Efficacy of platinum combination chemotherapy after first-line gefitinib treatment in non-small cell lung cancer patients harboring sensitive EGFR mutations

Purpose. Gefitinib is an effective first-line chemotherapy for advanced non-small cell lung cancer (NSCLC) patients harboring sensitive EGFR mutations. However, whether second-line platinum combination chemotherapy after first-line gefitinib treatment shows similar effects to first-line platinum combination chemotherapy in these patients remains unclear. Therefore, we here aimed to investigate the efficacy of platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations. Methods/patients. We retrospectively evaluated the clinical effects of second-line platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations (exon 19 deletion or exon 21 L858R mutation) at five institutions. All patients were initially treated with gefitinib (250 mg/day) followed by platinum combination chemotherapy as second-line chemotherapy. Results. Between January 2006 and December 2012, 42 patients [8 men, 34 women; median age, 63 years (range 39–75 years)] were enrolled. The overall response rate, disease control rate, and median progression-free survival (PFS) were 26.2, 61.9 %, and 5.1 months, respectively, after the second-line treatment. The corresponding values for first-line gefitinib treatment were 69.0, 95.2 %, and 11.1 months, respectively. Moreover, second-line platinum combination chemotherapy with pemetrexed or bevacizumab-containing regimens was independently associated with improved PFS. Conclusions. Second-line platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations was effective and showed equivalent outcomes to first-line platinum combination chemotherapy. After failure of first-line gefitinib therapy, second-line platinum combination chemotherapy with pemetrexed or bevacizumab might result in improved PFS (AU)

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Efficacy of platinum combination chemotherapy after first-line gefitinib treatment in non-small cell lung cancer patients harboring sensitive EGFR mutations.

PURPOSE: Gefitinib is an effective first-line chemotherapy for advanced non-small cell lung cancer (NSCLC) patients harboring sensitive EGFR mutations. However, whether second-line platinum combination chemotherapy after first-line gefitinib treatment shows similar effects to first-line platinum combination chemotherapy in these patients remains unclear. Therefore, we here aimed to investigate the efficacy of platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations. METHODS/PATIENTS: We retrospectively evaluated the clinical effects of second-line platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations (exon 19 deletion or exon 21 L858R mutation) at five institutions. All patients were initially treated with gefitinib (250 mg/day) followed by platinum combination chemotherapy as second-line chemotherapy. RESULTS: Between January 2006 and December 2012, 42 patients [8 men, 34 women; median age, 63 years (range 39-75 years)] were enrolled. The overall response rate, disease control rate, and median progression-free survival (PFS) were 26.2, 61.9%, and 5.1 months, respectively, after the second-line treatment. The corresponding values for first-line gefitinib treatment were 69.0, 95.2%, and 11.1 months, respectively. Moreover, second-line platinum combination chemotherapy with pemetrexed or bevacizumab-containing regimens was independently associated with improved PFS. CONCLUSIONS: Second-line platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations was effective and showed equivalent outcomes to first-line platinum combination chemotherapy. After failure of first-line gefitinib therapy, second-line platinum combination chemotherapy with pemetrexed or bevacizumab might result in improved PFS.

Loss of a member of the aquaporin gene family, aqpA affects spore dormancy in Dictyostelium.

We isolated and characterized a gene from Dictyostelium discoideum, which encodes a protein of 279 amino acids (30.6kDa) containing six transmembrane domains with two highly conserved motifs of asparagine-proline-alanine (NPA) found in the aquaporin family of water-channel proteins, although the second motif of the protein has been modified into NPV (asparagine-proline-valine). The deduced amino acid sequence of the gene, which we have named aqpA, is 39% identical to D. discoideum WacA, 26% identical to human Aqp5, 26% identical to Oryza sativa PIP2a, 25% identical to yeast Aqy1 and 24% identical to E.coli AqpZ. Southern analyses indicated that aqpA is present as a single copy in the genome. Northern blot analysis showed that the developmentally regulated 1kb mRNA transcript first appears at the tight mound stage (12h), and is abundant in fingers (16h) and late culminants (20h). In-situ hybridization of slugs revealed that aqpA mRNA accumulated in cells of the prespore region but not in those of the prestalk region. Disruption of aqpA by homologous recombination did not significantly affect growth or developmental morphogenesis. Although mutant spores were viable, when assayed soon after encapsulation, they became permeable to propidium iodide and lost viability after a week on the top of a fruiting body. Thus, AqpA is essential to maintain spore dormancy perhaps through the regulation of water flow.

The mitochondrial DNA of Dictyostelium discoideum: complete sequence, gene content and genome organization.

