Precision medicine in united airways disease: A "treatable traits" approach.

United airways disease (UAD) is the concept that the upper and lower airways, which are anatomically and immunologically related, form a single organ. According to this concept, upper and lower airway diseases are frequently comorbid because they reflect manifestations of a single underlying disease at different sites of the respiratory tract. Allergic asthma-allergic rhinitis is the archetypal UAD, but emerging data indicate that UAD is a heterogeneous condition and consists of multiple phenotypes (observable clinical characteristics) and endotypes (pathobiologic mechanisms). The UAD paradigm also extends to myriad sinonasal diseases (eg, chronic rhinosinusitis with or without nasal polyps) and lower airway diseases (eg, bronchiectasis, chronic obstructive pulmonary disease). Here, we review currently known phenoendotypes of UAD and propose a "treatable traits" approach for the classification and management of UAD, wherein pathophysiological mechanisms and factors contributing to disease are identified and targeted for treatment. Treatable traits in UAD can be analyzed according to a framework comprising airway inflammation (eosinophilic, neutrophilic), impaired airway mucosal defense (impaired mucociliary clearance, antibody deficiency), and exogenous cofactors (allergic sensitizers, tobacco smoke, microbes). Appreciation of treatable traits is necessary in advancing the effort to deliver precise treatments and achieve better outcomes in patients with UAD.

Working while unwell: Workplace impairment in people with severe asthma.

BACKGROUND: Severe asthma affects quality of life; however, its impact on workplace productivity is poorly understood. OBJECTIVE: To compare workplace productivity-absenteeism and presenteeism-and impairment in daily activities in severe and non-severe asthma over time and identify characteristics associated with presenteeism in severe asthma. METHODS: The Severe Asthma Web-based Database is an ongoing observational registry from Australia, New Zealand and Singapore. At April 2017, 434 patients with severe asthma and 102 with non-severe asthma were enrolled (18-88 years; 59% female). Participants provided comprehensive clinical and questionnaire data at baseline and were followed-up every 6 months for 24 months. Absenteeism (percentage of time not at work), presenteeism (self-reported impairment at work) and impairment in daily activities outside work due to health problems in the last week were calculated. RESULTS: At baseline, 61.4% of participants with severe asthma and 66.2% with non-severe asthma under 65 years were employed. At younger ages (30-50 years), fewer severe asthma participants were employed (69% vs 100%). Presenteeism and impairment in daily activity were more frequently reported in severe asthma and in participants with poorer asthma control, poorer lung function and more past-year exacerbations (P < .01). Over time, deteriorating asthma control was associated with increasing presenteeism. Although absenteeism was not different between severe and non-severe asthma, worse asthma control was associated with absenteeism (P < .001). In participants with severe asthma, presenteeism was reported more frequently in those with poorer asthma control, poorer asthma-related quality of life and symptoms of depression or anxiety (P < .01). CONCLUSION AND CLINICAL RELEVANCE: Severe asthma was associated with impairment at work and outside the workplace. Improving asthma control and mental health may be important targets for optimizing workplace productivity in severe asthma. Presenteeism and absenteeism may represent key metrics for assessing intervention efficacy in people with severe asthma of working age.

Long-term future risk of severe exacerbations: Distinct 5-year trajectories of problematic asthma.

BACKGROUND: Assessing future risk of exacerbations is an important component of asthma management. Existing studies have investigated short- but not long-term risk. Problematic asthma patients with unfavorable long-term disease trajectory and persistently frequent severe exacerbations need to be identified early to guide treatment. AIM: To identify distinct trajectories of severe exacerbation rates among "problematic asthma" patients and develop a risk score to predict the most unfavorable trajectory. METHODS: Severe exacerbation rates over five years for 177 "problematic asthma" patients presenting to a specialist asthma clinic were tracked. Distinct trajectories of severe exacerbation rates were identified using group-based trajectory modeling. Baseline predictors of trajectory were identified and used to develop a clinical risk score for predicting the most unfavorable trajectory. RESULTS: Three distinct trajectories were found: 58.5% had rare intermittent severe exacerbations ("infrequent"), 32.0% had frequent severe exacerbations at baseline but improved subsequently ("nonpersistently frequent"), and 9.5% exhibited persistently frequent severe exacerbations, with the highest incidence of near-fatal asthma ("persistently frequent"). A clinical risk score composed of ≥2 severe exacerbations in the past year (+2 points), history of near-fatal asthma (+1 point), body mass index ≥25kg/m2 (+1 point), obstructive sleep apnea (+1 point), gastroesophageal reflux (+1 point), and depression (+1 point) was predictive of the "persistently frequent" trajectory (area under the receiver operating characteristic curve: 0.84, sensitivity 72.2%, specificity 81.1% using cutoff ≥3 points). The trajectories and clinical risk score had excellent performance in an independent validation cohort. CONCLUSIONS: Patients with problematic asthma follow distinct illness trajectories over a period of five years. We have derived and validated a clinical risk score that accurately identifies patients who will have persistently frequent severe exacerbations in the future.

Adjuvant radiotherapy for endometrial cancer--a comparative review of radiotherapy technique with acute toxicity.

