A Case of Sorafenib-induced DRESS Syndrome in Hepatocelluar Carcinoma.

Sorafenib is currently the only targeted therapy available for advanced stage hepatocellular carcinoma (HCC). Cutaneous adverse events associated with sorafenib treatment include hand-foot skin reaction, but there has been no report of drug reaction (or rash) with eosinophilia and systemic symptoms (DRESS) syndrome. Here, we report a case of 72-year-old man with HCC and alcoholic liver cirrhosis who developed skin eruptions, fever, eosinophilia, and deteriorated hepatic and renal function under sorafenib treatment. He has since successfully recovered with conservative care.

Prevalence and risk factors for depression in Korean adult patients with asthma: is there a difference between elderly and non-elderly patients?

Depression is an important comorbidity of asthma. However, little information is available about depression and its potential impact on asthma control in Korean adult asthma patients. We aimed to estimate the prevalence and risk factors for depression in Korean adults with persistent asthma. The 127 non-elderly (20-64 yr) and 75 elderly (≥65 yr) patients with asthma were recruited. Demographic and clinical data were extracted, and the patients completed the Asthma Specific Quality of Life (AQOL) questionnaire and asthma control test (ACT). Depression status was defined using the Korean version of the Patient Health Questionnaire-9 (PHQ-9). Depression was more prevalent in non-elderly (18.9%) than in elderly patients with asthma (13.3%). Patients with depression were significantly younger, had lower economic status, shorter disease duration, poorer asthma control, and worse AQOL scores (P<0.05). Within the non-elderly group, younger age and shorter disease duration were significantly associated with depression (P<0.05). Within the elderly group, a higher body mass index and current smoking status were significantly associated with depression (P<0.05). The PHQ-9 score was significantly correlated with worse ACT and AQOL scores in both groups. In conclusion, depression is strongly associated with poor asthma control and quality of life in Korean adult asthma patients. Our results provide important clues that used to target modifiable factors which contribute to development of depression in asthma patients.

Characteristics of additional primary malignancies in Korean patients with non-small cell lung cancer.

BACKGROUND: Long-term cancer survival results in increasing numbers of multiple primary malignancies in one person, which represents growing clinical challenge in patients with lung cancer. This study was intended to assess the incidence rate, temporal relationship, and characteristics of additional primary malignancies (APM) in Korean patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We reviewed all 632 NSCLCs (313 adenocarcinomas, 276 squamous cell carcinomas, and 43 other NSCLCs) patients who underwent curative resection of NSCLC at the Dong-A University Medical Center from January 1991 to December 2009. We used the hospital information system and medical record to collect data about these patients and their tumors. In the data base, the following parameters were recorded: patient's demographics (age, gender and smoking habit), time interval between the diagnosis of the NSCLC and APM, NSCLC characteristics (date of diagnosis, histology, TNM staging, operative details, and survival) and characteristics of APM (site of tumor, date of diagnosis, histology, TNM staging, operative details, and survival). RESULTS: Eighty-one (12.8%) of the 632 patients with NSCLC had APMs. Thirty-three patients (40.8%) had APM in their history [occurring earlier than six months or more before NSCLC diagnosis; prior (P) group], 18 patients (22.2%) were diagnosed with an APM synchronously [diagnosed within six months before or after NSCLC; synchronous (S) group], and the remaining 30 patients (37.0%) were diagnosed with an APM during the follow-up period [occurring six months or more after NSCLC diagnosis; metachronous (M) group]. The second primary malignancy occurred most often two to five years in both P group (39.4%) and M group (36.7%). The most frequent APM was stomach cancer (25.0%), followed by colorectal cancer (19.0%), and thyroid cancer (10.7%). Interestingly, we found difference in the incidence of APM between different NSCLC histotypes. In the adenocarcinoma group, colorectal cancer was the most frequently discovered [12 of 46 events (26.1%)], followed by thyroid cancer [9 of 46 events (19.6%)]. In the squamous cell carcinoma group, stomach cancer occurred most frequently [12 of 36 events (33.3%)]. CONCLUSIONS: APMs are commonly seen in patients with NSCLC, either preceding or following its occurrence. Therefore, it is important to recognize the characteristic of NSCLC patients with APM in order to detect the second primary malignancy as early as possible and to achieve a possible cure of disease.

Liver cirrhosis as a delayed complication of Stevens-Johnson syndrome.

