Accumulation of activated invariant natural killer T cells in the tumor microenvironment after α-galactosylceramide-pulsed antigen presenting cells.

PURPOSE: The intravenous administration of α-Galactosylceramide (α-GalCer)-pulsed antigen presenting cells (APCs) is well tolerated and the increased IFN-γ producing cells in the peripheral blood after the treatment appeared to be associated with prolonged survival. An exploratory study protocol was designed with the preoperative administration of α-GalCer-pulsed APCs to clarify the mechanisms of these findings, while especially focusing on the precise tumor site. METHODS: Patients with operable advanced lung cancer received an intravenous injection of α-GalCer-pulsed APCs before surgery. The resected lung and tumor infiltrating lymphocytes (TILs) as well as peripheral blood mononuclear cells were collected and the invariant NKT (iNKT) cell-specific immune responses were analyzed. RESULTS: Four patients completed the study protocol. We observed a significant increase in iNKT cell numbers in the TILs and augmented IFN-γ production by the α-GalCer-stimulated TILs. CONCLUSION: The administration of α-GalCer-pulsed APCs successfully induced the dramatic infiltration and activation of iNKT cells in the tumor microenvironment.

Hepatic arterial infusion chemotherapy in combination with pegylated interferon-α-2b for advanced hepatocellular carcinoma.

BACKGROUND/AIMS: We previously reported that combination therapy comprising hepatic arterial infusion chemotherapy (HAIC) with 3 drugs, namely, cisplatin (CDDP), 5-fluorouracil (5-FU) (low-dose FP) and isovorin and interferon (IFN)-α-2b was not beneficial for patients with advanced hepatocellular carcinoma (HCC). In this study, we investigated the efficacy of combination therapy comprising HAIC and pegylated interferon (PEG-IFN)-α-2b in advanced HCC patients by comparing our results with previous data. METHODOLOGY: From a total of 29 patients, 12 received HAIC and PEGIFN- α-2b (PEG-IFN group) and 17 received HAIC and IFN-α-2b (IFN group). There were no significant differences in clinical characteristics between the 2 groups. RESULTS: The response rate was 33.3% (complete response (CR)=1; partial response (PR)=3) in the PEGIFN group and 47.1% (PR=8) in the IFN group. The 1-, 2- and 3-year cumulative survival rates were 50%, 25% and 8%, respectively, in the PEG-IFN group, whereas they were 53%, 18% and 12%, respectively, in the IFN group. There were no significant differences in the response rate (p=0.251) and survival (p=0.938) between the two groups. CONCLUSIONS: We found that combination therapy comprising HAIC using low-dose FP with isovorin and PEG-IFN-α-2b was not beneficial for advanced HCC.

A phase I-II study of alpha-galactosylceramide-pulsed IL-2/GM-CSF-cultured peripheral blood mononuclear cells in patients with advanced and recurrent non-small cell lung cancer.

To evaluate the safety, immune responses, and antitumor responses after the administration of alpha-galactosylceramide (alphaGalCer) KRN7000-pulsed PBMC cultured with IL-2 and GM-CSF (IL-2/GM-CSF-cultured PBMCs), a phase I-II study in patients with non-small cell lung cancer was conducted. Patients with advanced non-small cell lung cancer or recurrent lung cancer refractory to the standard therapy were eligible. alphaGalCer-pulsed IL-2/GM-CSF-cultured PBMCs (1 x 10(9)/m(2)) were i.v. administered four times. Immune responses were monitored weekly. Twenty-three patients were enrolled in this study and 17 cases (73.9%) completed. No severe adverse event related to the treatment was observed. After the injection of alphaGalCer-pulsed IL-2/GM-CSF-cultured PBMCs, an increased number of IFN-gamma-producing cells in the peripheral blood were detected in 10 patients (58.8%). Five cases remained as stable disease, and the remaining 12 cases were evaluated as progressive disease. The estimated median survival time (MST) of the 17 cases was 18.6 mo (range, 3.8 to 36.3 mo). Ten patients who displayed increased IFN-gamma-producing cells (> or =2-fold) showed prolonged MST (31.9 mo; range, 14.5 to 36.3 mo) as compared with poor-responder patients (n = 7) MST (9.7 mo; range, 3.8 to 25.0 mo) (log-rank test, p = 0.0015). The administration of alphaGalCer-pulsed IL-2/GM-CSF-cultured PBMCs was well tolerated and was accompanied by the successful induction of NKT cell-dependent immune responses. The increased IFN-gamma-producing cells that result from alphaGalCer stimulation in PBMCs were significantly associated with prolonged MST. These results are encouraging and warrant further evaluation for survival benefit of this immunotherapy.

