Progression to Lymph Node Metastasis After Spontaneous Regression of Pulmonary Adenocarcinoma Following Biopsy.

BACKGROUND/AIM: Spontaneous regression (SR) of cancer, which indicates the natural disappearance of malignant tumors, is rare. Little is known about the mechanisms underlying SR; however, immunological reactions, infections, injuries, and medications have been presumed. Among previously reported cases of SR, lung cancer cases have been extremely limited. CASE REPORT: Here, we present a case of lymph node metastasis exacerbation after SR of a primary adenocarcinoma following a biopsy. After complete disappearance of the primary site tumor, metastatic lymph nodes in the mediastinum gradually increased in size as a single lesion. Local treatment with resection and radiotherapy was effective for this metastasis, without recurrence for >3 years. CONCLUSION: This is an interesting case of SR of pulmonary adenocarcinoma with inconsistent features in the primary and metastatic lesions. When physicians encounter exacerbation of metastatic sites with SR of the primary site in lung cancer, local intervention may be considered as a curative treatment.

Therapeutic Resistance in G-CSF Producing Lung Cancer With EGFR Mutation.

Background/Aim: Granulocyte colony-stimulating factor (G-CSF)-producing neoplasms are relatively rare; however, little is known on the clinical features of G-CSF-producing lung cancer harboring activating epidermal growth factor receptor (EGFR) mutations. Case Report: A 66-year-old female was definitively diagnosed with G-CSF-producing lung cancer that was positive for EGFR mutations. She repeatedly received epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as osimertinib and afatinib. However, she developed resistance to these molecular-targeting drugs within 2 to 3 months after immediate shrinkage. Thus, the patient was treated with chemoimmunotherapy including bevacizumab, and demonstrated a slight survival benefit. Conclusion: Overall, G-CSF-producing lung cancers positive for EGFR mutations were resistant to different treatment modalities. Clinicians should be attentive to the potential resistance of G-CSF-producing EGFR mutant lung cancer to EGFR-TKI therapy.

Metabolic Tumor Volume as Significant Predictor for Chemotherapy Containing PD-L1 Blocker in Extensive Stage Small Cell Lung Cancer.

BACKGROUND/AIM: Chemo-immunotherapy, including the programmed death ligand 1 (PD-L1) antibody, is an effective treatment for patients with extensive-stage small-cell lung cancer (ES-SCLC). However, no biomarker has been established for the prediction of chemo-immunotherapy. Therefore, we investigated the potential of 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) as a predictive marker. PATIENTS AND METHODS: Forty-six patients with ES-SCLC who received 18F-FDG-PET immediately before combined platinum-based chemotherapy with PD-L1 blockade as a first-line treatment were eligible, and the maximum standard uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) on 18F-FDG uptake were evaluated. RESULTS: PD-L1 and tumor infiltrative lymphocytes (TILs) were immunohistochemically analyzed in 36 of the 46 patients. A high MTV was significantly associated with poor performance status and low albumin levels, and there was a significant association between low albumin and high TLG. Univariate analysis identified sex, Brinkman index, and MTV as significant predictors of progression-free survival (PFS), and sex, SUVmax, MTV, and TLG as significant factors of overall survival (OS). Multivariate analysis revealed that sex, Brinkman index, and MTV were independent prognostic factors for PFS, and sex, SUVmax, MTV, and TLG were significant predictors of OS. SUVmax was significantly higher in patients with positive PD-L1 expression than in those with negative expression but was not significantly different between positive and negative TILs. Moreover, the levels of MTV and TLG were not closely associated with the levels of PD-L1 and TILs. CONCLUSION: MTV or TLG metabolic tumor activity is suitable for the prediction of chemo-immunotherapy outcomes in patients with ES-SCLC.

Lack of antibodies against the antigen domain 2 epitope of cytomegalovirus (CMV) glycoprotein B is associated with CMV disease after renal transplantation in recipients having the same glycoprotein H serotypes as their donors.

