Drug reaction with eosinophilia and systemic symptoms syndrome is not uncommon and shows better clinical outcome than generally recognised.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare disease which can cause severe morbidity and mortality. The aim of this study is to evaluate the clinical manifestation and course of DRESS syndrome. METHODS: We conducted a retrospective analysis of prospectively collected data in 45 patients with DRESS syndrome diagnosed between September 2009 and August 2011. RESULTS: The most common causative drug group was antibiotics (n=13, 28.9%), followed by anticonvulsants (n=12, 26.7%), antituberculosis drugs (n=6, 13.3%), non-steroidal anti-inflammatory drugs (n=4, 8.9%), undetermined agents (n=4, 8.9%), allopurinol (n=3, 6.7%), and others (n=3, 6.7%). The latency period ranged from 2 to 120 days, with a mean of 20.2 ± 24.3 days. The longest latency period was noted for the antituberculosis drug group, at 46.5 ± 29.9 days. Eosinophilia in peripheral blood examination was noted in 35 subjects (77.8%). Atypical lymphocytosis was noted in 16 patients (35.6%), and thrombocytopenia in seven patients (15.6%). Hepatic involvement was noted in 39 (86.7%) study patients, kidney in eight (17.8%), lung in four (8.9%), and central nervous system in one (2.3%). Systemic corticosteroids were administered to 10 patients (22.2%). Forty-three patients (95.6%) showed complete recovery, while two patients had poor outcomes. CONCLUSIONS: DRESS syndrome was not more uncommon than generally recognised. Antibiotics were the most frequently implicated drug group, followed by anticonvulsants. Most patients with this disease showed a better clinical outcome than that which had been generally expected.

Uncertain areas in the diagnosis of allergic bronchopulmonary aspergillosis in patients with asthma.

BACKGROUND AND OBJECTIVE: The prevalence of allergic bronchopulmonary aspergillosis (ABPA) in patients with bronchial asthma remains unknown. We evaluated the roles of various laboratory tests in the diagnosis of ABPA, including, skin prick test (SPT) for Aspergillus fumigatus (Af), and serum Af specific IgE and IgG antibody measurement. METHODS: A total of 50 asthma patients with more than 1000cell/µL of peripheral blood eosinophils were prospectively collected between January 2007 and September 2011. Evaluations using SPT for Af, serum total IgE and specific IgE antibody to Af by CAP system, IgG antibody to Af by enzyme immunoassay (EIA) or CAP system were performed according to the essential minimal criteria for the diagnosis of ABPA - asthma, immediate cutaneous reactivity to Af, elevated total IgE, and raised Af specific IgE and IgG. RESULTS: Among 50 patients, three patients (6.0%) were diagnosed as ABPA, of whom each confirmed five items of the essential minimal diagnostic criteria for the diagnosis of ABPA. Six patients (12.0%) showed negative responses to Af in SPT, but positive responses in specific IgE by CAP system. Eight patients (16.0%) showed negative responses to IgG to Af by CAP system, but positive responses by enzyme immunoassay (EIA). CONCLUSIONS: SPT and serum IgE to Af measurement by CAP system should be performed simultaneously. It is reasonable to set up cut-off values in Af specific IgE/IgG by CAP system for the differentiation of ABPA from Af sensitised asthma patients.

The prevalence of metabolic syndrome and its association with alanine aminotransferase in clozapine-treated Korean patients with schizophrenia.

Widely ranging prevalence rates for metabolic syndrome (MetS) in patients taking clozapine have been reported on the basis of various criteria, and most studies have been carried out in non-Asian countries. Therefore, we examined the prevalence of MetS in Korean patients using three commonly applied criteria with two waist-circumference cutoff values. The indirectly standardized prevalence ratio (ISPR) was estimated using data from the Fourth Korean National Health and Nutrition Examination Survey (KNHNES, 2007) to compare the prevalence of MetS in patients with that in the general population. In addition, we also examined whether serum alanine aminotransferase (ALT) and aspartate aminotransferase levels serve as biochemical markers for the identification of MetS. We reviewed the electromedical records of patients with schizophrenia who had taken clozapine as the sole antipsychotic for 3 months or more. The prevalence of MetS ranged from 34.5 to 46.9%, and the ISPR ranged from 2.4 to 2.8, given the three definitions of MetS and the two waist-circumference cutoff points for women. The ISPR for MetS among those aged 18-30 years was the highest and decreased with age in both men and women. After adjusting for age, patients with normal serum ALT levels who were in the top third were significantly more likely to have MetS compared with those who were in the bottom third. Logistic regression analysis showed that serum ALT levels and use of antidepressants were significantly related to the presence of MetS. Korean patients with schizophrenia who were receiving clozapine as the sole antipsychotic showed a high prevalence of MetS. Although we found substantial differences in the prevalence according to criteria, the ISPR indicated significantly higher rates of MetS in this group than in the general population. In the general population, younger patients had a much higher risk for MetS than older patients. Elevated levels of serum ALT that were in the normal range were associated with the presence of MetS, which suggests the possibility of using serum ALT level as an early indicator for MetS in patients treated with clozapine.

Clinical features of drug-induced hypersensitivity syndrome in 38 patients.

BACKGROUND: The clinical features of drug-induced hypersensitivity syndrome (DIHS) or drug rash with eosinophilia and systemic symptoms (DRESS) syndrome are complicated, and the incidence of this condition is very low. OBJECTIVE: To evaluate the clinical course of DIHS/DRESS and identify effective treatment options. METHODS: This study was a retrospective analysis of prospectively collected clinical data in 38 consecutive patients with DIHS/DRESS diagnosed between March 2004 and January 2009. We investigated the clinical features, response to treatment, and outcome of 38 patients. RESULTS: The study patients consisted of 18 men (47.4%) and 20 women (52.6%). The most common causative drugs were anticonvulsants (47.4%) and antibiotics (18.4%), followed by nonsteroidal anti-inflammatory drugs (NSAIDs) (13.2%), allopurinol (5.3%), and undetermined agents (15.8%). The latency period ranged from 3 to 105 days, with a mean (SD) of 25.2 (21.5) days. Systemic corticosteroids were administered to 16 patients (42.1%). Twenty-two (57.9%) patients were treated with topical corticosteroids and antihistamines (no systemic corticosteroids). Complete recovery was noted in 36 patients (94.8%). Two of the patients treated with systemic corticosteroids had a poor outcome: one died due to an opportunistic infection secondary to long-term systemic corticosteroid treatment; the other showed progressive deterioration of liver damage, although the final outcome is not known. CONCLUSION: The drugs associated with DIHS/DRESS were variable and most frequently included anticonvulsants, beta-lactam antibiotics, and NSAIDs. The syndrome was more common than generally recognized. Additional studies are needed to evaluate the clinical indications for systemic corticosteroids in patients with DIHS/DRESS.

Oncolytic and immunostimulatory efficacy of a targeted oncolytic poxvirus expressing human GM-CSF following intravenous administration in a rabbit tumor model.

Targeted oncolytic poxviruses hold promise for the treatment of cancer. Arming these agents with immunostimulatory cytokines (for example, granulocyte-monocyte colony-stimulating factor; GM-CSF) can potentially increase their efficacy and/or alter their safety. However, due to species-specific differences in both human GM-CSF (hGM-CSF) activity and poxviruses immune avoidance proteins, the impact of hGM-CSF expression from an oncolytic poxvirus cannot be adequately assessed in murine or rat tumor models. We developed a rabbit tumor model to assess toxicology, pharmacodynamics, oncolytic efficacy and tumor-specific immunity of hGM-CSF expressed from a targeted oncolytic poxvirus JX-963. Recombinant purified hGM-CSF protein stimulated a leukocyte response in this model that paralleled effects of the protein in humans. JX-963 replication and targeting was highly tumor-selective after i.v. administration, and intratumoral replication led to recurrent, delayed systemic viremia. Likewise, hGM-CSF was expressed and released into the blood during JX-963 replication in tumors, but not in tumor-free animals. hGM-CSF expression from JX-963 was associated with significant increases in neutrophil, monocyte and basophil concentrations in the peripheral blood. Finally, tumor-specific cytotoxic T lymphocytes (CTL) were induced by the oncolytic poxvirus, and expression of hGM-CSF from the virus enhanced both tumor-specific CTL and antitumoral efficacy. JX-963 had significant efficacy against both the primary liver tumor as well as metastases; no significant organ toxicity was noted. This model holds promise for the evaluation of immunostimulatory transgene-armed oncolytic poxviruses, and potentially other viral species.

