Takafumi Kumamoto

Influence of Chemotherapy on Liver Regeneration Induced by Portal Vein Embolization or First Hepatectomy of a Staged Procedure for Colorectal Liver Metastases

BackgroundAlthough portal vein embolization (PVE) and staged hepatectomy (StHx), as well as prehepatectomy chemotherapy, have improved the resectability rate of patients with multiple bilobar colorectal liver metastases, the impact of prehepatectomy chemotherapy on liver hypertrophy following PVE and/or StHx has remained unclear.MethodsSixty patients who underwent PVE followed by one-stage hepatectomy and StHx with or without PVE were analyzed. Liver hypertrophy following PVE and/or the first hepatectomy of StHx and the clinical course after final hepatectomy was compared between patients with and without prehepatectomy chemotherapy.ResultsNo difference of volume of the future liver remnant (FLR) before or after the procedure was seen between the chemotherapy group and the nonchemotherapy group. Even in 38 patients who underwent right PVE prior to a planned right hemihepatectomy, the chemotherapy group (n = 14) and the nonchemotherapy group (n = 24) were comparable in terms of volumes of FLR before (P = 0.71) and after (P = 0.29) PVE and posthepatectomy courses. However, the liver hypertrophy ratio for patients showing steatosis in adjacent nonmalignant liver parenchyma, which frequently is induced by chemotherapy, was lower than that for patients without steatosis (P = 0.04).ConclusionsAlthough prehepatectomy chemotherapy did not impair liver hypertrophy, PVE and/or StHx accompanied by prehepatectomy chemotherapy should be performed with particular care to minimize risk of liver failure after the procedure.

Six Consecutive Cases of Successful Adult ABO-Incompatible Living Donor Liver Transplantation: A Proposal for Grading the Severity of Antibody-Mediated Rejection

Background. The clinical symptoms, histological findings, and treatments for antibody-mediated rejection (AMR), which is the leading cause of graft loss in adult ABO-incompatible liver transplantation (ABO-I-LT), have rarely been discussed. Methods. We performed adult living donor ABO-I-LT on six patients. We used anti-CD20 monoclonal antibody combined with plasma exchange preoperatively and intraportal or hepatic-arterial infusion, consisting of prostaglandin E1, corticosteroids, and protease inhibitor postoperatively to prevent AMR. Splenectomy was performed in patients 1, 4, 5 and 6 but not in patients 2 and 3. Weekly liver biopsies were performed after ABO-I-LT. When severe AMR was diagnosed, we performed plasma exchange combined with gamma-globulin bolus infusion (PE+IVIG). Results. In patients 1–3, severe jaundice, rapid decreases in platelet counts, and severe coagulopathy were observed in the early postoperative period. Liver biopsies sampled after the onset of these clinical findings were characterized by severe periportal and lobular hemorrhagic and neutrophil infiltration, suggesting that severe AMR occurred. However, after the initiation of PE+IVIG, AMR was remedied in all three patients. In patients 4–6, severe AMR was not observed. Mild AMR characterized by mild portal hemorrhagic infiltration was observed in patient 4, and moderate AMR characterized by moderate periportal and lobular hemorrhagic infiltration was observed in patient 6. Patients 4–6 did not require PE+IVIG and their clinical course was uneventful. Conclusion. Given the experience of these six patients, we consider that AMR may be graded based on liver biopsy findings including hemorrhagic infiltration and neutrophil infiltration, as well as clinical findings. All six patients are currently doing well.

Imaging and surgical planning for perihilar cholangiocarcinoma

Recent advances in multidetector computed tomography (MDCT) offer several benefits for management of perihilar tumors. Resection planning for perihilar cholangiocarcinoma should consider two factors: safety and curability. Recognition of individual anatomic variations is particularly important for avoiding intraoperative injury. In particular, hepatic arterial variations often restrict resection procedures. Extent of both longitudinal and vertical invasion by biliary tumors can be estimated from multiplanar reconstruction (MPR) images. Longitudinal extent of resection can be planned based on two anatomic landmarks, the U point and the P point, readily identifiable in preoperative 3‐dimensional (3D) images and by intraoperative inspection. Concerning vertical invasion, when direct vascular invasion is suspected from a finding of attachment of tumor and vessels such as portal veins and/or hepatic arteries without a thin low‐density plane of separation shown by MPR, these vessels should be resected en bloc with the tumor. Surgical team members can plan and simulate details of vascular resection and reconstruction using 3D images. Reduced operative morbidity and increased R0 resection rates are expected because of better planning of procedures. These techniques soon may increase long‐term survival for patients with perihilar cholangiocarcinoma.