A 26-year-old woman was referred to our department due to fever and skin rash after having taken medication for a common cold. Physical examination revealed erythematous skin changes on her body associated with mucosal involvement in her eyes and oral cavity. Peripheral blood examination revealed leukopenia and thrombocytopenia. Liver function test showed hyperbilirubinemia. She was managed with high dose intravenous immunoglobulin (IVIG) at 1.0 gm/kg of body weight infused for 5 consecutive days. Although the patient's skin lesion improved dramatically with IVIG therapy, her hyperbilirubinemia aggravated progressively. Eighteen months after her presentation, liver cirrhosis was diagnosed by ultrasonography, laboratory and liver biopsy findings.

Skills in handling turbuhaler, diskus, and pressurized metered-dose inhaler in korean asthmatic patients.

PURPOSE: The objective of this study was to evaluate skills in handling inhalers and factors associated with these skills among patients with asthma who had undergone treatment at special asthma and allergy clinics in Korea. METHODS: We enrolled 78 subjects who used Turbuhaler and 145 who used Diskus for asthma control at special clinics in 10 university hospitals and visually assessed their skills in handling these inhalers. We also evaluated skills in 137 subjects who had used pressurized metered-dose inhalers (pMDIs) for symptom relief. Age, sex, duration of asthma and inhaler use, smoking status, monthly income, highest grade completed in school and previous instruction for handling inhalers were also measured to evaluate their association with overall inhaler skills. RESULTS: Performance grade was inadequate for 12.8% of participants using Turbuhaler, 6.2% for Diskus, and 23.4% for pMDIs. The success rates for each step in handling the inhalers were relatively high except for the "exhale slowly to residual volume" step, in which success rates ranged from 24.2% to 28.5%. Older age, male sex, lower educational grade, and absence of previous instruction for handling inhalers were associated with inadequate inhaler technique in univariate analysis; however, only older age and absence of previous instruction remained significant independent risk factors in multivariate analysis. CONCLUSIONS: Among Korean asthmatic patients in special asthma and allergy clinics, skills in handling their inhalers were mostly excellent; meanwhile, older age and absence of previous instruction for handling inhalers were associated with inadequate techniques.

Phase I study of autologous dendritic cell tumor vaccine in patients with non-small cell lung cancer.

BACKGROUND: A dendritic cell vaccine has been developed as a novel strategy for generating antitumor immunity in the treatment of cancer. The purpose of this study was to assess the maximal tolerated dose, safety, and immunologic response of a new dendritic cell vaccine (DC-Vac) into which tumor lysate was loaded by electroporation and pulse in patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifteen patients with inoperable stage III or IV NSCLC were assigned to cohorts that received 3, 6, or 12 × 10(6) DC-Vac intradermally 3 times at 2 week intervals. We also evaluated immunologic and tumor responses. RESULTS: The maximum dose of DC-Vac (12 × 10(6)) was shown to be safe. In 5 of 9 patients, the vaccine resulted in increased interferon (IFN)-γ production by CD8+ cells after exposure to tumor lysate. Additionally, there were mixed responses which do fulfill progressive disease definition but demonstrate some clinical benefit in two patients. CONCLUSION: The administration of tumor lysate-loaded autologous dendritic cells by electroporation and pulse was non-toxic and induced immunologic responses to tumor antigens. The two mixed tumor responses which were achieved may represent a potential benefit of this new DC-Vac.

Four cases of a cerebral air embolism complicating a percutaneous transthoracic needle biopsy.

A percutaneous transthoracic needle biopsy is a common procedure in the practice of pulmonology. An air embolism is a rare but potentially fatal complication of a percutaneous transthoracic needle biopsy. We report four cases of a cerebral air embolism that developed after a percutaneous transthoracic needle biopsy. Early diagnosis and the rapid application of hyperbaric oxygen therapy is the mainstay of therapy for an embolism. Prevention is the best course and it is essential that possible risk factors be avoided.

Forkhead box M1 expression in pulmonary squamous cell carcinoma: correlation with clinicopathologic features and its prognostic significance.

