[Immunotherapy advances for lung cancer combined with chronic obstructive pulmonary disease].

Lung cancer is a major public health problem worldwide, with high rates of morbidity and mortality. It often coexists with chronic obstructive pulmonary disease (COPD), the diagnosis and management of which often receives insufficient attention. In particular, the presence of COPD has significant implications for the clinical management of lung cancer patients. This review systematically assesses the influence of COPD on the efficacy of immunotherapy and the occurrence of immune-related adverse events in patients with lung cancer, identifies existing challenges and proposes avenues for future research in this field.

Increasing insulin resistance is associated with increased severity and prevalence of gastro-oesophageal reflux disease.

BACKGROUND: The diagnosis of gastro-oesophageal reflux disease (GERD) is based on reflux symptoms. Although metabolic syndrome has been linked to erosive oesophagitis (EO), the impact of insulin resistance, the core of the metabolic syndrome, on reflux symptoms remains to be elucidated. AIM: To assess the effects of insulin resistance on GERD, including both endoscopic findings and symptoms. METHODS: A total of 743 sonographic noncirrhotic adult subjects, who underwent an upper gastrointestinal endoscopic examination, completed a gastro-oesophageal reflux questionnaire and had available fasting insulin data were included. Endoscopic findings were classified according to the Los Angeles classification. Homeostatic model assessment-insulin resistance (HOMA-IR) index was used to evaluate the status of insulin resistance. Univariate and multivariate approaches were used to evaluate the associations between insulin resistance and GERD. RESULTS: Older age, male gender, smoking and alcohol consumption increased the prevalence of EO, but not GERD symptoms. A large waist circumference, high fasting blood glucose levels and high number of metabolic syndrome components were associated with increased prevalence of both EO and GERD symptoms, while high blood pressure was associated with increased prevalence of EO only. Moreover, higher scores in the gastro-oesophageal reflux questionnaire were associated with higher HOMA-IR index, and higher HOMA-IR index was associated with increased prevalence of EO (adjusted odds ratio 1.14, 95% CI 1.03-1.26, P = 0.012). CONCLUSIONS: Our findings demonstrate clear associations between insulin resistance, metabolic syndrome and GERD. Whether reducing insulin resistance may improve GERD symptoms or EO deserves prospective study.

Sensitive measurement of quantity dynamics of FLT3 internal tandem duplication at early time points provides prognostic information.

BACKGROUND: The level of minimal residual disease (MRD) in acute myeloid leukemia (AML) at early time points (TPs) may be an important prognostic factor. Although internal tandem duplication of FLT3 (FLT3-ITD) as an MRD marker has been questioned for its instability based on semi-quantitative methods, we hypothesized that FLT3-ITD dynamics measured by sensitive quantitative real-time PCR at early TPs before appearance of instability may provide prognostic information. PATIENTS AND METHODS: We measured mutant quantity in 493 serial samples from 55 patients with a median follow-up time of 64.8 months. The FLT3-ITD quantities after induction (TP1) and after the first post-induction chemotherapy (TP2) were analyzed. RESULTS: We found that lower FLT3-ITD levels at TP2 predicted longer overall survival (OS) and disease-free survival (DFS) regardless of cytogenetic risk. Multivariate analysis showed that ≥3 log reduction of FLT3-ITD at TP2 independently predicted better DFS and a trend toward better OS. FLT3-ITD disappeared at relapse in 16.7% of patients and none in those harboring mutant NPM1 compared with 29.4% in those with wild-type NPM1 (P = 0.032). CONCLUSIONS: Though the mutation may disappear at relapse in a few patients, FLT3-ITD levels at early TPs after chemotherapy provide prognostic information. FLT3-ITD is significantly more stable in those with mutant NPM1.

Positioning a safe gastric puncture point before percutaneous endoscopic gastrostomy.

To position a safe gastric puncture point prior to the percutaneous endoscopic gastrostomy (PEG) a technique using an abdominal plain film with a gastric insufflation was assessed. After insufflated with 500 ml of air, an abdominal plain film was obtained before PEG in 84 patients. The body of the stomach near the angularis, equidistant from the greater and lesser curves, was defined as the optimal gastric puncture point. The location of the puncture points varied greatly, being situated over the right upper quadrant in 31% of patients, left upper in 59%, right lower in 5% and left lower quadrant in 5% of patients. The marked puncture points on abdominal film in some patients were shown to be partially covered by colon or small bowel loop, lie high under the costal margin, or low beneath the umbilicus. An abdominal plain film utilising a gastric insufflation technique prior to PEG may help to determine optimal gastric puncture site selection. Use this technique in clinical practice might hasten procedural time, provide better assurance to the clinical doctor, and provide an added margin of safety for the patient.