OBJECTIVES: The addition of pelvic radiotherapy to brachytherapy (EBRT-BT) in early-stage endometrial cancer is controversial and may cause unnecessary toxicity. The incidence of acute toxicity of EBRT-BT will have an impact on clinical decision and patient compliance but is currently poorly understood. This study compares the acute toxicities of EBRT-BT versus BT alone. MATERIALS AND METHODS: Seventy-nine patients with FIGO Stage IA-II endometrial cancer who underwent adjuvant radiotherapy, (EBRT-BT or BT alone) from 2001 to 2011 were included in the study. Medical records of these patients were reviewed retrospectively and toxicity graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Patients were followed up for at least three months post-treatment to assess resolution of toxicity. RESULTS: The mean age of the study group was 60.6 years. Median follow-up was four years. Forty patients received EBRT-BT. There was a 37% increase in Grade 1-3 diarrhea with the addition of pelvic radiotherapy (OR 18.67, p < 0.0005) and a 34% increase in lethargy (p < 0.0005). There was also an increased occurrence of genitourinary and skin toxicities. Two patients in the EBRT-BT group required hospitalisation for severe diarrhea and three patients were unable to complete the treatment. All acute toxicities had resolved by three months post treatment. CONCLUSION: EBRT-BT causes significantly more acute toxicities compared to BT alone. Patients should be informed of this during counselling.

Monoclonal antibody recognizing N-terminal epitope of hepatitis C virus nonstructural 5B inhibits viral RNA replication.

The nonstructural 5B (NS5B) protein of hepatitis C virus (HCV) is an RNA-dependent RNA polymerase (RdRp) with a key role in HCV replication. To characterize the functional roles of NS5B in HCV replication, we produced a panel of 10 monoclonal antibodies (mAbs) directed against NS5B protein from mice immunized with functionally active RdRp. The epitopes of eight mAbs are localized in the middle region (amino acid 240-263) of NS5B protein. On the other hand, the epitopes of two mAbs are mapped to amino acids 67-88 at the N-terminus of NS5B protein. To examine the effects of mAbs on HCV-RNA replication, we performed in vitro RdRp assay using either the 3'-untranslated region (UTR) or the full-length of HCV-RNA as a template in the presence of each mAb. mAbs specific for the middle region of NS5B had no effect on RdRp activity. Surprisingly, mAb recognizing the N-terminal region of NS5B inhibited RdRp activity in a dose-dependent manner. We have confirmed the same result using the other subclass of mAb, whose epitope is also localized to the same N-terminal region of NS5B. These data show that NS5B contains a B-cell epitope located between amino acid residues 67 and 88. Binding of this epitope with an antibody interferes with the enzymatic function of NS5B.

Advances in lung cancer diagnosis and staging: endobronchial ultrasound.

BACKGROUND: Endobronchial ultrasound (EBUS) is an accurate and relatively less invasive procedure for the diagnosis of lung lesions and mediastinal lymph node staging for lung cancer. We aimed to evaluate the clinical utility and safety of this new EBUS service established in our hospital. METHODS: Consecutive patients who underwent EBUS-transbronchial lung biopsy (EBUS-TBLB) for biopsy of peripheral pulmonary lesions or for transbronchial needle aspiration (TBNA) of mediastinal lymph node enlargement were included in this audit. Demographic and clinical data were obtained prospectively. Diagnostic yield from the results of EBUS was compared to other clinical information obtained. RESULTS: Thirty-eight patients underwent EBUS over a 10-month period. The yield from EBUS-TBLB was 62%. The average size of the lung lesions biopsied was 3.5 cm and 62% were located in the upper lobes. Malignancy was diagnosed in 14 cases and a benign aetiology in four. The yield from EBUS-TBNA was 88% and the average size of the lymph nodes was 2.3 cm. The lymph nodes were all located in the subcarinal station except for two that were in the lower paratracheal station. Malignancy was diagnosed in 10 cases on TBNA and 4 cases had benign pathology. There was one complication seen (small pneumothorax). CONCLUSION: EBUS is safe and an effective method for both, diagnosis of peripheral pulmonary lesions and staging for lung cancer.

Long-acting beta2-agonists versus theophylline for maintenance treatment of asthma.

BACKGROUND: Theophylline and long acting beta-2 agonists are bronchodilators used for the management of persistent asthma symptoms, especially nocturnal asthma. They represent different classes of drug with differing side-effect profiles. OBJECTIVES: To assess the comparative efficacy, safety and side-effects of long-acting beta-2 agonists and theophylline in the maintenance treatment of adults and adolescents with asthma. SEARCH STRATEGY: We searched the Cochrane Airways Group trials register and reference lists of articles. We also contacted authors of identified RCTs for other relevant published and unpublished studies and pharmaceutical manufacturers. Most recent search: November 2006. SELECTION CRITERIA: All included studies were RCTs involving adults and children with clinical evidence of asthma. These studies must have compared oral sustained release and/or dose adjusted theophylline with an inhaled long-acting beta-2 agonist. DATA COLLECTION AND ANALYSIS: In original review, two reviewers independently assessed trial quality and extracted data, similarly in this update two reviewers undertook this. Study authors were contacted for additional information. MAIN RESULTS: Thirteen studies with a total of 1344 participants met the inclusion criteria of the review. They were of varying quality. There was no significant difference between salmeterol and theophylline in FEV(1) predicted (6.5%; 95% CI -0.84 to 13.83). However, salmeterol treatment led to significantly better morning PEF (mean difference 16.71 L/min, 95% CI 8.91 to 24.51) and evening PEF (mean difference 15.58 L/min, 95% CI 8.33 to 22.83). Salmeterol also reduced the use of rescue medication. Formoterol, used in two studies was reported to be as effective as theophylline. Bitolterol, used in only one study, was reported to be less effective than theophylline. