Hypoxia-ischemic insult in neonatal rats induced slowly progressive brain damage related to memory impairment

The present study was designed to determine potential associations between the brain damage induced by hypoxic-ischemic (HI) insult and spatial learning impairment in an eight-arm radial maze task. We first determined the pathological outcomes after 2, 5, 9, and 17 weeks of recovery following the HI insult. The results show that the brain damage progressed from 2 up to 17 weeks of recovery. To clarify the time course of the brain damage changes, we investigated the histological changes of the same individual with magnetic resonance imaging (MRI) after 5, 9, and 57 weeks of recovery following the HI insult. The MRI changes were similar to the histological changes, and the brain damages were exacerbated in the contralateral hemisphere after 57 weeks of recovery following the HI insult. To investigate whether alteration in brain function was correlated with MRI and histological changes, the rats were made to find their way through an eight-arm radial maze was performed at either 7th or 16th weeks of recovery. According to the results, the spatial learning impairments of rats in the maze starting at 16 weeks of recovery were more severe than those at 7 weeks of recovery, indicating that the impairments were progressive and depended on the degree of brain damage. The results of the present study are the first demonstration that the evolutional and specific brain damage following the HI insult is slowly and progressively exacerbated to the contralateral hemisphere and rats who experience the HI are at risk for showing a late impairment of brain function.     

Argyrophilic nucleolar organizer regions of breast tumors: Assessment of aspirated cytological materials

To investigate the correlation between argyrophilic nucleolar organizer regions (Ag-NORs)and the malignant potential of breast tumors, we analyzed Ag-NORs of cytological specimens obtained from 190 patients with various types of breast disease by preoperative aspiration biopsy. The average number of Ag-NORs per nucleus was defined as the Ag-NOR score. The Ag-NOR score was 5.7 +/- 1.7 in the group of women with breast carcinoma (n =70), 2.6= 0.4 in the group with fibroadenoma (n= 54) and 2.9= 0.6 in the group with mastopathy (n= 66). The level was significantly higher in breast carcinoma than in each benign disease(P < 0.001 in both cases). The score was 6.5 +/- 2.3 in the group with four or more metastatic lymph nodes (n = 21), 5.2+/- 1.2 in the group with one to three metastatic lymph node (n= 10) and 5.1+/- 1.1 in that with no metastatic lymph node (n = 39);the score was significantly (P < 0.05) higher in the groups with four or more metastatic lymph modes than in the other groups, respectively. Thus, a correlaton was observed between the Ag-NOR score and lymph node status. These data suggest that a higher Ag-NOR score reflects high-grade malignancy.     

Effects of super-extended paraaortic lymphadenectomy (PAL) on biological responses in totally gastrectomized patients with T3 or T4 gastric cancer

Background. In Japan, much attention has recently been paid to super-extended paraaortic lymphadenectomy (PAL) for the treatment of advanced gastric cancer. However, it has been reported that PAL is associated with increased morbidity and mortality, as compared to conventional extended lymphadenectomy (D2 or D3). Therefore, an analysis of the effects of PAL on perioperative changes in the biological responses of patients essential for determining the potential utility of this procedure. Methods. The current non-randomized prospective study included evaluations of perioperative changes in parameters of surgical stress (series I; serum levels of antidiuretic hormone, interleukin-6, trypsin, and phospholipase A ₂ ) and immunocompetence (series II; phytohemagglutinin- and concanavalin A-induced blastogenesis, activity of natural killer cells and the ratio of CD4 cells to CD8 cells) in patients with advanced gastric cancer (T3 or T4), comparing groups treated with D3 plus PAL ( n = 12) and D3 ( n = 13), and a control group with early gastric cancer ( n = 16) treated with D1 lymphadenectomy (perigastric N1 nodes) between April 1995 and April 1997. Results. The duration of surgery and the amount of blood lost were longer and greater in the D3 plus PAL group than in the D3 and D1 groups. D3 plus PAL and D3 were associated with significant postoperative increases in parameters of surgical stress, as well as with significant postoperative immunosuppression, compared to results with D1. However, there were no significant differences in the respective parameters between the D3 plus PAL and D3 groups. Conclusions. Our results indicate that there are no essential differences in patients' biological responses between D3 plus PAL and D3 lymphadenectomy. It appears that PAL-associated morbidity can be minimized by very careful manipulation during the dissection of paraaortic lymph nodes. Received for publication on Feb. 10, 1998; accepted on Jun. 3, 1998     

Genomic determinants impacting the clinical outcome of mogamulizumab treatment for adult T-cell leukemia/lymphoma