Forkhead box M1 (FoxM1) transcription factor has been shown to play important roles in regulating the expression of genes that are involved in cell proliferation, differentiation, and transformation by promoting both G(1)/S and G(2)/M transition. Although it has been reported that the FoxM1 signaling network is frequently deregulated with an up-regulated FoxM1 expression in human malignancies, the role of FoxM1 in lung cancer remains to be determined. We performed immunohistochemical detection of FoxM1 protein in 69 tissue samples from patients with primary pulmonary squamous cell carcinoma using a tissue microarray, and Western blotting was done to confirm the immunohistochemical observations. FoxM1 immunoreactivity was observed in 26 (37.7%) of the 69 squamous cell carcinoma cases. Analysis of the FoxM1 expression in 12 squamous cell carcinoma tissues and 2 normal lung tissues by Western blotting confirmed the immunohistochemical results. A FoxM1 expression was more frequently detected in the moderately or poorly differentiated squamous cell carcinomas than in the well-differentiated squamous cell carcinomas (P = .008). The tumors with a positive FoxM1 expression more frequently showed lymph node metastasis (P = .027) and an advanced American Joint Committee on Cancer stage (P = .049). The Kaplan-Meier survival curves demonstrated that patients with a positive FoxM1 expression had a significantly shorter survival time than those patients with a negative FoxM1 expression (P = .003). The multivariate analysis revealed that the FoxM1 expression was an independent poor prognostic factor (P = .018). A subset of pulmonary squamous cell carcinoma with a FoxM1 expression was associated with progressive pathologic features and an aggressive clinical course.

Fatal interstitial lung disease after erlotinib administration in a patient with radiation fibrosis.

INTRODUCTION: Although gefitinib used for the treatment of non-small-cell lung cancer is a well-known cause of interstitial lung disease (ILD), few case reports on erlotinib-induced ILD have been issued. The common risk factor of both of these two drug-induced ILDs is idiopathic interstitial pneumonia, but ILD in a patient with radiation fibrosis has not been previously reported. METHODS: Report of a case. RESULTS: We recently experienced a case of fatal erlotinib-induced ILD, diagnosed based on clinical and radiologic findings, which occurred in a patient with radiation fibrosis. A 50-year-old male patient was started on erlotinib as a third-line chemotherapy. Six days after taking erlotinib, a chest radiograph showed rapid progression of reticular infiltration in both lung fields. High-resolution computed tomography scan findings were consistent with ILD, which was sufficient to diagnose as erlotinib-induced ILD. The patient died of respiratory failure after 8 days of steroid infusion and erlotinib discontinuation. CONCLUSION: Our case shows a fatal side effect of erlotinib. This case had radiation fibrosis, so we suggest that radiation fibrosis may be another contributor of the occurrence of ILD in patients taking erlotinib.

Genetic mechanism of aspirin-induced urticaria/angioedema.

PURPOSE OF REVIEW: Aspirin-induced urticaria/angioedema is a major aspirin-related hypersensitivity often associated with aspirin-intolerant asthma. Genetic studies on aspirin-intolerant asthma have shown chronic overproduction of cysteinyl leukotrienes. The genetic analysis of aspirin-induced urticaria/angioedema is limited, however. RECENT FINDINGS: A recent study on HLA genotypes has suggested that the HLA alleles DRB11302 and DQB10609 may be genetic markers for aspirin-induced urticaria/angioedema. A polymorphism study that examined nine single-nucleotide polymorphisms of five leukotriene-related genes [ALOX5 (encoding 5-lipoxygenase), ALOX5AP (5-lipoxygenase-activating protein), PTGS2 (cyclooxygenase 2), LTC4S (leukotriene C4 synthase), and CYSLTR1 (cysteinyl leukotriene receptor 1)] found that promoter polymorphisms of ALOX5 (-1708A>G) and CYSLTR1 (-634C>T) were significantly different between aspirin-intolerant asthma and aspirin-induced urticaria/angioedema, suggesting different contributions to the lipoxygenase pathway. A second polymorphism study, conducted on histamine-related genes, did not find any significant associations with aspirin-induced urticaria/angioedema for the genes HNMT (encoding histamine N-methyltransferase), HRH1 or HRH2 (encoding histamine receptor types 1 and 2 respectively), or the gene encoding high-affinity IgE receptor Ibeta (FcepsilonRIbeta); however, the FcepsilonRIalpha gene promoter polymorphism was significantly associated with aspirin-induced urticaria/angioedema. This finding has been supported by in vitro functional studies. SUMMARY: The HLA alleles DRB11302 and DQB10609, and the ALOX5 and FcepsilonRIalpha promoter polymorphisms, may contribute to the pathogenesis of aspirin-induced urticaria/angioedema. Further investigation to identify candidate genetic markers would help to elucidate the pathogenic mechanism of this condition.