Use of human amniotic membrane wrap in reducing perineural adhesions in a rabbit model of ulnar nerve neurorrhaphy.

The object of this experimental study was to assess the effect of wrapping human amniotic membrane around a repaired ulnar nerve in a rabbit model of perineural adhesion. Ulnar nerves from 10 white New Zealand rabbits were exposed bilaterally, dissected and repaired. Human amniotic membrane was then wrapped around the repair site in one limb with no such wrap in the neurorrhaphy of the contralateral limb. Three months later, the same nerves were re-explored and removed using microsurgical external neurolysis. Perineural adhesion around the ulnar nerve was evaluated by blinded surgical dissection and scored using a visual 4-point qualitative scale. Extent and grade of fibrosis around repair sites were measured microscopically (x 200) after Masson trichrome staining using measure of the depth of fibrosis and the grading criteria of adhesion. Quantitative morphometric analysis was also performed under light microscopy (x 200) with the aid of a digital counter and virtual slide imaging software (ScanScope T2, Vista, CA, USA). Human amniotic membrane wrapped nerves showed significantly less perineural adhesion and fibrosis than controls (P < 0.05). No nerve healing problems were encountered. This study suggests that human amniotic membrane application can reduce fibrosis and adhesion around neurorrhaphy sites in this animal model.

Syndecan-1 expression in gallbladder cancer and its prognostic significance.

AIM: To determine whether the immunohistochemical detection of syndecan-1 could provide useful information as a novel therapeutic or prognostic factor in primary gallbladder (GB) cancer. MATERIALS AND METHODS: Forty-three GB cancer tissues were evaluated by immunohistochemistry for syndecan-1 expression. The relationship between syndecan-1 expression and clinicopathological characteristics, and the univariate survival analysis for the influence of the syndecan-1 expression on the overall survival were analysed. RESULTS: Epithelial syndecan-1 immunoreactivity was observed in 25 (58.1%) of the 43 GB cancer cases. The tumors with a positive syndecan-1 expression more frequently showed lymph node metastasis (p = 0.037). Although there was no statistically significant association, the tumors with a positive syndecan-1 expression tended to show a deeper invasion depth (p = 0.087) and more frequent lymphovascular invasion (p = 0.064). The Kaplan-Meier survival curves demonstrated that patients with positive syndecan-1 expression had a significantly shorter survival time than those patients with negative syndecan-1 expression (p = 0.05). CONCLUSIONS: A subset of GB cancers revealed an epithelial overexpression of syndecan-1, which was associated with a progressive pathological feature and an aggressive clinical course. Therefore, epithelial syndecan-1 expression may be a predictor for a poor prognosis in patients with GB cancer.

Acute generalized exanthematous pustulosis as a manifestation of carbamazepine hypersensitivity syndrome.

Anticonvulsant hypersensitivity syndrome (AHS) is a multisystemic disorder involving cutaneous changes and typical blood abnormalities that can be triggered by aromatic anticonvulsant drugs.The syndrome is commonly associated with a macular or papular rash or erythroderma. Acute generalized exanthematous pustulosis is a very rare cutaneous manifestation of AHS. A 41-year-old man was referred to our hospital for evaluation of a 3-day history of fever, leukocytosis, and generalized skin eruption. The patient had been taking carbamazepine for 1 month to treat hand tremor following surgery for intracerebral hemorrhage. Physical examination revealed facial edema and a large number of variable-sized pustules covering the body. Initial laboratory testing showed peripheral blood eosinophilia and abnormal liver function.A biopsy of pustular lesions revealed intraepidermal pustules, with perivascular lymphocytic infiltration. The skin lesions and laboratory results improved after withdrawal of carbamazepine and treatment with oral corticosteroids.

