Chemotherapy for metastatic gastric cancer in Japan

Until the 1990s, there were no chemotherapy regimens with old-generation anticancer agents showing a survival benefit over 5-fluorouracil (FU) alone, and standard chemotherapy for metastatic gastric cancer had not been established. In the late 1990s, several new active agents were developed and some phase III trials with these agents were conducted; the new agent S-1 showed noninferiority to 5-FU in these trials. S-1 plus cisplatin is the first doublet chemotherapy to have shown a survival benefit over monotherapy with S-1. It has been demonstrated that capecitabine and oxaliplatin (OHP) can replace 5-FU and cisplatin (CDDP), offering more convenient treatment options. Thus, combination chemotherapy with an oral fluoropyrimidine (S-1 or capecitabine) and platinum (CDDP or OHP) has been recognized as standard chemotherapy for metastatic gastric cancer all over the world. However, it can be said that none of these new combination chemotherapies have shown remarkable progress from 5-FU plus cisplatin regimens. It is expected that triplet chemotherapy with a taxane; the use of molecular targeting agents; and the establishment of treatment strategies including second line chemotherapy, will lead to remarkable progress in personalized medicine in the near future.     

Treatment for locally advanced esophageal carcinoma complicated by fistulas: Case report

Two cases of advanced esophageal carcinoma complicated by fistula formation, treated with esophageal prostheses followed by chemotherapy or concurrent chemoradiotherapy, are reported. Chemoradiotherapy may be indicated in esophageal carcinoma cases with fistulas if an excellent antitumor response is expected. However, the indication for prosthesis insertion should be limited due to the risk of perforation, which may be a lethal complication.     

Target range of PTH in ESRD patients

The normal bone turnover is important for ESRD patients in not only skeletal problem but also patients QOL and survival. The abnormal bone turnover often induces the renal osteodystrophy and ectopic calcification. The major regulative factor on bone turnover is PTH. We propose here the target zone of PTH in ESRD patients with skeletal resistance for PTH. We recommended the intact-PTH 100 - 150 pg/mL for normal Ca/Pi/bone metabolism. This range of intact-PTH is equivalent to C-PTH 4.0 - 6.2 ng/mL, HS-PTH 10.0 - 16.0 ng/mL, and whole-PTH 80 - 110 pg/mL. The maintenance of normacalcemia and normophosphatemia are important for the arrival into the target zone of PTH using active vitamin D.     

ATA2 is predominantly expressed as system A at the blood-brain barrier and acts as brain-to-blood efflux transport for L-proline

Although system A is present at the blood-brain barrier (BBB), the physiological roles of system A have not been clarified. The efflux transport of the substrates of system A, such as L-proline (L-Pro), glycine (Gly), and alpha-methylaminoisobutyric acid (MeAIB), across the BBB was investigated using the in vivo Brain Efflux Index method. Over a period of 40 min, L-[(3)H]Pro and [(3)H]Gly underwent efflux from the brain, whereas [(3)H]MeAIB did not. The efflux of L-[(3)H]Pro was inhibited by the presence of unlabeled L-Pro and MeAIB, suggesting that carrier-mediated efflux transport of L-Pro across the BBB is involved in system A. L-[(3)H]Pro uptake by TR-BBB cells, used as an in vitro BBB model, was Na(+)-dependent with high-affinity (K(m1) = 425 microM) and low-affinity (K(m2) = 10.8 mM) saturable processes. The manner of inhibition of L-[(3)H]Pro uptake for amino acids was consistent with system A. Although GlnT, ATA2, and ATA3 mRNA were all expressed in TR-BBB cells, ATA2 mRNA was predominant. Under hypertonic conditions, ATA2 mRNA in TR-BBB cells was induced by up to 373%, and it activated [(3)H]MeAIB uptake. In light of these observations, our results indicate that L-Pro and Gly are transported from the brain across the BBB, whereas MeAIB is retained in the brain. System A is involved in efflux transport for L-Pro at the BBB. The predominantly expressed ATA2 mRNA at the BBB may play a role in maintaining the concentration of small neutral amino acids and cerebral osmotic pressure in the brain under pathological conditions.     

