Superior outcome of infant acute myeloid leukemia with intensive chemotherapy: results of the Japan Infant Leukemia Study Group.

This study analyzed data on 35 infants with acute myeloid leukemia (AML) who were treated with intensive chemotherapy between 1995 and 1998 in Japan. The incidence of boys, younger age (< 6 months old), and hyperleukocytosis at onset was high in patients with the M4/M5 subtype (n = 23) in the French-American-British classification, compared with the non-M4/M5 subtype (n = 12). Thirteen (56%) and 16 (70%) patients with the M4/M5 subtype also showed 11q23 translocations and MLL gene rearrangements, respectively, whereas only one patient with the non-M4/M5 subtype had this rearrangement. All 35 patients were treated with the ANLL91 protocol consisting of etoposide, high-dose cytarabine, and anthracyclines. Overall survival and the event-free survival (EFS) rates at 3 years of all patients were 76% (95% confidence interval [CI], 61.3%-90.7%) and 72% (95% CI, 56.4%-87.9%), respectively. EFS showed no significant difference between 2 subgroups divided by age, gender, presence of the MLL gene rearrangements, and white blood cell count at onset; EFS in patients with the M4/M5 subtype tended to be better than those with the non-M4/M5 subtype. Although all 6 patients who underwent allogeneic stem cell transplantation (SCT) have been in complete remission, no benefit of SCT was confirmed. These findings suggest that the intensive chemotherapy with the ANLL91 protocol might have been responsible for the observed good outcome of infant AML, even without SCT. The presence of the MLL gene rearrangements or the age at onset had no impact on the outcome of infant AML.

Effective hepatic artery chemoembolization for advanced hepatocellular carcinoma with extensive tumour thrombus through the hepatic vein.

BACKGROUND AND AIMS: Advanced hepatocellular carcinoma (HCC) with extensive tumour growth through the hepatic vein still has an extremely poor prognosis, even after cancer chemotherapy and/or transarterial embolization. Although aggressive surgical treatments using extracorporeal circulation and liver transplantation have been performed by some authors, the reported results were still unsatisfactory. In this study, we report the favourable result of hepatic artery chemoembolization and subsequent surgical resection in three patients with advanced HCC with extensive tumour thrombus through the hepatic vein. METHODS AND RESULTS: Three irresectable patients with HCC with extensive tumour thrombus through the hepatic vein underwent hepatic artery chemoembolization with aclarubicin, mitomycin C, lipiodol and/or Gelfoam. After the reduction of tumour extent with hepatic artery chemoembolization, two of the three patients underwent surgical resection. These two patients are still alive at 59 and 21 postoperative months, respectively. In the other case, the extent of the tumour and functional reserve of the liver prevented us from performing surgical resection, but the patient is doing well 62 months after the initial treatment. CONCLUSIONS: Hepatic artery chemoembolization with aclarubicin, mitomycin C, lipiodol and/or Gelfoam might be an effective treatment for irresectable advanced HCC with extensive tumour thrombus into the inferior vena cava or the right atrium through the hepatic vein. Radical surgical resection might be applicable for selected patients without high surgical risk after reducing tumour extent by hepatic artery chemoembolization.

Adjuvant regional chemotherapy after hepatic resection for colorectal metastases.

BACKGROUND: This study explored the possibility of achieving a better survival rate and reduced recurrence in the remaining liver in patients with colorectal hepatic metastases undergoing hepatic resection. Adjuvant postoperative regional chemotherapy was administered via the hepatic artery or the portal vein. METHODS: A retrospective study was performed on 174 patients after hepatic resection for colorectal metastases. These comprised 78 patients who had hepatic artery infusion (HAI) chemotherapy (HAI group), 30 who had portal vein infusion (PVI) chemotherapy (PVI group) and 66 who had no regional chemotherapy (resection alone group). The three groups were compared with one another in terms of complications, survival rate and patterns of recurrence. RESULTS: Severe complications did not occur at any point during adjuvant HAI or PVI chemotherapy. The 5-year disease-free survival rate of patients in the HAI, PVI and resection alone groups were 35, 13 and 9 per cent respectively, including six hospital deaths. Patients in the HAI group showed significantly improved recurrence rates in the remaining liver compared with the resection alone group (P = 0.03), and more prolonged disease-free and overall survival than those in the PVI (P = 0.01 and P = 0.02 respectively) and resection alone (P = 0.0001 and P = 0.0006 respectively) groups. CONCLUSION: This study suggests that adjuvant HAI chemotherapy after hepatic resection may have therapeutic potential for improved management of patients with colorectal metastases.

