Safety evaluation of immune-cell therapy for malignant tumor in the Cancer Immune-cell Therapy Evaluation Group (CITEG).

BACKGROUND AIMS: With the aim of strengthening the scientific evidence of immune-cell therapy for cancer and further examining its safety, in October 2015, our hospital jointly established the Cancer Immune-Cell Therapy Evaluation Group (CITEG) with 39 medical facilities nationwide. METHODS: Medical information, such as patients' background characteristics, clinical efficacy and therapeutic cell types obtained from each facility, has been accumulated, analyzed and evaluated by CITEG. In this prospective study, we analyzed the adverse events associated with immune-cell therapy until the end of September 2022, and we presented our interim safety evaluation. RESULTS: A total of 3839 patients with malignant tumor were treated with immune-cell therapy, with a median age of 64 years (range, 13-97 years) and a male-to-female ratio of 1:1.08 (1846:1993). Most patients' performance status was 0 or 1 (86.8%) at the first visit, and 3234 cases (84.2%) were advanced or recurrent cases, which accounted for the majority. The total number of administrations reported in CITEG was 31890, of which 960 (3.0%) showed adverse events. The numbers of adverse events caused by treatment were 363 (1.8%) of 19661 administrations of αßT cell therapy, 9 of 845 administrations of γδT-cell therapy (1.1%) and 10 of 626 administrations of natural killer cell therapy (1.6%). The number of adverse events caused by dendritic cell (DC) vaccine therapy was 578 of 10748 administrations (5.4%), which was significantly larger than those for other treatments. Multivariate analysis revealed that αßT cell therapy had a significantly greater risk of adverse events at performance status 1 or higher, and patients younger than 64 years, women or adjuvant immune-cell therapy had a greater risk of adverse events in DC vaccine therapy. Injection-site reactions were the most frequently reported adverse events, with 449 events, the majority of which were associated with DC vaccine therapy. Among all other adverse events, fever (228 events), fatigue (141 events) and itching (131 events) were frequently reported. In contrast, three patients had adverse events (fever, abdominal pain and interstitial pneumonia) that required hospitalization, although they were weakly related to this therapy; rather, it was considered to be the effect of treatment for the primary disease. CONCLUSIONS: Immune-cell therapy for cancer was considered to be a safe treatment without serious adverse events.

Laparoscopic surgery in the management of hypersplenism and esophagogastric varices: our initial experiences.

BACKGROUND: Owing to recent advances in laparoscopic surgery, devascularization of the upper stomach with splenectomy (Spx) or Hassab's procedure (Has) as well as Spx for patients with portal hypertension have been attempted laparoscopically in some facilities, the results of which have been reported. This article describes the authors' surgical techniques and their results. METHODS: Between August 1999 and August 2010, the authors treated 110 cases of portal hypertension with Spx or Has. Among these patients, 56 who simultaneously underwent additional major operations were eliminated from the study, leaving 54 patients eligible. They included 38 with open surgeries and 16 with laparoscopic surgeries, which consisted of 10 splenectomies and 6 Has operations. The perioperative data for the 2 groups were compared. RESULTS: Purely laparoscopic Spx (L-Spx) was completed for 9 patients. Conversion from laparoscopic to hand-assisted laparoscopic surgery (HALS) was necessary for 1 patient because of poor visualization. Operative time was significantly longer in L-Spx than in the open method. Postoperative hospital stays were shorter for L-Spx. HALS was used for all 6 laparoscopic Has patients. There was no conversion from the laparoscopic to the open method. Operative time was significantly longer for laparoscopic Has than for open Has. Postoperative complication rates were significantly reduced, and postoperative hospital stays were significantly shorter for laparoscopic Has. CONCLUSIONS: Although the data are still preliminary, laparoscopic surgery for patients with portal hypertension may prove to be a successful strategy.

Peroxisome proliferator-activated receptor α (PPARα) mRNA expression in human hepatocellular carcinoma tissue and non-cancerous liver tissue.