A set of genes associated with the interferon-γ response of lung cancer patients undergoing α-galactosylceramide-pulsed dendritic cell therapy.

Invariant natural killer T (iNKT) cells possess potent antitumor effects after activation with a specific glycolipid antigen, α-galactosylceramide (αGalCer). A phase I-II clinical study of αGalCer-pulsed dendritic cells (DC) to activate endogenous iNKT cells was previously performed in patients with non-small-cell lung cancer (NSCLC). In this clinical trial, the patients with increased interferon-γ (IFN-γ) production (>two-fold) in PBMC after the DC treatment (good responder group) experienced a prolonged overall survival time in comparison with the poor responder group. We extended the previous study and performed a microarray-based gene expression analysis using peripheral blood CD56(+) cells and CD56(-) CD3(+) T cells from patients enrolled in the above-mentioned clinical study. We sought to identify any biomarkers associated with the immune responses in this immunotherapy trial. Six patient samples corresponding to three subjects in the good responder group and three subjects in the poor responder group were included in the microarray analysis. Genes differentially expressed between pre-treatment and post-treatment samples were selected for analysis. Subsequently, genes that were only expressed in the good responder group or poor responder group were chosen. After these procedures, four selected genes were quantified by reverse transcriptase-polymerase chain reaction in another eight patient samples, and two genes, LTB4DH and DPYSL3, were confirmed to be candidate genes for the predictor of a good immune response. The expression profile of these two genes may be associated with the responsiveness of IFN-γ production after αGalCer-pulsed DC treatment.

[A case report of internal hernia through an abnormal defect in the broad ligament of the uterus].

We report a rare case of internal hernia through an abnormal defect in the broad ligament of the uterus. A 49-year-old woman, without any previous surgery, was admitted because of vomiting and lower abdominal pain. Three days after admission a small amount of small intestinal gas was pointed out on her plain abdominal X-ray film. An enema examination by ileus tube revealed a pooling of gastrografin on the left side of the pelvic cavity, showing an obstruction of the ileum. Therefore, an emergency operation was performed, whereupon we found an abnormal defect in the left broad ligament of the uterus. This case describes an internal hernia through an abnormal defect in a female ileus patient without a history of surgery.

Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma: Is the addition of subcutaneous interferon-alpha-2b beneficial?

AIM: We previously reported the benefits of hepatic arterial infusion chemotherapy (HAIC) using cisplatin (CDDP), 5-fluorouracil (5-FU) [low-dose FP], and leucovorin/isovorin for advanced hepatocellular carcinoma (HCC). In this study, we investigated the efficacy of combination therapy with HAIC and subcutaneous interferon (IFN)- alpha-2b in patients with advanced HCC. METHODS: Of the 48 patients, 31 received low-dose FP with leucovorin/isovorin (HAIC group) and 17 received combination therapy comprising low-dose FP with isovorin and subcutaneous IFN-alpha-2b (combination group). Prognostic factors were evaluated by univariate and multivariate analyses of the patient and the disease characteristics. RESULTS: There were no significant differences in the response rate (patients with complete or partial response/all patients; P = 0.736) and survival (P = 0.399) between both groups. Univariate analysis revealed that IFN therapy was not a significant prognostic factor. Multivariate analysis showed 3 variables, namely, Child-Pugh score (P = 0.010), alpha-fetoprotein level (P = 0.0047), and additional therapy (P = 0.002), to be significant prognostic factors. CONCLUSIONS: We considered that combination therapy with HAIC and subcutaneous interferon (IFN)-alpha-2b was not beneficial for advanced HCC.