Increasing EMMPRIN and matriptase expression in hepatocellular carcinoma: tissue microarray analysis of immunohistochemical scores with clinicopathological parameters.

AIMS: To examine the expression of extracellular matrix metalloprotease inducer (EMMPRIN) and matriptase in hepatocellular carcinoma (HCC) and to correlate this with tumour progression. METHODS AND RESULTS: Immunohistochemical analysis of EMMPRIN and matriptase was performed on tissue microarrays of 122 cases of HCC with various histological grades and/or clinical parameters. The expression of EMMPRIN and matriptase was undetectable in normal liver parenchyma of all eight control cases. However, among the 122 HCC cases, EMMPRIN and matriptase immunoreactivity was seen on the cell membrane and in the cytoplasm. The average immunostaining scores of EMMPRIN were 88 for grade I HCC, 195 for grade II HCC and 293 for grade III HCC. Of 85 HCC cases in 122 with detailed clinical TNM stages, the average immunostaining scores of EMMPRIN were 75 for stage T1, 177 for stage T2, 260 for stage T3 and 313 for stage T4 cases of HCC. In addition, the average immunostaining scores of matriptase were 84 for grade I HCC, 187 for grade II HCC, 302 for grade III HCC, and 72 for stage T1, 181 for stage T2, 224 for stage T3 and 284 for stage T4 cases of HCC. More advanced M and N stages of HCC were associated with higher intensity, greater percentages of tumour staining and immunostaining scores of EMMPRIN and matriptase. Higher EMMPRIN and matriptase immunostaining scores in HCCs also correlated significantly with tumour grading and TNM stages. CONCLUSIONS: Our findings demonstrate for the first time that EMMPRIN and matriptase are overexpressed in HCC. These may be novel biomarkers for the diagnosis and treatment of HCC.

A large ulcer and cutaneous small-vessel vasculitis associated with syphilis infection.

Cutaneous vasculitis (CV) is a condition with cutaneous manifestations and possible systemic involvement. The causative factors or associated diseases are usually drugs, infection, collagen vascular disease, or malignancy. Syphilis as a cause of cutaneous vasculitis is rare. We report the case of a large cutaneous ulcer and small-vessel vasculitis associated with syphilis infection. We suggest that in apparently idiopathic CV or a chronic ulcer refractory to treatment, screening should be performed to detect any underlying infection such as syphilis. It is important to have a rapid and accurate diagnosis because the lesions are very contagious, but may be rapidly and completely cured by early administration of antibiotic treatment.

Comparison of a 6-month course peginterferon alpha-2b plus ribavirin and interferon alpha-2b plus ribavirin in treating Chinese patients with chronic hepatitis C in Taiwan.

Previous studies in Caucasian patients showed treatment of chronic hepatitis C with pegylated interferon/ribavirin was well tolerated, and produced a higher response rate especially in genotype 1 infections. However, it is unknown whether this conclusion can be extrapolated to patients with Chinese ethnic origin. A total of 153 patients with biopsy-proven chronic hepatitis C were randomly assigned to receive either weekly injection of peginterferon alpha-2b 1.5 mcg/kg plus oral ribavirin (1000 or 1200 mg/day, depending on body weight) (PEG group, n = 76) or 3 MU of interferon alpha-2b t.i.w. plus ribavirin (IFN group, n = 77) for 24 weeks. Sustained virological response (SVR) was defined as the sustained disappearance of serum hepatitis C virus (HCV) RNA at 24 weeks after the end of treatment by polymerase chain reaction assay. Baseline demographic, viral and histological characteristics were comparable between the two groups. Using an intent-to-treat analysis, HCV genotype 1 patients showed a significantly higher SVR in patients receiving PEG-IFN rather than IFN (65.8%vs 41.0%, P = 0.019), but no difference was found in genotype non-1 patients (PEG vs IFN: 68.4%vs 86.8%, P = 0.060). Genotype 1 patients (28.6%) in the PEG-IFN group relapsed, as compared with 52.9% in the IFN group (P = 0.040). Multivariate analyses showed early virological response at week 12 of therapy and genotype non-1 were significant predictors to SVR. As compared with the IFN group, patients receiving PEG-IFN had a significantly higher rate of discontinuation, dose reduction, fever, headache, insomnia, leucopenia and thrombocytopenia. In genotype 1 chronic hepatitis C Chinese patient, PEG-IFNalpha2b ribavirin had significantly better SVR and lower relapse rate when compared to IFN/ribavirin. Both regimens can be recommended for genotype non-1 chronic hepatitis C Chinese patients. However, a higher rate of adverse events and discontinuance of therapy were noted in patients treated with PEG-IFNalpha2b ribavirin.