BACKGROUND: Peroxisome proliferator-activated receptor α (PPARα) regulates lipid metabolism in the liver. It is unclear, however, how this receptor changes in liver cancer tissue. On the other hand, mouse carcinogenicity studies showed that PPARα is necessary for the development of liver cancer induced by peroxisome proliferators, and the relationship between PPARα and the development of liver cancer have been the focus of considerable attention. There have been no reports, however, demonstrating that PPARα is involved in the development of human liver cancer. METHODS: The subjects were 10 patients who underwent hepatectomy for hepatocellular carcinoma. We assessed the expression of PPARα mRNA in human hepatocellular carcinoma tissue and non-cancerous tissue, as well as the expression of target genes of PPARα, carnitine palmitoyltransferase 1A and cyclin D1 mRNAs. We also evaluated glyceraldehyde 3-phosphate dehydrogenase, a key enzyme in the glycolytic system. RESULTS: The amounts of PPARα, carnitine palmitoyltransferase 1A and glyceraldehyde 3-phosphate dehydrogenase mRNA in cancerous sections were significantly increased compared to those in non-cancerous sections. The level of cyclin D1 mRNA tends to be higher in cancerous than non-cancerous sections. Although there was a significant correlation between the levels of PPARα mRNA and cyclin D1 mRNA in both sections, however the correlation was higher in cancerous sections. CONCLUSION: The present investigation indicated increased expression of PPARα mRNA and mRNAs for PPARα target genes in human hepatocellular carcinoma. These results might be associated with its carcinogenesis and characteristic features of energy production.

Risk factors for surgical site infection after hepatectomy for hepatocellular carcinoma.

BACKGROUND/AIMS: Clarification of risk factors for surgical site infection (SSI) after hepatectomy for hepatocellular carcinoma (HCC) is important for improvement of surgical outcome. METHODOLOGY: The incidences of SSI under various states were evaluated in 171 patients who underwent hepatectomy for HCC. Univariate and logistic regression analysis were performed to identify risk factors for SSI. The relation between postoperative hepatic failure and SSI was also evaluated. Data were analyzed using Stat View 5.0. RESULTS: SSI occurred in 36 patients (21%). Of the 36 patients with SSI, organ/space SSI occurred in 27. Bile leakage occurred in 22 patients, of which 18 patients had accompanying organ/space SSI. Postoperative hepatic failure occurred in 6 patients, and 5 of these 6 patients also had organ/ space SSI. The postoperative mortality rate was significantly higher in the patients with organ/space SSI (3 of 27 patients, 11%) than in those without organ/space SSI (1 of 144 patients, 0.7%). Logistic regression analysis revealed bile leakage and blood loss to be independent right factors for occurrence of organ/space SSI. CONCLUSIONS: Bile leakage frequently causes organ/space SSI after hepatectomy. Organ/space SSI is closely related to postoperative hepatic failure and death. Prevention of bile leakage is important to improve the surgical outcome of hepatectomy for HCC.

[A case of lumbar metastases from rectal cancer successfully treated by UFT plus oral leucovorin (LV) therapy].

A 63-year-old man had undergone a low anterior resection for rectal cancer with multiple liver metastases. Oral UFT (450 mg/day) administration alone was started after the operation. After 6 months post operatively, the patient was diagnosed as anastomosis recurrence because of ileus by abdominal X-ray. Transverse loop colostomy was performed by emergency surgery. After surgery, he suffered from paraplegia for lumbar vertebrae metastases. UFT+LV therapy was started. After chemotherapy a significant reduction of the lymph node and liver metastases and an apparent decrease in CEA and CA19-9 were observed. The patient left the hospital and showed no signs of tumor exacerbation for three months. The patient died of aggravation of primary disease afterwards. The therapy was safe and effective, and has successfully maintained the quality of life (QOL) of this patient.

Regulation of branched-chain amino acid metabolism and pharmacological effects of branched-chain amino acids.

Significant evidence of the pharmacological and physiological effects of branched-chain amino acids (BCAA) has accumulated, attracting the interest of not only clinicians but also basic medical researchers. We summarize here the characteristic features of BCAA catabolism, focusing on the initial two enzymes in the pathway, branched-chain aminotransferase and branched-chain alpha-keto acid dehydrogenase complex. In addition, we describe a unique characteristic of the valine catabolic pathway. Finally, we present evidence obtained in animal studies that indicates that BCAA treatment may be appropriate for liver cirrhosis, but not acute liver failure.

[A case of giant hepatocellular carcinoma treatable with radio frequent ablation therapy after effective UFT administration].

A 71-year-old man was diagnosed with giant hepatocellular carcinoma (HCC) and hepatitis C cirrhosis at a nearby hospital. Image diagnosis showed no other metastasis, but the tumor was very huge with daughter nodules in the bilateral lobe of the liver. He was thus treated by oral administration of UFT (300 mg/day). Two months later, the giant liver tumor had shrunk remarkably, and the daughter tumors had disappeared. Eight months later, the levels of serum AFP and PIVKA-II had also reduced remarkably. Twelve months following the first treatment, the levels of both serum AFP and PIVKA-II began increasing again, and he was referred to our hospital. CT showed 2 liver tumors, 1 of which showed viability with moderately differentiated hepatocellular carcinoma and the other evidencing necrosis histologically. Radio frequency ablation therapy was performed for 2 tumors by open laparotomy. It was considered that administration of UFT is a useful and safe therapy for far advanced HCC.