A successful treatment for hepatocellular carcinoma with atrial tumor thrombus.

A 66-year-old man with an advanced hepatocellular carcinoma and tumor thrombus extending into the right atrium was treated by transcatheter arterial infusion of lipiodol and aclarubicin. This brought about a remarkable reduction of the tumor and the disappearance of the right atrial tumor thrombus. The tumor was then radically resected by hepatic posterior segmentectomy with combined resection of the right hepatic vein, where the tumor thrombus remained. He is doing well without any signs of recurrence 22 months after the operation.

[Successful adjuvant therapy of M-CSF with chemotherapy of two cases of chemotherapy resistant acute promyelocytic leukemia].

We demonstrate two conventional chemotherapy-resistant cases of acute promyelocytic leukemia (APL) who were successfully treated with macrophage-colony stimulating factor (M-CSF). Case no 1 was a 40-year-old woman who was made diagnosis of APL on June, 1992, and treated repeatedly with a conventional chemotherapy, BHAC-DMP regimen, resulting in complete remission on October, 1992. After a couple of years, she had relapse with marked growth of APL cells in bone marrow. She was treated with BHAC-AMP and modified B-triple V but could not obtain remission. Case no 2 was a 36-year-old-man with APL who was treated with BHAC-DMP and BHAC-AMP and modified B-triple V therapy. These three conventional chemotherapy regimen were not effective for him. Eight million units of human native M-CSF was administered intravenously for 14 days after the last BHAC-AMP therapy in case no 1, and for 5 days after the last modified B-triple V therapy in case no 2. After the therapy, APL cells in peripheral blood or bone marrow of both patients disappeared completely and normal hemopoietic cells increased, obtaining in complete remission in both cases. These successful cases treated with M-CSF combining chemotherapy may suggest a new therapeutic strategy for APL in addition to all-trans retinoic acid.

[Intraportal infusion of 5-FU and lipiodol-aclarubicin after hepatic resection for colorectal liver metastasis].

Fifty-five patients with hepatic metastasis from colorectal cancer underwent curative hepatic resection. Postoperative intraportal infusion of 5-fluorouracil (500mg per day) for 14 days from 21 postoperative days (POD) and lipiodol-aclarubicin (40mg) at 35 POD was carried out in twenty-eight patients for reducing the recurrence in the remnant liver and improving the prognosis. Twenty-seven patients had hepatectomy alone as controls. Intraportal infusion chemotherapy did not induce any hepatotoxicity and hematologic severe abnormalities. The cumulative survival rates for the infusion group and the control group, respectively, were 89.3% and 63.0% at 1 year; 55.2% and 43.3% at 2 year; 27.0% and 27.5% at 3 year. The survival rate for the infusion group was significantly higher than that for the control group at 1 year (p < 0.05). No difference of the recurrent rate in the remnant liver was found between the two groups. It is suggested that intraportal infusion chemotherapy after curative hepatic resection for colorectal liver metastasis might improve survival rate at the early postoperative period. Intraportal infusion chemotherapy could be an effective adjuvant therapy especially in the patients with bilateral and multiple hepatic metastasis.

Targeted chemotherapy for unresectable primary and metastatic liver cancer.

In targeted chemotherapy, Lipiodol Ultrafluid was used as a carrier of anticancer drugs; these combinations were termed oily anticancer agents. Arterial injection therapy with these oily anticancer agents was performed in 330 patients with unresectable hepatocellular carcinoma (HCC) and 110 patients with unresectable metastatic liver cancer. The alpha-fetoprotein (AFP) level decreased in 178 of 186 AFP-positive patients with HCC. Tumor size was reduced in 256 of 269 evaluable patients with HCC. The treatment seemed to prolong survival and in 193 HCC patients who were good candidates for therapy (those without Child C liver cirrhosis, without tumor occupying all four segments of the liver, or without extrahepatic spread) the 1-, 2-, and 5-year survival rates were 85, 52, and 34% respectively. In the 110 patients with metastatic liver cancer, the carcinoembryonic antigen level and tumor size were reduced. The 1-, 2-, and 5-year survival rates of these 110 patients were 61, 32, and 22% respectively.