Effect of in vitro and in vivo aerosolized treatment with geniposide on tracheal permeability in ovalbumin-induced guinea pigs.

The primary objective of this study was to investigate the effect of geniposide, a potent anti-inflammatory, on ovalbumin-antigen-induced tracheal permeability and transepithelial electrical resistance in guinea pigs. Two weeks after sensitization with ovalbumin (100 mg/ml), the permeability of guinea-pig tracheas was evaluated by flux measurements using the transcellular tracer, [(14)C]estradiol, and the paracellular tracer, [(14)C]mannitol. The effect of extracellular Ca(2+) with geniposide was also studied, using deletion of Ca(2+) in the donor chamber. The in vivo treatment effect of aerosolized geniposide on tracheal permeability in the ovalbumin-sensitized guinea pigs was also evaluated. The results indicate that tight junction permeability of ovalbumin-sensitized trachea was significantly dose dependent and decreased by geniposide (1-10 mM), as evidenced by substantial recovery of transepithelial electrical resistance and decreased transepithelial permeability of [(14)C]mannitol at (1.32+/-0.12) x 10(-5) cm/s. The effect of combination of the removal of extracellular Ca(2+) with geniposide had no effect on tight junction permeability of ovalbumin-sensitized trachea and revealed that transepithelial electrical resistance and junction permeability did not recover. In addition, the cAMP levels and phosphodiesterase activity were not significantly influenced in ovalbumin-sensitized tracheal tissues after geniposide treatment. Inhaled geniposide (50 mM, 30 min after ovalbumin sensitization) significantly restored junction permeability induced by ovalbumin (100 mg/ml, 2 min). Junction permeability did not recover on pretreatment with geniposide (50 mM for 30 min over 16 days consecutive before ovalbumin sensitization) after exposure of conscious guinea pigs to aerosol ovalbumin. In conclusion, geniposide has inhibitory effects on ovalbumin-induced junction permeability and recovery of transepithelial electrical resistance in guinea pig trachea, showing its potential as anti-asthma therapy.

No sex and age influence on the expression pattern and activities of human gastric alcohol and aldehyde dehydrogenases.

BACKGROUND: Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the principal enzymes responsible for ethanol metabolism in humans. The stomach is involved in the metabolism of alcohol during absorption. Conflicting reports exist with regard to the influence of sex and age on the activity of ADH in the human gastric mucosa. The purpose of the present study was to determine the effects of age and sex on the expression pattern and activities of stomach ADH and ALDH. METHODS: A total of 115 endoscopic gastric biopsy specimens were investigated from Han Chinese men (n = 70) and women (n = 45) aged 20-79 years with approximately even distribution among 10-year age intervals. The expression patterns of ADH and ALDH were identified by isoelectric focusing, and the activities were assayed spectrophotometrically. RESULTS: The expression patterns of gastric ADH and ALDH remained unchanged with respect to sex and age. At 33 mM or 500 mM ethanol, pH 7.5, the ADH activities did not differ significantly among the various age groups or between men and women. At 200 microM or 20 mM acetaldehyde, the ALDH activities did not differ significantly in relation to sex and age. No correlations were found between the ADH or ALDH activities at both the high and low substrate concentrations and the ages in men and women. CONCLUSIONS: The results indicate that there is no significant effect of either sex or age on the expression pattern and activity of ADH and ALDH in the human gastric mucosa. The stomach ADH seems unlikely to account for possible variations in the first-pass metabolism of alcohol with regard to sex and age.

Chinese alcoholic patients with esophageal cancer are genetically different from alcoholics with acute pancreatitis and liver cirrhosis.