Prognostic value of expression of ERCC1, thymidylate synthase, and glutathione S-transferase P1 for 5-fluorouracil/oxaliplatin chemotherapy in advanced gastric cancer.

BACKGROUND: The aim of this study was to determine whether expressions of the excision repair cross-complementing (ERCC1), thymidylate synthase (TS), and glutathione S-transferase P1 (GSTP1) predict clinical outcome in patients with advanced gastric cancer treated with fluorouracil (5-fluorouracil)/oxaliplatin chemotherapy. PATIENTS AND METHODS: The study population consisted of 64 advanced gastric cancer patients (median age 51 years). Patients were treated with oxaliplatin 85 mg/m(2) as a 2-h infusion at day 1 plus leucovorin 20 mg/m(2) over 10 min, followed by 5-FU bolus 400 mg/m(2) and 22-h continuous infusion of 600 mg/m(2) at days 1-2. Treatment was repeated in 2-week intervals. The expressions of ERCC1, TS, and GSTP1 of primary tumors were examined by immunohistochemistry. RESULTS: The positive rates of ERCC1, TS, and GSTP1 were 70.3%, 29.7%, and 50.0%, respectively. The patients without ERCC1 expression were more likely to respond to chemotherapy (P = 0.045). There were no significant differences between response and TS or GSTP1 expression pattern (P = 0.813, P = 0.305, respectively). Median overall survival (OS) was significantly longer in patients without ERCC1 expression (P = 0.0396). TS or GSTP1 expression were not related to survival (P = 0.4578, P = 0.8121, respectively). Multivariate analysis revealed that ERCC1 expression significantly impacted on OS (hazard ratio 1.92, P = 0.037). CONCLUSION: Immunohistochemical studies for ERCC1 may be useful in prediction of the clinical outcome in advanced gastric cancer patients treated with 5-FU and oxaliplatin.

Systemic armed oncolytic and immunologic therapy for cancer with JX-594, a targeted poxvirus expressing GM-CSF.

Targeted oncolytic viruses and immunostimulatory therapeutics are being developed as novel cancer treatment platforms. These approaches can be combined through the expression of immunostimulatory cytokines from targeted viruses, including adenoviruses and herpesviruses. Although intratumoral injection of such viruses has been associated with tumor growth inhibition, eradication of distant metastases was not reported. The major limitations for this approach to date have been (1) inefficient intravenous virus delivery to tumors and (2) the lack of predictive, immunocompetent preclinical models. To overcome these hurdles, we developed JX-594, a targeted, thymidine kinase(-) vaccinia virus expressing human GM-CSF (hGM-CSF), for intravenous (i.v.) delivery. We evaluated two immunocompetent liver tumor models: a rabbit model with reproducible, time-dependent metastases to the lungs and a carcinogen-induced rat liver cancer model. Intravenous JX-594 was well tolerated and had highly significant efficacy, including complete responses, against intrahepatic primary tumors in both models. In addition, whereas lung metastases developed in all control rabbits, none of the i.v. JX-594-treated rabbits developed detectable metastases. Tumor-specific virus replication and gene expression, systemically detectable levels of hGM-CSF, and tumor-infiltrating CTLs were also demonstrated. JX-594 holds promise as an i.v.-delivered, targeted virotherapeutic. These two tumor models hold promise for the optimization of this approach.

Relationship between micropapillary component and micrometastasis in the regional lymph nodes of patients with stage I lung adenocarcinoma.

