Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines.

System L is a major nutrient transport system responsible for the transport of large neutral amino acids including several essential amino acids. We previously identified a transporter (L-type amino acid transporter 1: LAT1) subserving system L in C6 rat glioma cells and demonstrated that LAT1 requires 4F2 heavy chain (4F2hc) for its functional expression. Since its oncofetal expression was suggested in the rat liver, it has been proposed that LAT1 plays a critical role in cell growth and proliferation. In the present study, we have examined the function of human LAT1 (hLAT1) and its expression in human tissues and tumor cell lines. When expressed in Xenopus oocytes with human 4F2hc (h4F2hc), hLAT1 transports large neutral amino acids with high affinity (K(m)= approximately 15- approximately 50 microM) and L-glutamine and L-asparagine with low affinity (K(m)= approximately 1.5- approximately 2 mM). hLAT1 also transports D-amino acids such as D-leucine and D-phenylalanine. In addition, we show that hLAT1 accepts an amino acid-related anti-cancer agent melphalan. When loaded intracellularly, L-leucine and L-glutamine but not L-alanine are effluxed by extracellular substrates, confirming that hLAT1 mediates an amino acid exchange. hLAT1 mRNA is highly expressed in the human fetal liver, bone marrow, placenta, testis and brain. We have found that, while all the tumor cell lines examined express hLAT1 messages, the expression of h4F2hc is varied particularly in leukemia cell lines. In Western blot analysis, hLAT1 and h4F2hc have been confirmed to be linked to each other via a disulfide bond in T24 human bladder carcinoma cells. Finally, in in vitro translation, we show that hLAT1 is not a glycosylated protein even though an N-glycosylation site has been predicted in its extracellular loop, consistent with the property of the classical 4F2 light chain. The properties of the hLAT1/h4F2hc complex would support the roles of this transporter in providing cells with essential amino acids for cell growth and cellular responses, and in distributing amino acid-related compounds.

How extensive should lymph node dissection be for cancer of the thoracic esophagus?

From 1985 to 1992, 171 patients with cancer of the thoracic esophagus underwent esophagectomy with systematic dissection of regional lymph nodes including cervical nodes. The hospital mortality rate was 5.3%. The dissected nodes were classified into four groups: the deep cervical (C), upper mediastinal and cervical paratracheal (U), middle and lower mediastinal (L), and upper perigastric (G) groups. The U group mainly consisted of nodes beside the recurrent laryngeal nerves. The phase of cancer infiltration of lymph nodes was evaluated by the total number and the distribution of involved nodes. Of cases with nodal involvement, only 37% were in the late phase, in which more than seven nodes or in which the U, L, and G groups were all involved. Of cases in the earliest phase in which only one node was involved, 93% had either the U or G group involved. The C group of nodes was infrequently involved until the late phase. Cancer had metastasized to the U and G groups across a considerable anatomic distance even in earlier phases. Outcomes of the cases with nodal involvement not in the late phase were satisfactory; the cumulative survival was 60% at 3 years and 54% at 5 years. Systematic nodal dissection would benefit even cases with nodal involvement, unless the disease is in the late phase. Nodes beside the recurrent nerves and upper perigastric nodes should be dissected with higher priority, though they are located anatomically distant.

The influence of relative body weight on toxicity of combination chemotherapy with cisplatin and etoposide.

PURPOSE: This study was conducted to determine whether there was any relationship between the adverse toxicity of combination chemotherapy and clinical values including age, sex, creatinine clearance (Ccr), body surface area and relative body weight. METHODS: Cisplatin at a dose of 80 mg/m2 on day 1 and etoposide at a dose of 100 mg/m2 on days 1, 2 and 3 were given to 42 consecutive patients with solid tumors. All patients had normal major organ function and received uniform hydration therapy. RESULTS: Body Mass Index as a measure of relative body weight was inversely correlated with the percentage decrease in white blood cells (P = 0.0681) and platelet count (P = 0.0115). Body surface area was also inversely correlated with leukopenia (P = 0.0171) and thrombocytopenia (P = 0.0058). In contrast, age, sex and Ccr had no significant relationship with adverse toxicity. CONCLUSIONS: It is concluded that dose adjustment of combination chemotherapy with cisplatin and etoposide according to age or ideal body weight is not appropriate and that a conventional dose modification method based solely on body surface area is probably not sufficient to reduce interpatient variability of cancer chemotherapy. A pharmacokinetic and pharmacodynamic study of combination chemotherapy is warranted to establish the ideal dose modification method.

[A case of traumatic tricuspid regurgitation].

Tricuspid regurgitation due to nonpenetrating trauma occurred in a 60-year-old male patient who had received chest trauma in a motorcycle accident. He was admitted because of shortness of breath and palpitation on exertion. On admission physical examinations revealed pulsated and dilated jugular veins, hepatomegaly, and systolic murmur. The chest X-ray film showed an enlarged heart and electrocardiograms revealed complete right bundle branch block. Echocardiography demonstrated systolic prolapse of the tricuspid anterior leaflet into the right atrium. Right atrial v wave pressure was 20 mmHg. Tricuspid valve replacement with a Carpentier-Edwards 33 mm using super interpose method was performed successfully 13 years after the trauma. At operation, it was found that the chordae tendineae of the anterior leaflet was ruptured.

[Lung cancer].

The five year survival rate of lung cancer patients is only 10% in Japan. The staging system of c-TNM is more important than p-TNM when deciding treatment modality for lung cancer. Compared to other solid cancers, neoadjuvant therapy in lung cancer treatment has a more important position. A clinical protocol study should be carried out with the idea of "intent to treat" and medical oncology will play a more important role in the treatment of lung cancer.

Successful treatment of duodenal carcinoid tumor by laparoscopy-assisted endoscopic full-thickness resection with lymphadenectomy.

Reports on endoscopic full-thickness resection of the duodenum using the endoscopic submucosal dissection technique are rare. Here we present a case of a duodenal bulb carcinoid tumor successfully treated by laparoscopy-assisted endoscopic full-thickness resection (LAEFR). An asymptomatic 65-year-old woman had a 10-mm, submucosal tumor on the anterior wall of the duodenal bulb. Abdominal CT revealed an enlarged lymph node adjacent to the duodenum and pancreas. Although we informed the patient of the need for pancreatoduodenectomy with a lymphadenectomy, the patient expressly requested LAEFR. After negative nodal metastasis was confirmed by an intraoperative frozen section of the enlarged nodes, LAEFR was performed using the endoscopic submucosal dissection technique under the laparoscopic assistance. The duodenal wall defect was closed by laparoscopy with an Albert anastomosis. The entire circumferential margin of the specimen was histopathologically negative for carcinoid tumor cells. In summary, LAEFR enables en bloc and whole-layer excision of nonperiampullary duodenal lesions with a sufficient surgical margin, both vertically and laterally. LAEFR is a minimally invasive and effective treatment for selected patients with duodenal carcinoid tumor.