OBJECTIVE: It is a mystery why some alcoholic patients acquire certain organ-specific complications of alcoholism, whereas other alcoholic patients acquire different ones. The aim of this study was to investigate the differences among Chinese alcoholic patients with esophageal cancer, acute pancreatitis, and liver cirrhosis by studying the genetic polymorphisms of ADH2, ADH3, ALDH2, and P4502E1. METHODS: Liver alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and cytochrome P4502E1 (P4502E1) are polymorphic at the ADH2, ADH3, and ALDH2 loci and the 5'-flanking region of the P4502E1. Using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, we determined the polymorphism of the above-mentioned alcohol metabolizing genes in 59 alcoholics with carcinoma of the esophagus (alcoholic esophageal Ca), 87 acute alcoholic pancreatitis patients, 116 alcoholics with liver cirrhosis (alcoholic cirrhosis), 19 alcoholics with both liver cirrhosis and acute pancreatitis (alcoholic P plus C), and 241 nonalcoholic patients. RESULTS: The results showed that the allele frequency of ALDH2*2 was significantly higher in the alcoholic esophageal Ca group than in the alcoholic pancreatitis and alcoholic cirrhosis groups. The allele frequency of ADH2*1 was significantly higher in the alcoholic esophageal Ca patients than in nonalcoholic control groups. The ALDH2*2 was significantly lower in alcoholic groups (except the alcoholic esophageal Ca group) than in nonalcoholic control groups. The allele frequencies of ADH2*1 and ALDH2*2 are higher in alcoholic patients with esophageal Ca than alcoholic patients without it. The genotype distribution of P4502E1, detected by RsaI and PstI, was not different among alcoholic patients with different organ diseases. CONCLUSIONS: The allele frequency of ADH2*1 and ALDH2*1 are different among subpopulations of alcoholics, suggesting that alcoholic patients with different specific types of organ damage are genetically different. The Chinese alcoholic patients with the ADH2*1 and ALDH2*2 allele are more susceptible to esophageal Ca.

Bcl-2 accelerates retinoic acid-induced growth arrest and recovery in human gastric cancer cells.

The role of Bcl-2 as an anti-apoptotic protein has been well documented. In the present work, we present evidence that Bcl-2 may also be involved in cell growth regulation. SC-M1 is an unique cell line which responds to retinoic acid (RA) treatment with reversible growth arrest [Shyu, Jiang, Huang, Chang, Wu, Roffler and Yeh (1995) Eur. J. Cancer 31, 237-243]. In this study, when treated with RA, SC-M1/Bcl2 cells, which were generated by transfecting SC-M1 cells with bcl-2 DNA, were growth-arrested two days earlier than SC-M1/neo cells, which were generated by transfecting SC-M1 cells with vector DNA. This indicates that Bcl-2 accelerates RA-induced growth arrest. In addition to the accelerated growth arrest, RA-treated SC-M1/Bcl2 cells also recovered from growth arrest two days faster than SC-M1/neo cells after the removal of RA. Previously, we had identified the cyclin-dependent kinase inhibitor p21((WAF1/CIP1)) (p21) as a mediator of RA-induced growth arrest [Tsao, Li, Kuo, Liu and Chen (1996) Biochem. J. 317, 707-711]. In a search for the mechanism by which Bcl-2 affects growth regulation, we found that p21 gene expression was more prominent in SC-M1/Bcl2 cells than in SC-M1/neo cells in the presence of RA, but when RA was removed, p21 gene expression levels in SC-M1/Bcl2 cells were also reduced earlier than in SC-M1/neo cells. The present report is the first to show that Bcl-2 accelerates not only growth arrest but also recovery from growth arrest. Moreover, the close correlation between the effect of Bcl-2 on both RA-induced growth arrest and RA-induced p21 gene expression suggests the possibility that Bcl-2 affects cell growth through the mechanism of p21.

Chronic idiopathic intestinal pseudo-obstruction.