AIMS: To determine whether a micropapillary component is a prognostic predictor, with particular reference to nodal micrometastasis, in patients with stage I lung adenocarcinomas. METHODS AND RESULTS: Thirty-five cases with stage I lung adenocarcinomas, obtained from lobectomies or pneumonectomies, and 434 dissected hilar and mediastinal lymph nodes, were retrospectively reviewed. A micropapillary component and nodal micrometastasis were found in 16 (45.7%) and 14 (40%) of the 35 cases, respectively, with nodal micrometastasis in 24 (5.5%) of the 434 lymph nodes, in an immunohistochemical study using an anti-cytokeratin antibody. Ten (62.5%) of the 16 cases with a micropapillary component, and four (21.1%) of the remaining 19 cases, showed nodal micrometastases (P = 0.014). Kaplan-Meier survival curves demonstrated that there was no significant difference between the cases with and without a micropapillary component (P = 0.28). However, the 5 years' survival of the cases with and without nodal micrometastases were 71.4% and 35.7%, respectively (P = 0.03). CONCLUSIONS: A micropapillary component may be a manifestation of aggressive behaviour, as shown by frequent micrometastasis, for stage I lung adenocarcinomas.

Tumor budding as a useful prognostic marker in esophageal squamous cell carcinoma.

We examined the prognostic significance of tumor budding in patients with esophageal squamous cell carcinoma, particularly in comparison to other routine pathological findings. Fifty-six cases who underwent an esophagectomy were reviewed. We defined tumor budding as an isolated single cancer cell or a cluster composed of fewer than five cancer cells and divided these into two grades; low-grade (< 5 budding foci) and high-grade (> or = 5 budding foci) within a microscopic field of x 200. There were 22 (39.3%) and 34 (60.7%) cases with low- and high-grade budding, respectively. There were significant differences in the patients with low- and high-grade budding in relation to tumor size, pT stage, lymphovascular invasion, perineural invasion, circumferential resection margin involvement, and AJCC stage (P < 0.05). The 3-year survival rates of the patients with low- and high-grade budding were 72.3% and 30.7%, respectively (P = 0.04). We propose that tumor budding may be a pathological marker suggesting high malignancy potential and decreased postoperative survival in patients with esophageal squamous cell carcinoma.

Mechanism of histone deacetylase inhibitor Trichostatin A induced apoptosis in human osteosarcoma cells.

Although histone deacetylase (HDAC) inhibitors are emerging as a promising new treatment strategy in malignancy, how they exert their effect on osteosarcoama cells is as yet unclear. This study was undertaken to investigate the underlying mechanism of a HDAC inhibitor Trichostatin A (TSA)-induced apoptosis in a osteosarcoma cell line HOS. We observed that TSA treatment decreased the viability of the cells and prominently increased acetylation of histone H3. Evidence was obtained indicating that TSA induced apoptosis of HOS cells as follows: (1) Generation of DNA fragmentation; (2) activation of procaspase-3; (3) cleavage of PARP; and (4) increase of DNA hypoploidy. The reduction of MMP and the release of cytochrome c to cytosol were also shown, indicating that TSA induces apoptosis in HOS cells in a histone acetylation- and mitochondria-dependent fashions. We also examined whether TSA can sensitize HOS cells to the action of an antitumor agent genistein. The combination therapy of TSA and genistein showed synergistic anticancer effect indicating that TSA can be considered as a novel therapeutic strategy for osteosarcoma not only from its direct apoptosis-inducing activity but also from the possibility of sensitization to other antitumor agents.

Ganglioneuroblastoma presenting as dilated cardiomyopathy.

We report an unusual presentation of ganglioneuroblastoma with features of dilated cardiomyopathy in a 22 month old girl. She was admitted with cardiomegaly; during echocardiography a suspicious abdominal mass was detected by chance. Further imaging studies, including abdominal ultrasonography and spiral computed tomography, revealed a solid mass originating in the right adrenal gland. Metabolic studies and pathological findings were compatible with ganglioneuroblastoma. Following tumour removal and supportive therapy for cardiomyopathy, her clinical condition and laboratory findings improved. Although ganglioneuroblastoma with features of dilated cardiomyopathy is rare, because neurogenic tumours may be involved in its development, measurement of catecholamines in children with dilated cardiomyopathy is strongly recommended.

The presence of colorectal hepatic metastases does not preclude pulmonary metastasectomy.