The Tumor Burden Score: A New “Metro-ticket” Prognostic Tool For Colorectal Liver Metastases Based on Tumor Size and Number of Tumors

Objective: To apply the principles of the Metro-ticket paradigm to develop a prognostic model for patients undergoing hepatic resection of colorectal liver metastasis (CRLM). Background: Whereas the hepatocellular “Metro-ticket” prognostic tool utilizes a continuum of tumor size and number, a similar concept of a CRLM Metro-ticket paradigm has not been investigated. Methods: Tumor Burden Score (TBS) was defined using distance from the origin on a Cartesian plane incorporating maximum tumor size (x-axis) and number of lesions (y-axis). The discriminatory power [area under the curve (AUC)] and goodness-of-fit (Akaike information criteria) of the TBS model versus standard tumor morphology categorization were assessed. The TBS model was validated using 2 external cohorts from Asia and Europe. Results: TBS (AUC 0.669) out-performed both maximum tumor size (AUC 0.619) and number of tumors (AUC 0.595) in predicting overall survival (OS) (P < 0.05). As TBS increased, survival incrementally worsened (5-year OS: zone 1, zone 2, and zone 3—68.9%, 49.4%, and 25.5%; P < 0.05). The stratification of survival based on traditional tumor size and number cut-off criteria was poor. Specifically, 5-year survival for patients in category 1, category 2, and category 3 was 58.3%, 45.5%, and 50.6%, respectively (P > 0.05). The corrected Akaike score information criteria value of the TBS model (2865) was lower than the traditional tumor morphologic categorization model (2905). Survival analysis revealed excellent prognostic discrimination for the TBS model among patients in both external cohorts (P< 0.05). Conclusions: An externally validated “Metro-ticket” TBS model had excellent prognostic discriminatory power. TBS may be an accurate tool to account for the impact of tumor morphology on long-term survival among patients undergoing resection of CRLM.

Transfection of NF-κB Decoy Oligodeoxynucleotides into Macrophages Reduces Murine Fatal Liver Failure After Excessive Hepatectomy

BACKGROUND Macrophages play an important role in the initiation of hypercytokinemia, which is involved in the development of liver failure after excessive hepatectomy. This study was aimed at evaluating whether the selective suppression of nuclear factor kappa B (NF-kappaB) in macrophages by decoy oligodeoxynucleotides (ODN) could prevent liver failure after excessive hepatectomy. MATERIALS AND METHODS Ninety percent hepatectomy was performed in 8-wk-old mice. NF-kappaB/decoy/ODN was transfected into the liver by the hemagglutinating virus of Japan-liposome method. The survival rate, serum levels of interleukin (IL)-1beta IL-6, and tumor necrosis factor-alpha, and the histological findings in the remnant liver were compared between the 90%-hepatectomized mice transfected with the decoy ODN (decoy group) and the 90%-hepatectomized mice injected with saline (control group). RESULT The control group mice died within 48 h of the operation, while the survival rate in the decoy group at 48 h after the operation was 35%, and at 2 wk, 15%. The serum levels of all cytokines were significantly lower in the decoy group than in the control group. The number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling-positive cells in the remnant liver was smaller in the decoy group. CONCLUSION Transfection of NF-kappaB/decoy/ODN reduces fatal liver failure in mice after excessive hepatectomy by suppressing hypercytokinemia, but offers only a low rate of survival.

Prostaglandin E1 prevents liver failure after excessive hepatectomy in the rat by up-regulating Cyclin C, Cyclin D1, and Bclxl.

Prostaglandin E1 (PGE1) has wide‐ranging effects on cytoprotection and may play a role in preventing liver failure following excessive hepatectomy. We examined the effect of PGE1 on hepatocyte apoptosis and liver regeneration after 95% hepatectomy in a rat model. PGE1 or vehicle was intravenously administered 30 minutes before and during hepatectomy. The extent of hepatocyte injury was evaluated by serum alanine aminotransferase and aspartate aminotransferase levels. To evaluate hepatocyte apoptosis and liver regeneration, terminal deoxynucleotidyl transferase dUTP nick end labeling staining and Ki67 labeling were performed. The expression levels of Bcl‐xL, Bcl‐2, Bax, Cyclin C, Cyclin D1, Cyclin E, p21, transforming growth factor‐β, plasminogen activator inhibitor‐1, and glyceraldehyde‐2‐phosphate dehydrogenase mRNA were also examined by reverse transcription‐polymerase chain reaction. Survival was improved in the PGE1 group (26.6%), whereas all rats in the vehicle group died within 60 hours. PGE1 significantly suppressed the release of alanine aminotransferase and aspartate aminotransferase at 12 hours postoperatively. Pretreatment with PGE1 significantly increased the Ki67‐positive cell count and decreased the terminal deoxynucleotidyl transferase dUTP nick end labeling positive cell count after hepatectomy, and also significantly increased the expression levels of Bcl‐xL, Cyclin C, and Cyclin D1. Our results suggest that pretreatment with PGE1 may increase survival following hepatectomy by salvaging the remaining liver tissue, which it does by inhibiting apoptosis and stimulating hepatocyte proliferation.