Portal vein infusion of cancer chemotherapeutic agent emulsified with Lipiodol in regenerating liver after partial hepatectomy in rats.

Portal vein infusion of aclarubicin (ACR) emulsified with Lipiodol (LP) in regenerating liver after 70% partial hepatectomy in rats was evaluated for its safety and usefulness. DNA synthesis in regenerating liver was transiently suppressed by LP, ACR or LP+ACR, but no obvious inhibition was seen in aminopyrine N-demethylase activity and liver weights. LP significantly enhanced hepatic tissue levels of ACR and its active metabolites by long-term retention in the sinusoidal space. This study demonstrates that in rats LP has a powerful effect on the long-term retention of anticancer agents in the sinusoidal space after infusion into the portal vein, without aggravating hepatic damage by anticancer agents.

Collection of peripheral blood stem cells mobilized by high-dose Ara-C plus VP-16 or aclarubicin followed by recombinant human granulocyte-colony stimulating factor.

We developed an effective method for harvesting large numbers of peripheral blood stem cells (PBSC) for use in autotransplantation. Twenty patients with hematological malignancies were treated with high doses of Ara-C (12 g/m2) and VP-16/aclarubicin followed by administration of rhG-CSF (50 micrograms/m2). The optimal time for starting PBSC collection was determined by monitoring the CD34-positive stem cells in blood using immunomagnetic beads. PBSC were collected with a CS-3000 blood cell separator. A total blood volume between 7000 and 9000 ml was processed in each apheresis. Under these conditions, a total of 64 apheresis procedures was performed in the 20 patients. The mean numbers of mononuclear cells and of CFU-GM harvested per apheresis were 4.1 x 10(8)/kg and 110 x 10(4)/kg, respectively. A number of CFU-GM sufficient for engraftment (> 30 x 10(4)/kg) could be harvested by a single apheresis in 15 of the 20 patients. So far, 11 patients have been transplanted with PBSC and obtained rapid hematopoietic recovery. The median time to recover neutrophils more than 0.5 x 10(9)/l was 10 days, and that for platelets 50 x 10(9)/l was 11 days. This method for harvesting large numbers of PBSC allows safer autotransplantation in patients with chemoradiosensitive tumors, and is applicable to older patients.

A new approach to chemoembolization for unresectable hepatocellular carcinoma using aclarubicin microspheres in combination with cisplatin suspended in iodized oil.

Sixty-six consecutive patients with unresectable hepatocellular carcinoma (HCC) were treated with transcatheter arterial chemoembolization (TACE) using aclarubicin microspheres (ACRms) in combination with cisplatin suspended in iodized oil (Lipiodol, Laboratoire Guerbert, Paris, France) (CSL). The stages of the disease were as follows: Stage I (n = 1), Stage II (n = 10), Stage III (n = 26), and Stage IV (n = 29). The effectiveness of TACE was assessed by comparing ACRms with CSL with ACRms without CSL. Of 66 patients treated with ACRms and CSL, 62 (93.9%) could be examined for response. According to response criteria, there were 31 (50.0%) partial responses and 17 (27.4%) minor responses. In 13 cases (21.0%) there was no change and in 1 case (1.6%) there was progressive disease. The cumulative survival rate was 80.7% at 1 year, 64.2% at 2 years, and 50.6% at 3 years. The rates were significantly higher than those of the group treated with ACRms. Eleven patients in the ACRms and CSL group experienced clinical complications: cholecystitis (4.5%), pancreatitis (3.0%), liver abscess (3.0%), hepatic failure (3.0%), gastrointestinal bleeding (1.5%), and renal failure (1.5%). No lethal side effects related to the therapy were observed. TACE using ACRms in combination with CSL prolongs the survival of patients with unresectable HCC.

[Enhancement of selective drug accumulation and retention in normal and regenerating liver by the use of lipiodol in portal venous infusion in rats].

We studied selective accumulation and retention of lipiodol (LP) and anticancer agents in normal and regenerating liver tissue following portal infusion in rats. Total concentration of Aclarubicin (ACR) and its metabolites in liver tissue was higher in ACR + LP portal infusion group than in ACR portal infusion group both in normal and regenerating liver, concentration of active metabolites of ACR was higher in ACR portal infusion group than in ACR peripheral infusion group. Much higher concentration was found in ACR + LP portal infusion group. Histologic examination revealed more toxic effect on regenerating liver in ACR portal infusion group than in ACR + LP portal infusion group. Oil red staining demonstrated the retention of lipiodol more than 7 days following intraportal infusion in regenerating liver tissue. This study confirms that the ACR + LP portal infusion induces selective accumulation and long-term retention in normal and regenerating liver tissue, and may enhance the antitumor effect of drugs.