We present an overview of the gene content and organization of the mitochondrial genome of Dictyostelium discoideum. The mitochondria genome consists of 55,564 bp with an A + T content of 72.6%. The identified genes include those for two ribosomal RNAs (rn1 and rns), 18 tRNAs, ten subunits of the NADH dehydrogenase complex (nad1, 2, 3, 4, 4L, 5, 6, 7, 9 and 11), apocytochrome b (cytb), three subunits of the cytochrome oxidase (cox1/2 and 3), four subunits of the ATP synthase complex (atp1, 6, 8 and 9), 15 ribosomal proteins, and five other ORFs, excluding intronic ORFs. Notable features of D. discoideum mtDNA include the following. (1) All genes are encoded on the same strand of the DNA and a universal genetic code is used. (2) The cox1 gene has no termination codon and is fused to the downstream cox2 gene. The 13 genes for ribosomal proteins and four ORF genes form a cluster 15.4 kb long with several gene overlaps. (3) The number of tRNAs encoded in the genome is not sufficient to support the synthesis of mitochondrial protein. (4) In total, five group I introns reside in rnl and cox1/2, and three of those in cox1/2 contain four free-standing ORFs. We compare the genome to other sequenced mitochondrial genomes, particularly that of Acanthamoeba castellanii.

Regioselective synthesis of p-nitrophenyl glycosides of beta-D-galactopyranosyl-disaccharides by transglycosylation with beta-D-galactosidases.

The beta-D-galactosidase from porcine liver induced regiospecific transglycosylation of beta-D-galactose from beta-D-Gal-OC6H4NO2-o to OH-6 of, respectively, p-nitrophenyl glycoside acceptors of Gal, GlcNAc and GalNAc to afford beta-Gal-(1-->6)-alpha-Gal-OC6H4NO2-p, beta-Gal-(1--> 6)-beta-Gal-OC6H4NO2-p, beta-Gal-(1-->6)-alpha-GalNAc-OC6H4NO2-p, beta-Gal-(1-->6)-beta-GalNAc-OC6H4NO2-p, beta-Gal-(1-->6)-alpha-GlcNAc-OC6H4NO2-p, and beta-Gal-(1-->6)-beta-GlcNAc-OC6H4NO2-p. The enzyme showed much higher transglycosylation activity for the alpha-glycoside acceptors than the corresponding beta-glycoside acceptors. The regioselectivity of the beta-D-galactosidase from Bacillus circulans ATCC 31382 greatly depended on the nature of the acceptor. When alpha-D-GalNAc-OC6H4NO2-p and alpha-D-GlcNAc-OC6H4NO2-p were used as acceptors, the enzyme showed high potency for regioselective synthesis of beta-Gal-(1-->3)-alpha-GalNAc-OC6H4NO2-p and beta-Gal-(1-->3)-alpha-GlcNAc-OC6H4NO2-p in high respective yields of 75.9 and 79.3% based on the acceptors added. However, replacement of beta-D-Gal-OC6H4NO2-p by beta-D-GalNAc-OC6H4NO2-p did change the direction of galactosylation. The enzyme formed regioselectively beta-Gal-(1-->6)-beta-Gal-OC6H4NO2-p with (beta-Gal-1-->(6-beta-Gal-1-->)n6-beta-Gal-OC6H4NO2-p, n = 1-4). No beta-(1-->3)-linked product was detected during the reaction. Use of the two readily available beta-D-galactosidases facilitates the preparation of (1-->3)- and (1-->6)-linked disaccharide glycosides of beta-D-Gal-GalNAc and beta-D-Gal-GlcNAc.

The Dictyostelium developmental cDNA project: generation and analysis of expressed sequence tags from the first-finger stage of development.

In an effort to identify and characterize genes expressed during multicellular development ill Dictyostelium, we have undertaken a cDNA sequencing project. Using size-fractionated subsets of cDNA from the first finger stage, two sets of gridded libraries were constructed for cDNA sequencing. One, library S, consisting of 9984 clones, carries relatively short inserts, and the other, library L, which consists of 8448 clones, has longer inserts. We sequenced all the selected clones in library S from their 3'-ends, and this generated 3093 non-redundant, expressed sequence tags (ESTs). Among them, 246 ESTs hit known Dictyostelium genes and 910 showed significant similarity to genes of Dictyostelium and other organisms. For library L, 1132 clones were randomly sequenced and 471 non-redundant ESTs were obtained. In combination, the ESTs from the two libraries represent approximately 40% of genes expressed in late development, assuming that the non-redundant ESTs correspond to independent genes. They will provide a useful resource for investigating the genetic networks that regulate multicellular development of this organism.

Collective review of small carcinomas of the pancreas.