Cytomegalovirus (CMV) reinfection of seropositive individuals has been associated with adverse outcomes in organ transplantation and is a frequent cause of congenital infection. Previously we demonstrated that mismatching of CMV glycoprotein H (gH) serotypes was associated with CMV disease after renal transplantation. Because the antigen domain 2 (AD2) epitope of glycoprotein B (gB) is conserved among CMV isolates and is one of the known targets of neutralizing antibodies, in this study we investigated whether antibodies against the epitope contribute to protection from CMV reinfection in renal transplantation, irrespective of gH serological matching. For this purpose, the gB and gH serology and clinical outcomes were analyzed retrospectively for 77 transplant recipients in the donor positive/recipient positive setting, who were managed by preemptive strategy. We found that there was a good negative correlation between the numbers of antigenemia-positive cells and the levels of antibodies against gB AD2 in the CMV-gH antibody matched group, but not in the CMV-gH antibody mismatched group. None of the recipients with antibodies against both gB AD2 and strain-specific epitopes of gH have experienced CMV disease during 6 month after transplantation, while 28% of those who lacked either/both antibody response needed preemptive therapy. Because the outcome was statistically significant, antibodies against gB AD2 can be a useful indicator to predict emergence of CMV disease for preemptive therapy, in addition to antibodies against the mismatched gH types.

Urinary urgency - translating the evidence base into daily clinical practice.

AIM: To consider the currently available knowledge and understanding of the symptom of urgency. MATERIALS & METHODS: Each faculty member reviewed the literature base of a different aspect of urgency and along with their personal clinical experience provided a base of evidence for discussion. RESULTS: This overview summarises relevant published literature and the current clinical experience of the authors. DISCUSSION: Whilst the mechanisms producing the sensation of urgency are still not fully understood and we are working within a definition that may complicate measurement and treatment, our pressing need is to effectively manage our patients for whom the practical nature of urgency can be all too apparent. CONCLUSION: Health care professionals have an important role to play today in helping to alleviate the widespread problem of urgency and its consequences.

Phase I Study Evaluating the Combination of Afatinib with Carboplatin and Pemetrexed After First-line EGFR-TKIs.

BACKGROUND/AIM: Promising reports have described the combination of first-generation epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKIs) with carboplatin plus pemetrexed or bevacizumab. However, no analysis of afatinib with platinum-doublet chemotherapies has been performed. PATIENTS AND METHODS: We evaluated the safety and antitumor efficacy of afatinib combined with carboplatin and pemetrexed in EGFR-mutated non-small-cell lung cancer (NSCLC) patients who progressed during first-generation EGFR-TKIs. RESULTS: Ten patients received 20 or 30 mg/day afatinib with carboplatin (area under the curve, 5) and pemetrexed (500 mg/m2). Dose-limiting toxicities included delay of afatinib ≥14 days, grade 3 diarrhea, grade 3 hypokalemia, grade 3 serum amylase increase and grade 4 thrombocytopenia. The recommended dose of afatinib was 20 mg/day in this combination therapy. Overall response rate was 30% and median progression-free survival was 13.7 months. CONCLUSION: This is the first study to investigate the combination of afatinib, carboplatin and pemetrexed. At the recommended dose, this combination was well tolerated and had a good clinical efficacy.

In vitro hydrolysis of oligomannose-type sugar chains by an alpha-1,2-mannosidase from microsomes of developing castor bean cotyledons.

An alpha-1,2-mannosidase involved in the processing of N-linked oligosaccharides was prepared from the microsomal fraction of developing castor bean cotyledons. The processing alpha-mannosidase was solubilized with 1.0% Triton X-100 and purified by ion-exchange chromatography followed by two gel filtration steps. The enzyme obtained could convert Man9GlcNAc2-PA to Man5GlcNAc2-PA, but this enzyme was inactive with Man5GlcNAc2-PA, Man4GlcNAc2-PA, and p-nitrophenyl-alpha-D-mannopyranoside. The enzyme was optimally active between pH 5.5-6.0. The processing mannosidase was inhibited by deoxymannojirimycin, EDTA, and Tris ions but not by swainsonine. Structural analyses of the mannose-trimming intermediates produced by the alpha-mannosidase revealed that specific intermediates were formed during conversion of Man9GlcNAc2-PA to Man5GlcNAc2-PA.

The healing process of infarct-related plaques. Insights from 18 months of serial angioscopic follow-up.