Two-stage hepatectomy with effective perioperative chemotherapy does not induce tumor growth or growth factor expression in liver metastases from colorectal cancer

BACKGROUND Although short- and long-term results have been described in previous reports of 2-stage hepatectomy, growth activity in metastases resected at the first versus second hepatectomy has not been compared. METHODS We analyzed growth activity of liver metastases from colorectal cancers resected at first and second hepatectomy by real-time reverse-transcription polymerase chain reaction and immunohistochemistry in 21 patients undergoing 2-stage hepatectomy to justify the 2-stage approach. RESULTS Of 24 patients planned to undergo 2-stage hepatectomy for colorectal liver metastases, 21 had completion of both stages. Although maximum tumor size and serum carcinoembryonic antigen before and after the first procedure did not differ, volume of the future liver remnant increased after the first procedure. Ki67 and proliferating cell nuclear antigen positivity rates were comparable between initially and subsequently resected tumors (P = .09 and P = .83, respectively). Expression of mRNA (relative to glyceraldehyde-3-phosphate dehydrogenase mRNA) in initially versus subsequently resected tumors for cyclin D1 (4.27 ± 1.29 vs 6.52 ± 2.23; P = .90), cyclin E1 (24.18 ± 16.81 vs 10.53 ± 2.28; P = .60), hepatocyte growth factor (3.16 ± 1.42 vs 0.58 ± 0.15; P = .11), basic fibroblast growth factor (5.42 ± 1.54 vs 5.92 ± 3.33; P = .13), epidermal growth factor (19.56 ± 14.76 vs 9.07 ± 4.54; P = .74), and transforming growth factor-α (2.63 ± 1.02 vs 2.07 ± 1.15; P = .29) showed no differences between the 2 time points. CONCLUSION Two-stage hepatectomy did not seem to induce tumor growth activity or growth factor expression. The 2-stage strategy in combination with effective preoperative chemotherapy is a valuable strategy for colorectal metastases.

Major liver resection stimulates stromal recruitment and metastasis compared with repeated minor resection

BACKGROUND The present study examined the effects of types of liver resection on the growth of liver and lung metastases. METHODS Experimental liver metastases were established by spleen injection of the Colon 26 murine adenocarcinoma cell line expressing green fluorescent protein (GFP) into transgenic nude mice expressing red fluorescent protein. Experimental lung metastases were established by tail-vein injection with Colon 26-GFP. Three days after cell injection, groups of mice underwent (35% + 35% repeated minor resection versus 70% major resection versus 35% minor resection). Metastatic tumor growth was measured by color-coded fluorescence imaging of the GFP-expressing cancer cells and red fluorescent protein-expressing stroma. RESULTS Although major and repeated minor resection removed the same total volume of liver parenchyma, the 2 procedures had very different effects on metastatic tumor growth. Major resection stimulated liver and lung metastatic growth and recruitment of host-derived stroma compared with repeated minor resection. Repeated minor resection did not stimulate metastasis or stromal recruitment. No significant difference was found in liver regeneration between the 2 groups. Host-derived stroma density, which was stimulated by major resection compared with repeated minor resection, might stimulate growth in the liver-metastatic tumor. Transforming growth factor-β is also preferentially stimulated by major resection and might play a role in stromal and metastasis stimulation. CONCLUSIONS The results of the present study indicate that when liver resection is necessary, repeated minor liver resection will be superior to major liver resection, because major resection, unlike repeated minor resection, stimulates metastasis. This should be taken into consideration in clinical situations that require liver resection.

Severity and prognostic assessment of the endotoxin activity assay in biliary tract infection

Acute cholangitis and cholecystitis (AC) often progress to severe septic conditions. We evaluated the endotoxin activity assay (EAA) for assessment and prediction of the severity of AC.

A Survival Case of ABO-Incompatible Liver Transplantation Complicated With Severe Preoperative Infection and Subsequent Overwhelming Postsplenectomy Infection

A 47-year-old Japanese man was transferred to our hospital because of acute-on-chronic hepatitis B virus infection. On admission, he was suffering from sepsis due to a catheter infection and respiratory failure caused by pulmonary edema and pneumonia, but, as a result of preoperative intensive care, we avoided septic shock. ABO-incompatible liver transplantation (ABO-I-LT) was performed. In accordance with our ABO-I-LT protocol, we administered, rituximab and performed plasma exchange, splenectomy as well as hepatic artery infusion. The patient was discharged 80 days after living donor transplantation (LDLT). However, 136 days after LDLT, he experienced recurrent respiratory failure due to severe pneumonia. At that time, the CD19(+) B-cell count in the peripheral blood flow remained below 1%. We suspected a mixed infection involving Streptococcus pneumonia, Pneumocystis carinii, and fungus. The cause of the complication was overwhelming postsplenectomy infection (OPSI). We started administration of sulfamethoxazole and trimethoprim, ciprofloxacin hydrochloride, and micafungin sodium therapy as well as gamma-globulin. Oxygenation improved gradually; the patient was discharged at 41 days after re-admission. Although this patient survived the OPSI, it was clear that some aspects of the ABO-I-LT protocol should also be altered.