In order to identify genomic biomarkers for the outcome of mogamulizumab-containing treatment, an integrated molecular analysis of adult T-cell leukemia/lymphoma (ATL) was conducted on 64 mogamulizumab-naïve patients. Among driver genes, CCR4 and CCR7 alterations were observed in 22% and 11% of the patients, respectively, both consisting of single nucleotide variants (SNV)/insertion-deletions (indels) in the C-terminus. Patients with CCR4 alterations or without CCR7 alterations exhibited a more favorable clinical response (complete response [CR] rate 93%, 13/14; P=0.024, and CR rate 71%, 40/56; P=0.036, respectively). Additionally, TP53, CD28, and CD274 alterations were identified in 35%, 16%, and 10% of the patients, respectively. TP53 alterations included SNV/indels or copy number variations (CNV) such as homozygous deletion; CD28 alterations included SNV, CNV such as amplification, or fusion; CD274 alterations included CNV such as amplification, or structural variants. Univariate analysis revealed that TP53, CD28 or CD274 alterations were associated with worse overall survival (OS) (hazard ratio [HR]: 2.330, 95% confidence interval [CI]: 1.183-4.589; HR: 3.191, 95% CI: 1.287-7.911; HR: 3.301, 95% CI: 1.130-9.641, respectively) but that CCR4 alterations were associated with better OS (HR: 0.286, 95% CI: 0.087-0.933). Multivariate analysis indicated that in addition to performance status, TP53, CCR4 or CD274 alterations (HR: 2.467, 95% CI: 1.197-5.085; HR: 0.155, 95% CI: 0.031-0.778; HR: 14.393, 95% CI: 2.437-85.005, respectively) were independently and significantly associated with OS. The present study contributes to the establishment of precision medicine using mogamulizumab in ATL patients.     

Genetic variations and haplotype structures of the ABC transporter gene ABCC1 in a Japanese population

Multidrug resistance-related protein 1 (MRP1), an ATP-binding cassette transporter encoded by the ABCC1 gene, is expressed in many tissues, and functions as an efflux transporter for glutathione-, glucuronate- and sulfate-conjugates as well as unconjugated substrates. In this study, the 31 exons and their flanking introns of ABCC1 were comprehensively screened for genetic variations in 153 Japanese subjects to elucidate the linkage disequilibrium (LD) profiles and haplotype structures of ABCC1 that is necessary for pharmacogenetic studies of the substrate drugs. Eighty-six genetic variations including 31 novel ones were found: 1 in the 5'-flanking region, 1 in the 5'-untranslated region (UTR), 20 in the coding exons (9 synonymous and 11 nonsynonymous variations), 4 in the 3'-UTR, and 60 in the introns. Of these, eight novel nonsynonymous variations, 726G>T (Trp242Cys), 1199T>C (Ile400Thr), 1967G>C (Ser656Thr), 2530G>A (Gly844Ser), 3490G>A (Val1164Ile), 3550G>A (Glu1184Lys), 3901C>T (Arg1301Cys), and 4502A>G (Asp1501Gly), were detected with an allele frequency of 0.003. Based on the LD profiles, the analyzed regions of the gene were divided into five LD blocks (Blocks -1 and 1 to 4). The multiallelic repeat polymorphism in the 5'-UTR was defined as Block -1. For Blocks 1, 2, 3 and 4, 32, 23, 23 and 13 haplotypes were inferred, and 9, 7, 7 and 6 haplotypes commonly found on > or = 10 chromosomes accounted for > or = 91% of the inferred haplotypes in each block. Haplotype-tagging single nucleotide polymorphisms for each block were identified to capture the common haplotypes. This study would provide fundamental and useful information for the pharmacogenetic studies of MRP1-dependently effluxed drugs in Japanese.     

Fulminant Respiratory Failure Caused by Anti-asparaginyl tRNA Synthetase (Anti-KS) Antibody Syndrome-related Interstitial Lung Disease

Anti-asparaginyl transfer RNA (tRNA) synthetase (KS) antibodies, detected in <5% patients with anti-aminoacyl-tRNA synthetase antibody syndrome, are strongly associated with interstitial pneumonia but not myositis and skin symptoms. A recent report suggested that most patients with interstitial pneumonia and anti-KS antibody (KS-ILD) may present with chronic disease. We herein report a rare case of severe acute respiratory failure in a KS-ILD patient requiring extracorporeal membrane oxygenation (ECMO). ECMO is useful for facilitating not only lung rest until recovery but also the definitive diagnosis and treatment of ILD. KS-ILD can develop acutely with fulminant respiratory failure, as observed in this case.     

Effects of intra- and extrahepatic portal systemic shunts on insulin metabolism

To study the effects of intra- and extrahepatic portal-systemic shunts on insulin degradation, 11 patients with liver cirrhosis and 7 noncirrhotic patients with liver disease were studied with percutaneous transhepatic catheterization. Insulin levels in portal and peripheral blood were measured simultaneously for 1-2 hr after intravenous administration of glucose. The degrees of intra- and extrahepatic portal-systemic shunting were measured with this technique using 131I-macroaggregated albumin and 99mTc-macroaggregated albumin. The amount of insulin secreted and insulin degraded were assessed from the areas under blood concentration curves for portal and peripheral blood. Insulin degradation was significantly reduced in cirrhotics compared to noncirrhotics with liver disease, although there was no difference in the amount of insulin secreted between these two groups. It was also correlated significantly with the degree of intrahepatic shunting but not with the degree of extrahepatic shunting. These results suggest that intrahepatic shunting plays an important role in the reduction of insulin degradation in cirrhosis.