Antagonistic effects of antimuscarinic drugs on alpha 1-adrenoceptors

We previously observed that noradrenaline (NA)-induced contraction of the portal vein of rabbit was relaxed by the antimuscarinic drugs of atropine sulfate, but not scopolamine hydrobromide. In the present study we examined the possible effect of the antimuscarinic drugs of atropine sulfate, scopolamine hydrobromide, p-fluoro-hexa-hydro-sila-difenidol ( p-F-HHSiD, the M(3)-receptor antagonist) and pirenzepine (the M(1)-receptor antagonist) on alpha(1)-adrenoceptor (AR).Atropine and p-F-HHSiD relaxed the alpha(1)-AR agonist methoxamine-induced contraction of the rabbit portal vein in a concentration-dependent manner; however, scopolamine and pirenzepine had no such inhibitory effect. Radioligand binding studies with the alpha(1)-AR ligand 2-[2-(4-hydroxy-3-[(125)I]iodo-phenyl)ethylaminomethyl]-alpha-tetralone ([(125)I]HEAT) in membrane preparations from mouse whole brain showed that atropine (p K(i)=5.33) and p-F-HHSiD (p K(i)=5.88) had higher affinities than scopolamine (p K(i)=3.17) and pirenzepine (p K(i)<2.70). Furthermore, atropine and p-F-HHSiD had higher affinities for all human cloned alpha(1)-ARs than scopolamine and pirenzepine. The results show that the antimuscarinic drugs atropine and p-F-HHSiD have a direct but weak antagonistic activity against alpha(1)-ARs.     

Association between aldehyde dehydrogenase gene polymorphisms and the phenomenon of field cancerization in patients with head and neck cancer

Patients with squamous-cell carcinoma in the head and neck (HNSCC) often develop second primary esophageal squamous-cell carcinomas (ESCC). In addition, widespread epithelial oncogenic alterations are also frequently observed in the esophagus and can be made visible as multiple Lugol-voiding lesions (multiple LVL) by Lugol chromoendoscopy. Multiple occurrences of neoplastic change in the upper aerodigestive tract have been explained by the concept of 'field cancerization', usually associated with repeated exposure to carcinogens such as alcohol and cigarette smoke. However, the etiology of second ESCC in HNSCC patients remains unclear and acetaldehyde, the first metabolite of ethanol, has been implicated as the ultimate carcinogen in alcohol-related carcinogenesis. We first investigated the relation between second ESCC and multiple LVL in 78 HNSCC patients. Multiple LVL and second ESCC were observed in 29 (37%) and 21 (27%) patients, respectively. All of the second ESCC were accompanied by multiple LVL. This may indicate that episodes of multiple LVL are precursors for second ESCC. We then examined the association of multiple LVL with the patients' characteristics, including genetic polymorphisms of the alcohol metabolizing enzymes, alcohol dehydrogenase type 3 (ADH3) and aldehyde dehydrogenase type 2 (ALDH2). We also investigated acetaldehyde concentrations in the breath of 52 of the 78 patients. All the patients with multiple LVL were both drinkers and smokers. Multivariable logistic analysis showed that the inactive ALDH2 allele (ALDH2-2) was the strongest contributing factor for the development of multiple LVL (odds ratio 17.6; 95% confidence intervals 4.7-65.3). After alcohol ingestion, acetaldehyde in the breath was elevated to a significantly higher level in all patients with the ALDH2-2 allele than in those without it. The high levels of breath acetaldehyde were significantly modified by the slow-metabolizing ADH3-2 allele. These results reveal strong evidence for a gene-environmental interaction between the ALDH2-2 allele and alcohol consumption, for the risk of developing multiple LVL, resulting in the development of second ESCC in patients with HNSCC. Ultimately, increased local acetaldehyde exposure thus appears to be a critical determinant of the phenomenon of 'field cancerization'.     

Cirrhosis: modified caudate-right lobe ratio

PURPOSE: To determine whether a modified caudate-right lobe ratio (C/RL) with use of the right portal vein to set the lateral boundary (C/RL-r) is more accurate for diagnosing cirrhosis and evaluating its clinical severity than is the previously described C/RL with use of the main portal vein to set the lateral boundary (C/RL-m). MATERIALS AND METHODS: Two hundred thirty-six patients (121 with pathologically proved cirrhosis and 115 without history of chronic hepatic diseases) underwent magnetic resonance (MR) imaging. Two independent observers measured C/RL-r and compared it with C/RL-m. Results were compared by using receiver operating characteristic (ROC) curves and accuracy measures at various thresholds. RESULTS: The area below the ROC curve was greater for C/RL-r (0.797) than for C/RL-m (0.731; P =.040). By using a C/RL-r greater than 0.90, the sensitivity, specificity, and accuracy for the MR imaging diagnosis of cirrhosis were 71.7%, 77.4%, and 74.2%, respectively. The highest accuracy of the C/RL-m was 65.7%, when the C/RL-m was greater than 0.55. Interobserver agreement was statistically confirmed for both measurements by using kappa analysis. Significant differences were found among the three Child-Pugh classes by using C/RL-r (P =.0105) but not by using C/RL-m. CONCLUSION: C/RL-r is more accurate for diagnosing cirrhosis and evaluating its clinical severity than is C/RL-m.