Chronic idiopathic intestinal pseudo-obstruction (CIIP) is a rare heterogeneous clinical syndrome characterized by recurrent episodes of symptoms and signs of intestinal obstruction in the absence of a mechanically obstructing lesion. Dilatation of other viscera, such as the renal pelvis, ureter or urinary bladder, is identified in a minority of patients. We report the cases of two patients with CIIP presenting with abdominal fullness and constipation. Radiologic examination of the first patient revealed dilatation of the esophagus, stomach, duodenum and bowel loops up to the ascending colon. The nerve conduction velocity study of the right extremities revealed polyneuropathy and urinary bladder manometry revealed poor sensation. The patient had been admitted to our hospital three times for symptomatic relief within the prior six months. During the last admission, his symptoms persisted without response to medical treatment. Soon after discharge, the patient underwent surgery at another hospital and died of nutritional problems. The second patient was transferred to our hospital after an exploratory laparotomy was performed one month earlier. A radiographic examination revealed distention of the stomach, duodenum, small intestine and ascending colon, as well as bilateral hydronephrosis. Rheumatologic examination revealed no evidence of autoimmune disorder. The patient also had heavy proteinuria due to minimal change disease that was proven by renal biopsy. After receiving prokinetic, cathartic and corticosteroid medication for kidney disease, symptoms improved, but hydronephrosis persisted.

Conformation of heterocycles controlled by the existence of unusual C-H...X hydrogen bonds: syntheses and structure determination of aluminum aryloxides.

The reactions of AlMe3 in diethyl ether with 1 molar equiv of 2,2'-methylenebis(4-methyl-6-tert-butylphenol) (MMBP-H2), 2,2'-methylenebis(4,6-di-tert-butylphenol) (MDBP-H2), and 2,2'-ethylidenebis(4,6-di-tert-butylphenol) (EDBP-H2) afford series of four-coordinate monomeric aluminum aryloxides, MeAl(O-O)(OEt2), 1-3 (1, (O-O) = MMBP; 2, (O-O) = MDBP; 3, (O-O) = EDBP). In THF, 1 molar equiv of EDBP-H2 reacts with AlMe3 to provide the THF-coordinated complex MeAl(EDBP)(THF) 4. However, in the absence of a coordinating solvent, the reaction of EDBP-H2 with AlMe3 yields the dimeric complex [MeAl(mu-EDBP)]2 (5). Complex 5 further reacts with Et4NCl, Et4NBr, and Ph3PO to afford the corresponding monomeric ionic complex [Et4N][MeAl(EDBP)(X)] (6, X = Cl; 7, X = Br) and the neutral complex [MeAl(EDBP)(O=PPh3)] (8), respectively. Complexes 1, 2, 4 and 6-8 are subjected to X-ray structure analyses, and the solid state structures reveal that the conformations of the eight-membered heterocycles are governed by the formation of the unusual C-H...X hydrogen bonds.

Cystic lymphangioma of the transverse colon: report of a case and review of the literature.

A 32-year-old Chinese man with cystic lymphangioma of the transverse colon is described. He presented with a 1-year history of altered bowel habits. Double-contrast barium enema study demonstrated a submucosal lesion in the midportion of the transverse colon with intact mucosa. Computed tomography (CT) showed a round 3.0-cm submucosal cystic mass lesion. Colonoscopy revealed a smooth, soft polypoid mass on a broad base. He underwent segmental resection of the colon. Histologically, the lesion was characterized by cystic lymphangioma originating from the submucosa. The clinical features, radiology, appropriate treatment, and possible pathogenesis of colonic lymphangioma are discussed.

The importance of conserved residues in human liver UDPglucose pyrophosphorylase.

Comparison of the amino acid sequences of five eukaryotic UDPglucose pyrophosphorylases has identified a number of conserved residues that may be important for substrate binding or catalysis. Using the cloned cDNA for the human liver enzyme, we have investigated the role of several of these residues by site-directed mutagenesis. Changing the single conserved cysteine (residue 123) to serine resulted in an active enzyme, as did mutating the single concerned histidine (residue 266) to arginine. The two conserved tryptophans were each altered to serine; W218S is active while W333S is not. In the latter case, the enzyme does not appear to fold correctly, and a similar result was obtained by mutation to lysine at one (residue 391) of the four conserved arginines. The other three arginines are not essential, as judged by the observation that R389H, R422Q and R445H are all active. The kinetic properties of each active mutant were investigated and in most cases were found to be similar to those of wild-type. The most dramatic change is a sevenfold increase in the Km for magnesium pyrophosphate with C123S. Overall, none of these conserved residues appears to be essential for activity, although such a role cannot be ruled out for W333 and R391 where mutation resulted in defective folding.