared to control conditions. These results suggest that future ocean acidification may lead to reduced primary polyp growth and delayed establishment of symbiosis. Stress exposure experiments using longer experimental time scales and lower levels of CO2 concentrations than those used in this study are needed to establish the threshold of CO2 emissions required to sustain coral reef ecosystems.

Papillary Function of Patients with Juxtapapillary Duodenal Diverticulum Consideration of Pathogenesis of Common Bile Duct Stones

The papillary function of cholelithiasis patients with and without juxtapapillary duodenal diverticulum (JPDD) was examined manometrically. The papillary function was evaluated on the basis of dP(0.5), the pressure difference between the resting pressure and the perfusion pressure. Patients with a dP(0.5) less than 5 cm H2O were considered to have papillary dysfunction. In cholecystolithiasis patients the incidence of papillary dysfunction was significantly greater in those with JPDD than in those without JPDD (p less than 0.05). However, there was no significant difference in dP(0.5) between those with and without JDPP because of the small number of patients involved. Also, in patients with choledocholithiasis there was no difference in the papillary function between those with and without JPDD. All who had JPDD showed papillary dysfunction. From our results, JPDD is suspected to have an important role in causing papillary dysfunction or loss of papillary muscle tone. This dysfunction may be closely connected with the formation of common bile duct stones.

Randomized clinical trial of hepatectomy using intermittent pedicle occlusion with ischaemic intervals of 15 versus 30 minutes

The optimal ischaemic interval during hepatectomy with intermittent pedicle occlusion (IPO) remains to be established. The aim of the present randomized clinical trial was to compare the short‐term outcome of hepatectomy using IPO with an ischaemic interval of 15 versus 30 min.

Extended right hemihepatectomy for gallbladder carcinoma involving the hepatic hilum

Major hemihepatectomy for advanced gallbladder carcinoma remains controversial as it is associated with serious postoperative complications and poor prognosis.

Left hepatic trisectionectomy for advanced perihilar cholangiocarcinoma.

Data on outcomes of left hepatic trisectionectomy (LT) for perihilar cholangiocarcinoma are limited. The aim of this study was to clarify short‐ and long‐term outcomes of LT for perihilar cholangiocarcinoma.

Management of gallstones in cirrhotic patients

Abstract34 cirrhotic patients who underwent either cholecystectomy alone or in conjunction with common duct exploration were retrospectively reviewed. In Child A and B patients morbidity was low and there were no postoperative deaths. However, all patients who underwent additional cholecystectomy during the non-shunting operation for esophageal varices required blood transfusion. Cholecystectomy in Child C patients is frequently associated with considerable intraoperative bleeding and subsequent postoperative complications. In the 23 patients who were not operated upon for gallstones, no patients developed symptomatic biliary disease. Ultrasonographically, most of these gallstones were strongly suspected to be black stones. Elective surgical intervention for symptomatic Child A and B patients would normally be warranted, but hemorrhage and resulting complications due to additional cholecystectomy for asymptomatic gallstones during the non-shunting operation should be minimized. An additional cholecystectomy should be considered, provided such a cholecystectomy is thought to be easily performed judging from the degree of development of collateral circulation around the hepatoduodenal ligament and unless black stones are suspected ultrasonographically. For symptomatic gallstones in Child C patients every type of medical treatment should be attempted. After considering the bleeding tendency or ascites, percutaneous transhepatic gallbladder drainage is considered to be one of the safest treatments.

Clinicopathological features of recurrent primary liver cancer in Japan

In this chapter, the clinicopathological features of recurrent hepatocellular carcinoma (HCC), especially after hepatectomy, are described along with a review of some articles and the author’s experiences.