OBJECTIVES: To clarify the healing process of disrupted culprit plaques of acute myocardial infarction (MI), we serially observed the culprit plaques for 18 months after the onset of acute MI by angioscopy. BACKGROUND: Although it has been reported that disruption of the yellow plaque and subsequent thrombosis cause acute MI and that the thrombogenicity of the plaque lasts for a month, the healing process of the plaque after disruption has not been clarified. METHODS: Eighty-five patients with acute MI were prospectively and consecutively enrolled. Angioscopic studies were performed immediately and at 1, 6 and 18 months after successful reperfusion. The prevalence of yellow plaques and thrombus was examined. The color grade of the plaque was determined as 0 (white), 1 (light yellow), 2 (yellow) or 3 (bright yellow). RESULTS: Although yellow plaque was present at the culprit lesion in most patients throughout follow-up, its color grade was reduced from one to six months (1.9 +/- 0.6 vs. 1.1 +/- 0.7, p = 0.0003) after reperfusion, especially in the patients without hyperlipidemia (HL). The incidence of thrombus was 92.5% immediately after reperfusion, which was reduced significantly to 63.8%, 4.8% and 11.8% at 1, 6 and 18 months, respectively. The incidence of thrombus (77.8% vs. 45.0%, p = 0.03) at one month was higher in the patients with diabetes mellitus (DM). CONCLUSIONS: The healing process of yellow plaques at the culprit lesions of MI was detected by angioscopy as reductions of color grade and thrombogenicity at six months and partially at one month after the onset of acute MI. This healing process appears to deteriorate by complicating cases of DM or HL.

Extensive development of vulnerable plaques as a pan-coronary process in patients with myocardial infarction: an angioscopic study.

OBJECTIVES: To test our hypothesis that the development of vulnerable plaques is not limited to the culprit lesions, but is a pan-coronary process, we directly observed all three major coronary arteries by angioscopy and evaluated the prevalence of yellow plaques in patients with myocardial infarction (MI). BACKGROUND: Although pathologic studies have suggested that the disruption of atheromatous plaque plays a major role in the development of acute MI, the prevalence of yellow plaques in the whole coronary arteries of patients with MI has not been clarified. METHODS: Thirty-two patients undergoing follow-up catheterization one month after the onset of MI were prospectively and consecutively enrolled in this study. The prevalence of yellow plaques and thrombus in the major coronary arteries was successfully evaluated in 20 patients (58 coronary arteries, 21 culprit lesions) by coronary angioscopy. The diameter stenosis (DS) of the culprit lesions and the maximal diameter stenosis (maxDS) of nonculprit segments were angiographically measured for each coronary artery. RESULTS: The DS of the culprit lesions and maxDS were 27 +/- 17% and 19 +/- 13%, respectively. Yellow plaques and thrombus were detected in 19 (90%) and 17 (81%) of 21 culprit lesions, respectively. Yellow plaques were equally prevalent in the infarct-related and non-infarct-related coronary arteries (3.7 +/- 1.6 vs. 3.4 +/- 1.8 plaques/artery). However, thrombus was only detected in the nonculprit segments of one (2%) coronary artery. CONCLUSIONS: In patients with MI, all three major coronary arteries are widely diseased and have multiple yellow though nondisrupted plaques. Acute MI may represent the pan-coronary process of vulnerable plaque development.

The genetic structure of natural populations of Drosophila melanogaster. XI. Genetic variability in a local population.

