Salvage chemoradiotherapy for locally advanced esophageal carcinomas.

'Salvage chemoradiotherapy (CRT)' was introduced in 2005 to treat thoracic esophageal carcinomas deemed unresectable based on the intraoperative findings. The therapeutic concept is as follows: the surgical plan is changed to an operation that aims to achieve curability by the subsequent definitive CRT. For this purpose, the invading tumor is resected as much as possible, and systematic lymph node dissection is performed except for in the area around the bilateral recurrent nerves. The definitive CRT should be started as soon as possible and should be performed as planned. We hypothesized that this treatment would be feasible and provide good clinical effects. We herein verified this hypothesis. Twenty-seven patients who received salvage CRT were enrolled in the study, and their clinical course, therapeutic response, and prognosis were evaluated. The patients who had poor oral intake because of esophageal stenosis were able to eat solid food soon after the operation. The radiation field could be narrowed after surgery, and this might have contributed to the high rate of finishing the definitive CRT as planned. As a result, the overall response rate was 74.1%, and 48.1% of the patients had a complete response. No patient experienced fistula formation. The 1-, 3-, and 5-year overall survival rates were 66.5%, 35.2%, and 35.2%, respectively. Salvage CRT had clinical benefits, such as the fact that patients became able to have oral intake, that fistula formation could be prevented, that the adverse events associated with the definitive CRT could be reduced, and that prognosis of the patients was satisfactory. Although the rate of recurrent nerve paralysis was relatively high even after the suspension of aggressive bilateral recurrent nerve lymph node dissection, and the rate of the progressive disease after the definitive CRT was high, salvage CRT appears to provide some advantages for the patients who would otherwise not have other treatment options following a non-curative and residual operation.

Ikaros is a mutational target for lymphomagenesis in Mlh1-deficient mice.

Deficiencies in DNA mismatch repair (MMR) result in replication errors within key tumor suppressor genes or oncogenes, and cause hereditary nonpolyposis colorectal cancer (HNPCC). Hematological malignancy with microsatellite instability is also associated with defective MMR, but little is known about the target genes for MMR. Here we identified Ikaros, a master transcription factor of lymphoid lineage commitment and differentiation, as a mutational target in spontaneous and radiation-induced T-cell lymphomas in Mlh1-deficient mice. Three quarters of lymphomas lacked Ikaros protein expression, which resulted from a frameshift mutation that created a stop codon. Mononucleotide repeat sequences at 1029-1034(C)6 and 1567-1572(G)6 in Ikaros were mutational hot spots with a one-base deletion occurring with a frequency of 45 and 50%, respectively. Point mutations and splicing alterations were also observed. In total, 85% of the lymphomas showed aberrations in Ikaros. The characteristic of Mlh1-deficient lymphomas is harboring of multiple mutations simultaneously in the same tumor, displaying a combination of two frameshift mutations at different repeats, frameshift and point mutations, and/or deletion mutations. This is the first report of Ikaros mutations coupled with Mlh1 deficiency in lymphomagenesis.

[A patient with small-cell carcinoma of the esophagus with synchronous liver metastasis surviving 48 months after surgery].

Small-cell carcinoma of the esophagus is regarded as having a poor prognosis with frequent and early systemic metastasis. Recently, several reports have described small-cell carcinoma satisfactorily treated by chemotherapy and radiation therapy combined with surgery. We herein report a patient with small-cell carcinoma of esophagus with synchronous multiple liver metastasis who survived 44 months after surgery. A 70-year-old man was found to have a polypoid lesion at the abdominal esophagus by upper gastrointestinal endoscopy. A biopsy specimen of the lower esophagus demonstrated undifferentiated carcinoma of the esophagus. Ultrasonographic investigation demonstrated solitary SOL in the liver. The patient underwent a total gastrectomy and lower esophagectomy by an abdominal approach. As ultrasonographic evaluation during laparotomy revealed multiple liver metastases, a hepatic artery infusion catheter was inserted into the proper hepatic artery. A pathological study of the resected esophagus and a biopsy specimen of the liver revealed undifferentiated cell carcinoma of the esophagus (small-cell type). During hospitalization, hepatic artery infusion therapy (CDDP 20 mg/4 h and 5-FU 750 mg/5 h) was given for 4 days starting on days 14 and 28. After chemotherapy, liver metastasis could not be detected by ultrasonographic investigation. At the outpatient clinic bi-weekly hepatic artery infusion of 5-FU (1,500 mg/body/5 h) was continued for 30 months. The patient is alive 48 months after surgery without any evidence of recurrence.