Diffuse alveolar hemorrhage associated with antineutrophil cytoplasmic antibody levels in a pregnant woman taking propylthiouracil.

Propylthiouracil (PTU) is known to be a potential cause of antineutrophil cytoplasmic antibody (ANCA) positive small vessel vasculitis, resulting in glomerulonephritis and diffuse alveolar hemorrhage (DAH). Herein, we describe a 25-year-old pregnant woman who developed a perinulcear ANCA (p-ANCA) and myeloperoxidase ANCA (MPO-ANCA) positive DAH during PTU therapy. The patient improved after corticosteroid therapy and discontinuation of the PTU. Methimazole was prescribed in spite of the risk of recurrence of DAH because of the pregnancy. The patient is currently free from pulmonary problems. Our case shows that the alternative agent, methimazole, can be used to treat hyperthyroidism in a pregnant patient with PTU associated DAH.

Acute and chronic changes of vascular endothelial growth factor (VEGF) in induced sputum of toluene diisocyanate (TDI)-induced asthma patients.

Vascular endothelial growth factor (VEGF) is a multi-functional cytokine involved in inflammation, repair and angiogenesis in asthmatic airway. This study aimed to evaluate the role of VEGF in immediate bronchoconstriction induced by TDI inhalation, and in chronic TDI-asthma patients. 11 newly diagnosed TDI-asthma patients (group I), 12 chronic TDI-asthma patients with persistent asthma symptoms followed for >4 yr and 15 unexposed healthy controls were enrolled. In group I, induced sputum and serum were collected before and 7 hr after placebo- and TDI-bronchoprovocation test (BPT). In group II, induced sputum and serum were collected every 2 yr. VEGF levels were measured by ELISA. There were no significant differences in sputum and serum VEGF levels between patients and controls. Before and after placebo and TDI-BPT, no significant changes were noted in sputum and serum VEGF levels of group I. In group II patients, sputum VEGF showed variable changes at 1-yr, then decreased significantly at 2-yr (p<0.05), while serum VEGF showed variable changes at 2-yr, which decreased significantly at 4-yr (p<0.05). These results suggest that VEGF may play a minor role in immediate bronchoconstriction after TDI-BPT. In chronic TDI-asthma, VEGF may be involved to 2 yr after the diagnosis and the contribution may decrease after then.

Exposure to toluene diisocyanate (TDI) induces IL-8 production from bronchial epithelial cells: effect of pro-inflammatory cytokines.

This investigation was designed to confirm IL-8 production from human bronchial epithelial cells with toluene diisocyanate (TDI) exposure and to examine the effects of pro-inflammatory cytokine and dexamethasone. We cultured Beas-2B, a bronchial epithelial cell line with TDI-HSA conjugate and compared with those without conjugate. IL-8 in the supernatant was measured by ELISA. To evaluate the effect of proinflammatory cytokines, peripheral blood mononuclear cells (PBMC) were collected from TDI- and non-TDI asthma patients, and were added to the epithelial cell culture. Dexamethasone or antibodies to TNF-alpha and IL-1beta were pre-incubated with PBMC supernatant. There was a significant production of IL-8 from bronchial epithelial cells with addition of TDI-HSA conjugate in a dose-dependent manner, which was significantly augmented with addition of PBMC supernatant. Higher production of IL-8 was noted with addition of PBMC supernatant from TDI-asthma patients than in those from non-TDI asthma patients. IL-1beta and IL-1beta/TNF alpha antibodies were able to suppress the IL-8 productions. Pre-treatment of dexamethasone induced dose-dependent inhibition of the IL-8 production. These results suggest that the IL-8 production from bronchial epithelial cells contribute to neutrophil recruitment occurring in TDI-induced airway inflammation. IL-1beta released from PBMC of TDI-induced asthma patients may be one of the pro-inflammatory cytokines to enhance IL-8 production.

Eosinophil inflammation of nasal polyp tissue: relationships with matrix metalloproteinases, tissue inhibitor of metalloproteinase-1, and transforming growth factor-beta1.