Six hundred and ninety-one second chromosomes were extracted from a Raleigh, North Carolina population, and the following experimental results were obtained: (1) Salivary gland chromosomes of all lines were observed and the number of inversion-carrying chromosomes was 130, among which 76 carried In(2R)NS, 36 carried In(2L)t, 4 carried In(2L)t and In(2R)NS, and 14 carried different kinds of rare inversions. (2) Viabilities of homozygotes and heterozygotes were examined. The frequency of lethal-carrying chromosomes was 275/691 (or 0.398):70/130 (or 0.538) in inversion-carrying chromosomes and 205/561 (or 0.365) in inversion-free chromosomes. The former is significantly higher than the latter. The average homozygote viability was 0.4342 including lethal lines and 0.7163 excluding those, the average heterozygote viability being 1.0000. The detrimental load to lethal load ratio (D:L ratio) was 0.334/0.501 = 0.67. The average viability of lethal heterozygotes was less than that of lethal-free heterozygotes, significantly in inversion-free individuals but not significantly so in inversion-carrying individuals. Inversion heterozygotes seem to have slightly better viability than the inversion-free heterozygotes on the average, but not significantly so. (3) The average degree of dominance of viability polygenes was estimated to be 0.293 +/- 0.071 for all heterozygotes whose component chromosomes had better viabilities than 0.6 of the average heterozygote viability, 0.177 +/- 0.077 for inversion-free heterozygotes and 0.489 +/- 0.082 for inversion heterozygotes. (4) Mutation rates of viability polygenes and lethal genes were estimated on the basis of genetic loads and average degrees of dominance of lethal genes and viability polygenes. Estimates were very close to those obtained by direct estimation. (5) Possible overdominance and epistasis were detected, but the magnitude must be very small. (6) The effective size of the population was estimated to be much greater than 10,000 by using the allelism rate of lethal-carrying chromosomes (0.0040) and their frequency.-On the basis of these findings and the comparison with the predicted result (Mukai and Maruyama 1971), the mechanisms of the maintenance of genetic variability in the population are discussed.

Variation of spontaneous occurrence rates of chromosomal aberrations in the second chromosomes of Drosophila melanogaster.

After accumulating mutations by the aid of marked inversions, spontaneous occurrence rates of chromosome aberrations were estimated for 1148 chromosome lines that originated from five stem line second chromosomes of Drosophila melanogaster. In chromosome lines originating from three stem chromosomes (CH, PQ, and RT), mutations were accumulated for 7550, 7252, and 7256 chromosome generations, respectively, but no structural change was detected. For the chromosome lines that originated from the other two stem chromosomes, the situation was different: Twenty aberrations (19 paracentric inversions and 1 translocation between the second and the third chromosomes) during 45990 chromosome generations took place in the 500 chromosome lines derived from stem line chromosome (AW), and 92 aberrations (83 paracentric inversions, 6 pericentric inversions, 2 translocations between the second and the third chromosomes and 1 transposition) arose during 45006 chromosome generations in the 500 chromosome lines derived from stem line chromosome (JH). For the AW group the occurrence rate becomes 0.00043 per chromosome per generation for all aberrations and 0.00041 for inversions. For the JH group the corresponding rates are 0.00204 and 0.00198, respectively.-A non-random distribution of the breakpoint on the salivary gland chromosome was observed and the breakpoints were concentrated in the regions 26, 29, 33, and 34.-The cytoplasms and the chromosomes (other than the second chromosomes) were made approximately uniform throughout the experiments. Thus, this remarkable variability in the occurrence rate is most probably due to the differences in one or more chromosomal elements on the original five stem chromosomes. The mutable chromosomes (AW and JH) appear to carry a kind of mutator factor such as hi (Ives 1950).

High Rates of Occurrence of Spontaneous Chromosome Aberrations in DROSOPHILA MELANOGASTER.

Spontaneous mutations were accumulated for 40 generations in 140 unrelated second chromosomes with the standard gene arrangement. These were extracted from the same population by using the marked inversion technique, and the following findings were obtained: (1) In 42 out of the 140 chromosome lines, chromosome aberrations were detected by examining the salivary gland chromosomes: 40 paracentric and 15 pericentric inversions, 2 reciprocal translocations between the second and the third chromosomes, and 6 transpositions. (2) In 63 out of the 90 originally lethal-free lines, recessive lethal mutations occurred. (3) There were only 3 lines that acquired chromosome aberrations (inversions) with no lethal effects in the homozygous condition. (4) In a comparison of these results with those of the (CH), (PQ), and (RT) chromosomes in which no chromosome aberrations occurred after accumulating mutations for 22058 chromosome.generations (Yamaguchi and Mukai 1974), it was concluded that some of these 140 chromosomes carried a kind of mutator. (5) The frequency of mutator-carrying chromosome lines was estimated to be 0.66 on the basis of the distribution of the break-points on the chromosome lines and the frequency of lines that acquired neither recessive lethal mutations nor chromosome aberrations. Thus, the average number of breaks per mutator-carrying chromosome was estimated to be about 0.19/generation.On the basis of these estimates, the nature of the mutator factor was discussed.