Hepatic metastases due to colorectal carcinoma have often been felt to preclude pulmonary metastasectomy. With the recent advances in surgical options, should patients with both liver and lung metastases be considered for surgical resection? The current study reviews the impact of such aggressive management on disease-free and overall survival (OS). The clinical course of 63 patients presenting with colorectal metastasis to the lung alone (group 1, n = 45) or combined hepatic and lung metastases (group 2, n = 18) were reviewed. All patients underwent complete resection of their lung metastases. Surgical control of hepatic tumor burden was achieved by tumor ablation, intra-arterial therapy, and/or resection. All patients in group 1 and group 2 were available for a mean follow-up of 27 and 24 months, respectively. The presence of hepatic metastases, the resectability of hepatic tumor burden, and the disease-free interval after pulmonary metastasectomy did not significantly influence survival. These findings demonstrate that aggressive surgical management of pulmonary metastases in the presence of liver metastases offers a similar benefit as compared to patients with pulmonary metastases alone. Therefore, hepatic metastatic disease does not preclude an attempt at pulmonary metastasectomy if hepatic metastases can be resected or remains responsive to therapy. Such an approach achieves comparable OS and mean survival when compared to pulmonary metastasectomy alone.

The use of a personal digital assistant for wireless entry of data into a database via the Internet.

BACKGROUND: Researchers typically record data on a worksheet and at some later time enter it into the database. Wireless data entry and retrieval using a personal digital assistant (PDA) at the site of patient contact can simplify this process and improve efficiency. METHODS: A surgeon and a nurse coordinator provided the content for the database. The computer programmer created the database, placed the pages of the database on the PDA screen, and researched and installed security measures. RESULTS: Designing the database took 6 months. Meeting Health Insurance Portability and Accountability Act of 1996 (HIPAA) requirements for patient confidentiality, satisfying institutional Information Services requirements, and ensuring connectivity required an additional 8 months before the functional system was complete. CONCLUSIONS: It is now possible to achieve wireless entry and retrieval of data using a PDA. Potential advantages include collection and entry of data at the same time, easy entry of data from multiple sites, and retrieval of data at the patient's bedside.

Epithelioid angiosarcoma of the pleura: a case report.

Angiosarcomas of the pleura are very rare tumors and it is difficult to differentiate them from other common pleural tumors such as mesothelioma and metastasic carcinoma clinically and pathologically. We report a case of a young Korean woman with angiosarcoma arising in the pleura. A 34-yr-old woman presented with dyspnea and chest tightness and pain for several months. A computed tomographic scan of the chest showed diffuse thickening of the left pleura and effusion with passive atelectasis. At thoracotomy the left pleura was thick and indurated. Histologically, the decorticated pleura revealed infiltration of sheets or cords of polygonal and epithelioid tumor cells showing rudimentary vascular differentiation. Immunohistochemically, the tumor cells were strongly positive for CD31, CD34, and vimentin, whereas weakly positive for factor VIII, and negative for cytokeratin, which are characteristic and specific findings of angiosarcoma.

Age-related regional difference of interleukin-1 expression in rat brain after lipopolysaccharide treatment.

Aging is associated with altered immune responses including dysregulation of cytokine production. Of cytokines, interleukin-1 (IL-1) family has been primarily involved with central nervous system. To evaluate the age-related different response of IL-1 family following peripheral administration of lipopolysaccharide (LPS), immunohistochemical study of IL-1beta and IL-1 receptor expression was performed on Sprague-Dawley rat brain. Experimental animals were divided into four groups; saline-treated young (3-5 months) and old (over 24 months), and LPS-treated young and old groups. After intraperitoneal (i.p.) injection of LPS, three to five rats within each group were killed at 1, 2, 4, 8 and 16 hr. After fixation in 4% neutral buffered formalin, the brain slices were paraffin-embedded. Immunohistochemical staining using labelled streptavidin biotin was performed. The results showed that IL-1beta immunoreactivity was seen in the endothelial cell of pons in both LPS-treated young and old rats, with slightly longer persistency in old group. IL-1RI immunoreactivity appeared initially in the neurons of cerebral cortex in LPS-treated old group, compared with predominantly the cerebellum in LPS-treated young group. In conclusion, our study shows that there is age-related, different neuronal localization of IL-1RI expression at different points of time after LPS treatment.