Giant cavernous hepatic hemangioma shrunk by use of sorafenib.

Here we report a case of a 76-year-old man with a giant cavernous hepatic hemangioma of more than 20 cm in diameter. Since the hepatic hemangioma was actually growing and might possibly rupture and he complained of abdominal symptoms, we decided to perform interventional therapy. First we performed transcatheter arterial embolization (TAE) of the hepatic arteries. However, since this was not sufficiently effective, we added sorafenib (600 mg/day). As a result, the tumor shrank with symptomatic improvement. Subsequently, an adverse event occurred, and we suspended the sorafenib therapy. Then, the tumor began to grow, and we resumed administering sorafenib at 400 mg/day. The tumor shrank again, and we continued the sorafenib therapy thereafter. The tumor shrinkage, although possibly induced by the effect of TAE, is considered primarily due to the effect of treatment with sorafenib, because (1) TAE did not sufficiently reduce the blood supply to the inside of the tumor; (2) other tumors shrank in the area not targeted by TAE; and (3) the tumor grew during suspension of sorafenib therapy and shrank again after resuming the treatment.

Effect of a late evening snack using branched-chain amino acid-enriched nutrients in patients undergoing hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma.

AIM: A late evening snack (LES) is recommended for protein-energy malnutrition in patients with liver cirrhosis. This study investigated energy metabolism in cirrhotic patients with hepatocellular carcinoma (HCC) and the effects of LES using a branched-chain amino acid (BCAA)-enriched nutrient in cirrhotic patients with advanced HCC undergoing hepatic arterial infusion chemotherapy (HAIC). METHODS: Energy metabolism was measured using indirect calorimetry for 10 cirrhotic patients without HCC and 36 patients with various stages of HCC. Next, in 23 cirrhotic patients with advanced HCC undergoing HAIC, 13 patients received LES (LES group), and 10 patients received ordinary food (control group). Changes in energy metabolism and glucose tolerance were examined using indirect calorimetry and 75-g oral glucose tolerance test (OGTT) before and after 1 cycle of treatment. RESULTS: Non-protein respiratory quotient (npRQ) was significantly lower in patients with advanced HCC than in cirrhotic patients without HCC, or in patients with early-stage HCC. In cirrhotic patients with advanced HCC undergoing HAIC, npRQ, BCAA/tyrosine ratio (BTR), and prealbumin and ALT levels were significantly improved in the LES group, but not in controls. In addition, area under the concentration curve for glucose (AUC glucose) tended to be improved in the LES group. CONCLUSIONS: LES using BCAA-enriched nutrients appears to improve energy metabolism and glucose tolerance in cirrhotic patients with advanced HCC undergoing HAIC.

Pilot study of combination therapy with transcatheter arterial infusion chemotherapy using iodized oil and percutaneous radiofrequency ablation during occlusion of hepatic blood flow for hepatocellular carcinoma.

OBJECTIVE: We have reported that radiofrequency (RF) ablation with balloon occlusion of the hepatic artery (balloon-occluded RF ablation) increases the coagulation area compared with standard RF ablation. In this study, we evaluated the efficacy and safety of combination therapy with transcatheter arterial infusion chemotherapy (TAI) using iodized oil and balloon-occluded RF ablation in patients with hepatocellular carcinoma. PATIENTS AND METHODS: We studied 12 patients with 12 HCC nodules (mean tumor diameter, 27.3 mm). All patients were classified as Child-Pugh Class A. Immediately after TAI using iodized oil, we performed balloon-occluded RF ablation. RESULTS: One treatment session of the combination therapy was done for 10 of 12 nodules (83%). The greatest long-axis and short-axis dimensions of the area coagulated after the combination therapy were 48.8+/- 5.5 mm and 41.9 +/- 4.1 mm, respectively. During follow-up (mean, 33.4 months), there was no local recurrence. The 1, 2, and 3-year survival rates were 100%, 92%, and 83%, respectively. No fatal complications were observed. CONCLUSIONS: The combination therapy is an effective and safe treatment under favorable liver reserve capacity. Using the combination therapy, it is possible to finish one treatment session for patients with HCC nodules measuring less than 3 cm in greatest dimension.