Eosinophil and mast cell infiltrations are consistent findings in nasal polyp tissue. Previous studies have shown that matrix metalloproteinases (MMPs) may be involved in eosinophil infiltration in airway mucosa of asthmatic patients, and that transforming growth factor-beta1 (TGF-beta1) induces extracellular matrix deposition in nasal polyp tissue. The aim of this study was to evaluate the role of MMPs and tissue-inhibitor of metalloproteinase-1 (TIMP-1) in association with TGF-beta1, eosinophils and mast cell activation in nasal polyp tissue. Nasal polyp tissues from 20 patients who underwent polypectomies were collected and prepared into tissue homogenate. Eosinophil cationic protein (ECP) and tryptase levels were measured by CAP system (Pharmacia, Sweden). MMP-2, MMP-9, TIMP-1 and TGF-beta1 levels were measured by enzyme-liked immunosorbent assay. MMP-2 was the predominant form of MMPs, followed by MMP-9 and TIMP-1. There were significant correlations between ECP, and MMP-9, MMP-2, TGF-beta1 and tryptase, but not with TIMP-1. Significant correlations were noted between tryptase, and MMP-2, MMP-9, and TGF-beta1, but not with TIMP-1. Close correlations were noted between TGF-beta1, and MMP-9 and MMP-2, but not with TIMP-1. MMP-2, MMP-9, and TGF-beta1 may contribute to eosinophil and mast cell migrations into nasal polyp tissue.

Gene Expression Profiling of Non-Small Cell Lung Cancer.

PURPOSE: cDNA microarray provided a powerful alternative, with an unprecedented view scope, in monitoring gene expression levels, and led to the discovery of regulatory pathways involved in complicated biological processes. This study was performed to gain better understanding of the molecular mechanisms underlying the carcinogenesis and progression of lung cancer. MATERIALS AND METHODS: Using a cDNA microarray, representing 4, 600 cDNA clusters, we studied the expression profiles in 10 non-small cell lung cancer (NSCLC) samples and the adjacent noncancerous lung tissues form the same patients. The alterations in the levels of gene expression were confirmed by reverse-transcription PCR in 10 randomly selected genes. RESULTS: Genes that were differently expressed in the cancerous and noncancerous tissues were identified. One hundred and nine genes (of which 68 were known) and 69 cDNAs (of which 32 were known) were up- and down-regulated in>70% of the NSCLC samples, respectively. In the cancerous tissues, the genes related to the cell cycle, metabolism, cell structure and signal transduction, were mostly up-regulated. Furthermore, we identified a few putative tumor suppressor genes that had previously been proposed by other workers. CONCLUSION: S: These results provide, not only a new molecular basis for understanding the biological properties of NSCLC, but also useful resources for the future development of diagnostic markers and therapeutic targets for NSCLC.

Relationship between PTEN and Vascular Endothelial Growth Factor Expression in Non-Small Cell Lung Cancer.

PURPOSE: This study was performed to determine the relationship between PTEN and vascular endothelial growth factor (VEGF) expression and to assess their roles in the tumor-induced angiogenesis and tumor progression in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded tissues, from 96 patients diagnosed with NSCLC, were evaluated for VEGF and PTEN expression using immunohistochemical methods. The results of the expression pattern of VEGF alone, or in combination with PTEN expression, were compared with clinicopathological parameters. RESULTS: VEGF expression was seen in 54 (56.3%) of the 96 NSCLCs evaluated, and was significantly correlated with histological type, and seen more frequently in adenocarcinomas compared to the other histological types (p<0.05). There were no significant associations between VEGF expression and tumor size, lymph node metastasis and stage. The microvessel density (MVD) determined by CD34 staining were significantly higher in tumors with VEGF expression (62.9+/-21.8) than those without (55.1+/-15.1). Loss of PTEN expression was seen in 33 (34.4%) of the 96 NSCLCs evaluated. VEGF expression was more frequently detected in the tumors with loss of PTEN expression (69.7%) than in those with PTEN expression (49.2%). When the combined VEGF/ PTEN phenotypes were divide into two groups; group I (VEGF-/PTEN+) and group II (VEGF-/ PTEN-, VEGF+/PTEN+, VEGF+/PTEN-), a significant correlation was also seen between the groups and the histologic types. There was a trend for the tumors in group II to show more frequent lymph node metastasis (50.0%) than those in group I (31.5%), although there was no statistical significance. The MVDs were significantly higher in group II (63.1+/-20.7) than in group I (53.4+/-17.2). CONCLUSION: These findings demonstrate an inverse correlation between the expressions of PTEN and VEGF. It is possible that PTEN may repress VEGF expression, and modulate VEGF-mediated angiogenesis, which suggests further analysis of the complex phenomenon of neo-angiogenesis in NSCLC is essential.