The genetic structure of natural populations of Drosophila melanogaster. XII. Linkage disequilibrium in a large local population.

Seven hundred and three second chromosomes were extracted from a Raleigh, North Carolina population of Drosophila melanogaster in 1970. Additionally, four hundred and eighty-nine third chromosomes were extracted from a large cage population founded from the flies in the 1970 Raleigh collection. The alpha glycerol-3-phosphate dehydrogenase-1, malate dehydrogenase-1, alcohol dehydrogenase, and alpha amylase loci were studied from the second chromosomes, and the esterase-6, esterase-C, and octanol dehydrogenase loci were analyzed from the third chromosomes. Inversions, relative viability and fecundity were studied for both classes of chromosomes. The following significant findings were obtained: (1) All loci examined were polymorphic or had at least two alleles at appreciable frequencies. Analysis of the combined data from this experiment with that of Mukai, Mettler and Chigusa (1971) revealed that the frequencies of the genes in the second chromosomes collected in early August were approximately the same over three years. (2) Linkage disequilibria between and among isozyme genes inter se were not detected except in a few cases which can be considered due to non-random sampling. (3) Linkage disequilibria between isozyme genes and polymorphic inversions were detected when the recombination values between the breakage points of the inversions and the genes in question were small. In only a few cases, were second and third order linkage disequilibria including polymorphic inversions detected. (4) Evidence for either variation among genotypes within loci or cumulative effects of heterozygosity was found for viability and fecundity. As a result of these findings, it was tentatively concluded that although selection might be perceptibly operating on some polymorphic isozyme loci, most of the polymorphic isozyme genes are selectively neutral or near-neutral in the populations studied.

Linkage disequilibrium in isolated populations of Drosophila melanogaster.

In order to test the interaction effect of overdominance and random genetic drift on the formation of linkage disequilibria under the condition of multiplicative gene action, linkage disequilibria between isozyme genes, inter se, and between polymorphic inversions and isozyme genes were tested for the second chromosomes of Drosophila melanogaster sampled from two isolated Pacific islands and one locality of the northern district of the mainlands of Japan. The effective sizes of these populations were known to be approximately 3,000 to 6,000 on the basis of the allelism rate of lethal chromosomes and their frequencies. The following results were obtained: (1) No linkage disequilibrium considered to be induced by epistasis, including the interaction between overdominance and random genetic drift, was detected. (2) Nonrandom association between polymorphic inversions and isozyme genes that are included in the inversions or located in the adjacent region outside the inversions was detected. (3) On the basis of the comparison of chi (2) values, indicating the magnitudes of linkage disequilibrium, between the present isolated populations and the Raleigh, N.C., population (Mukai et al. 1974, 1977), the characteristics of the isolated populations and the nature of these linkage disequilibria are discussed.

The genetic variability of third chromosomes in a local population of Drosophila melanogaster.

Five hundred and two third chromosomes were extracted from a large cage population of Drosophila melanogaster initiated two months after collection of the progenitors near Raleigh, North Carolina in 1970.---Salivary gland chromosomes of 489 chromosome lines were examined and 54 chromosomes were found to carry inversions. The inversions were classified into three polymorphic types [In (3L)P, In (3R)P, and In (3R)C] and two unique types. The polymorphic inversions were found in frequencies of 0.012, 0.88, and 0.010, respectively.--Viabilities of homozygotes and heterozygotes were examined. Chromosomes with lethals occurred with a frequency of 0.495: 0.537 in the group of inversion-carrying chromosomes and 0.490 in the group of inversion-free chromosomes. The average homozygote viability computed on the basis of an average heterozygote viability of 1.0000 was 0.3235 if lethal lines were included and 0.6290 if they were excluded. The detrimental load to lethal load ratio (D:L ratio) was 0.70 (=0.4636-0.6650). The average viability of lethal heterozygotes was significantly larger than that of lethal-free heterozygotes. It appears, however, that lethal genes in heterozygotes have deleterious effects on fitness as a whole.--The average degree of dominance for viability polygenes was estimated to be about 0.3-0.4 in lethal-free individuals and nearly zero in lethal heterozygotes. Overdominance or some form of balancing selection was suggested at some loci. The difference between the values obtained for average degree of dominance due to genetic backgrounds and superior vibaility of lethal heterozygotes (but not fitness as a whole) suggest that some epistasis or coadaptation occurs.--The results described above are similar to those obtained for the second chromosomes.