To determine problems involved in the treatment and diagnosis of pancreatic cancer, a collective study of small carcinoma of the pancreas (2 cm or less in diameter) was performed. One hundred six cases were collected and analyzed. The results were as follows: In small carcinoma of the pancreas, the resectability rate was 99.0% and the operative mortality rate was 4%. Only 44% of the patients belonged to Stage I, and 14% belonged to Stage III or IV. Lymph node involvement, capsular invasion, retroperitoneal invasion, and vascular invasion were found in 30, 20, 12, and 9% of the patients, respectively. The postoperative cumulative 5-year survival rate was 30.3%, and that of Stage I was 37.0%. A small-sized tumor of the pancreas is not always an early carcinoma, but a tumor in Stage I may be regarded as an early carcinoma. Percutaneous transhepatic cholangiography and endoscopic retrograde cholangiopancreatography were the main diagnostic indicators in cases with and without jaundice, respectively. There was no specific single serum test for detecting small pancreatic cancer.

Long-term results of surgical treatment for intrahepatic stones.

One hundred and nineteen patients with intrahepatic stones treated surgically in Nagasaki University Hospital from 1969 to 1984 were reviewed. The patients were divided into four types according to location of the stones and the presence or absence of stenotic lesions and/or localized dilatation of the intrahepatic bile ducts. Types I and II patients were treated with choledocholithotomy or choledochojejunostomy, while type III patients underwent hepatic resection and type IV patients were treated by partial hepatic resection with bilioenteric anastomosis, including extended hepatico-choledochojejunostomy. The majority of operative or early deaths belonged to type IV and residual stones were present in almost all patients. The long-term results for the 88 patients revealed that the rate of improvement was 100 per cent for type I, 87 per cent for type II, 83 per cent for type III and 84 per cent for type IV. In type IV, the most excellent results (92 per cent) were obtained by extended hepaticocholedochojejunostomy, especially with hepatectomy. It is suggested that extended hepaticocholedochojejunostomy with partial hepatic resection is a reasonable procedure for treating patients with type IV intrahepatic stones.

[Morphological studies on the pathogenesis and treatment of hepatolithiasis].

Review of 108 patients with hepatolithiasis showed a recent increase of primary intrahepatic gallstones. 55 per cent of cases with hepatolithiasis had their gallstones in the left intrahepatic bile ducts. Clinicopathological study on the resected hepatic specimens of 33 patients revealed numerous intrahepatic periductal glandular formations. Periductal glandular formations were classified into the intramural and extramural glands. The mucous substances which might had been released from the periductal glands seemed to play a role in the formation of stones in combination with bilirubin pigments, cholesterin, bacterial organisms, cellular debris and other bile component. Intrahepatic gallstones and extramural glands were seen in the intrahepatic segment and area ducts. The defunctionalized atrophic hepatic lobe or segment should be resected in order to remove the calculi completely and to prevent the recurrence.

[Evaluation of the lipid and glucose metabolism on the apancreatic status with insulin supplement and with pancreatic autotransplantation].

To evaluate the effect of pancreatic fragments transplantation on glucose and lipid metabolism in the apancreatic status, 22 healthy mongrel dogs were totally pancreatectomized and then divided into three groups, (1) 5 dogs without any supplement , (2) 5 dogs with insulin replacement, and (3) 12 dogs with additional pancreatic fragments transplantation. In these three groups, changes in fasting plasma sugar, triglyceride, total cholesterol, phospholipid and lipoprotein fractions were studied. Stability of serum glucose levels were compared between the dogs with insulin replacement and those with transplantation by using glucose infusion and insulin test. Without insulin replacement or transplantation, apancreatic dogs showed high serum glucose levels immediately after total pancreatectomy. With pancreatic transplantation, serum glucose levels and lipids were well controlled within normal limits for a long time period after the operation. However, in the dogs with insulin replacement, serum glucose levels and lipids were remarkably unstable in fasting period and also showed easily tendencies to become hypoglycemic status by insulin test and diabetic ketoacidosis by glucose infusion test as compared with those in the transplanted dogs.

Ultrastructural studies of human acute pancreatitis.

The pancreatic tissue from a patient with acute hemorrhagic necrotizing pancreatitis was studied by routine electron microscopic observation. The remarkable change was the destruction of pancreatic acinar units. 1) The acinar lumen was dilated with filling of fibrillar materials, which occasionally contained degenerated cellular components or neutrophils. 2) Accumulations of fibrillar materials were present at the periphery in the acinar cells, especially depositted thickly at the basal portion. 3) In some acinar cells, the accumulation of fibrillar materials occupied the entire acinar cell, accompanied by disappearance of luminal margin, and the intracellular fibrillar materials were mixed with acinar lumen contents. 4) The acinar units which showed above described changes had almost intact basal lamina.