[Pharmacokinetics of "subselective" arterial infusion chemotherapy].

Arterial infusion chemotherapy is mainly used for lymph node and peritoneal metastases. Generally, it is said that the concentration of a drug in abdominal organs is higher with arterial infusion chemotherapy than that with systemic chemotherapy. In this study, the pharmacokinetics of arterial infusion chemotherapy for a patient who had an arterial infusion port for lymph node metastasis and peritoneal metastasis, and a hepatic arterial infusion port for liver metastasis, was evaluated. Sequential arterial infusion chemotherapy with methotrexate (MTX) and 5-FU was given. One hundred mg of methotrexate (MTX) was infused over 20 minutes into the aorta, followed by 750 mg of 5-FU over 10 minutes 2 hours later. Blood samples from a peripheral vein and hepatic artery were collected at 10, 20 and 125 minutes from the beginning of the arterial infusion chemotherapy. Then the serum concentration of MTX and 5-FU was examined. The serum concentration of MTX in the hepatic artery was 1.4 to 2.3 times higher than that in peripheral venous blood. The serum concentration of 5-FU in the hepatic artery was 4.9 to 6.0 times higher than that in peripheral venous blood. The serum concentration of drug in abdominal organ was higher with arterial infusion chemotherapy than with systemic chemotherapy. It would thus seem that the effect of arterial infusion chemotherapy is higher than that of systemic chemotherapy.

Cell type- and positionally specific regulation of the aldolase P gene expression in rice seedlings.

We describe here different regulation of the AldP gene, a nuclear gene encoding chloroplast aldolase, in different tissues and growth ages of rice seedlings. Expression of the AldP gene is mesophyll cell-specific, and increases from the basal to the upper region in each leaf. The gene expression is repressed in the dark-grown leaf blade, but is induced by a short-term-exposure to light, to a level higher than that seen in the normal leaf blade. However, the light-inducibility differs among the tissues, and shows different patterns among leaf positions; i.e., the extent of light-induction is higher in the third leaf blade as compared with the earlier developed second leaf blade. Such positional differences in the regulation are also seen in the leaf sheath. These responses are not accompanied by changes of the cell type specificity in the expression.

Structural analysis of the chloroplastic and cytoplasmic aldolase-encoding genes implicated the occurrence of multiple loci in rice.

The genes AldP and AldC-a, encoding the rice chloroplastic (cp) and cytoplasmic (ct) types of aldolase, respectively, were isolated and sequenced, and their transcription start points (tsp) were determined. Organization of the two genes was found to differ greatly; AldP consisted of six exons while AldC-a consisted of two exons. The deduced amino acid (aa) sequence of AldP contained a cp stromal targeting signal, followed by a sequence that matches the experimentally determined N-terminal sequence of mature AldP. The two enzymes share only 55% aa identity. However, rice AldP had about 73% homology with the cp aldolase of spinach. Also, the homology of AldC-a with maize, spinach and Arabidopsis thaliana cytoplasmic aldolases ranged from 70 to 90%. Southern blot analyses indicated that AldP is encoded at a single locus, whereas the gene encoding the ct counterpart is distributed at three loci on the genome. This feature is quite different from those of maize and spinach, in which only one locus was found for the ct aldolase.