Chemical structures of two subunits, A-subunit and B-subunit, of galactose-specific isolectins from Erythrina variegata seeds.

We previously isolated galactose-specific isolectins, EVLI, EVLII, and EVLIII, from the Erythrina variegata seeds [J. Chromatogr. 597, 207-211 (1992)]. The amino acid sequences of the two subunits, A- and B-subunits, of which the isolectins are composed, were determined. A comparison of the amino acid sequences of tryptic peptides from the two subunits revealed seven amino acid substitutions. Among them, Asn46, to which the oligosaccharide chain is linked in the A-subunit, is replaced by Asp46 in the B-subunit, causing the B-subunit to lack one glycosylation site. The N-linked oligosaccharides of these subunits were also analyzed. The N-linked oligosaccharides were first liberated by hydrazinolysis. After N-acetylation, the reducing ends of the oligosaccharides were coupled with 2-aminopyridine, and then the pyridylamino (PA-) derivatives were purified by gel filtration and HPLC on an ODS-silica column. One major sugar chain, accounting for more than 98% of the total, was purified from both species. The structure of this major sugar chain was established to be Man alpha 6(Man alpha 3)(Xyl beta 2)Man beta 4GlcNAc beta 4(Fuc alpha 3)GlcNAc. This finding that there is no structural difference of the sugar chains linked to the two subunits of E. variegata lectins, together with the results of amino acid sequence comparisons, indicates that the difference in molecular mass of these two subunits results almost wholly from the difference in the number of oligosaccharides linked to them.

Enhancement of mycinamicin production by dotriacolide in Micromonospora griseorubida.

Production of macrolide antibiotic mycinamicin was greatly increased by addition of sulfate ion into the culture medium of Micromonospora griseorubida. An O-sulfate ester compound, also produced by the strain, was shown to be dotriacolide. In an M. griseorubida dotriacolide non-producing strain, the production level of mycinamicin remained low, but increased to the level of dotriacolide producing strain by the addition of dotriacolide. Dotriacolide enhanced mycinamicin production in M. griseorubida by the formation of micelles with mycinamicin. As a result, dotriacolide played a critical role in mycinamicin production in M. griseorubida.

A new assay for classical swine fever virus based on cytopathogenicity in porcine kidney cell line FS-L3.

A new assay termed the dome disappearance method for classical swine fever virus (CSFV) using FS-L3 cells with serum-free culture medium was developed. The CSFV live vaccine GPE- strain grows well and shows a slight cytopathic effect (CPE) in FS-L3 cells. This CPE results in the disappearance of the unique fluid-filled multicellular domes on a single monolayer of FS-L3 cells. By using this phenomenon, dome disappearance, as a marker of infection, it was possible to determine the titers of CSFV and its neutralizing antibody. The virus titer determined by this method shows a good correlation with that determined by immunochemical and interference methods. Furthermore, the amount of neutralizing antibody measured by this method also correlated with that measured by the Exaltation of Newcastle Disease Virus (END) neutralizing method. The dome disappearance method developed in this experiment is a simple and safe procedure and has the great advantage that bovine serum, which may contain antibody against bovine viral diarrhea virus, is not necessary for the cultivation of FS-L3 cells.

Prototype of a reflux-preventing ureteral stent and its clinical use.

We have experimentally produced a ureteral stent which prevents vesicorenal reflux. This stent has a thin silicon sleeve at its distal end (intravesical portion). In a model experiment the sleeve demonstrated an excellent capability to prevent reflux. The sleeve allowed flow of fluid with minimal pressure rise. A patient with bilateral ureteral obstruction was managed with endoscopic insertion of a sleeved stent in the right ureter and a usual pigtail stent in left ureter. During cystography vesicorenal reflux was not observed on the right side while reflux occurred on the left side. Excretory urography forty days after stent placement demonstrated recovery of renal function and maintenance of drainage in both renal units. Thus, the drainage characteristic of this stent appears to be approximately the same as that of usual stent.