Targeting cancer chemotherapeutic agents by use of lipiodol contrast medium.

Arterially administered Lipiodol Ultrafluid contrast medium selectively remained in various malignant solid tumors because of the difference in time required for the removal of Lipiodol contrast medium from normal capillaries and tumor neovasculature. Although blood flow was maintained in the tumor, even immediately after injection Lipiodol contrast medium remained in the neovasculature of the tumor. To target anti-cancer agents to tumors by using Lipiodol contrast medium as a carrier, the characteristics of the agents were examined. Anti-cancer agents had to be soluble in Lipiodol, be stable in it, and separate gradually from it so that the anti-cancer agents would selectively remain in the tumor. These conditions were found to be necessary on the basis of the measurement of radioactivity in VX2 tumors implanted in the liver of 16 rabbits that received arterial injections of 14C-labeled doxorubicin. Antitumor activities and side effects of arterial injections of two types of anti-cancer agents were compared in 76 rabbits with VX2 tumors. Oily anti-cancer agents that had characteristics essential for targeting were compared with simple mixtures of anti-cancer agents with Lipiodol contrast medium that did not have these essential characteristics. Groups of rabbits that received oily anti-cancer agents responded significantly better than groups that received simple mixtures, and side effects were observed more frequently in the groups that received the simple mixtures. These results suggest that targeting of the anti-cancer agent to the tumor is important for treatment of solid malignant tumors.

Immunotherapy using Freund's adjuvant and recombinant interleukin-2 combined with transarterial chemoembolization for hepatocellular carcinoma.

A new immunotherapy for hepatocellular carcinoma (HCC) using Freund's adjuvant and recombinant interleukin-2 (IL-2) combined with conventional transarterial chemoembolization therapy was performed. In 16 patients with HCC and one patient with metastatic liver cancer receiving this therapy, decrease and suppression of reelevation of alpha-fetoprotein after therapy was observed. Disappearance of tumor thrombi of HCC in the main portal vein was observed in a patient, and decrease of carcinoembryonic antigen was also observed in a patient with metastatic liver cancer. The present therapy using Freund's adjuvant and IL-2 is likely to open a new avenue for the treatment of patients with advanced liver cancer.

[Pharmacokinetic validation of the antitumor efficacy of aclarubicin administered by various routes in CBF1 mice with Ca 755 carcinoma]. / Farmakokineticheskoe obosnovanie protivoopukholevoiéffektivnosti aklarubitsina pri razlichnykh sposobakh primeneniia u myshei linii CBF1 s kartsinomoi Ca 775.

Aclarubicin was established to be more active against murine mammary gland carcinoma Ca 755 after its intravenous injection as compared to oral administration. Pharmacokinetics of aclarubicin and its biologically active metabolites MA 144 N1, MA 144 T1 and MA 144 M1 was studied by HPLC in the tumour tissues. Not only quantitative but also qualitative differences in the ratios of the unchanged antibiotic and its metabolites in tumour Ca 755 were detected after aclarubicin administration by these methods. Diverse therapeutic activity was shown to be due to these differences.

[Experimental antimetastatic activity of aclarubicin]. / Antimetastaticheskaia aktivnost' aklarubitsina v éksperimente.

Marked antimetastatic activity of aclarubicin, an anthracycline antibiotic, was demonstrated on models of spontaneous and artificial metastases of murine tumors such as Lewis lung carcinoma and melanoma B16. The activity depended on the antibiotic dose and administration regimen. The highest antitumor effect of aclarubicin was observed when the antibiotic was used at the earliest periods after intravenous injection of the tumor cells (the model of artificial metastases) or after amputation of the limb with the tumor (spontaneous metastases). Aclarubicin was active after administration by any of the routes used: intravenous, intraperitoneal and oral, the latter by its efficiency being not inferior to the parenteral administration. When used intravenously aclarubicin showed activity similar to that of adriamycin. However, after oral administration only aclarubicin had antimetastatic action.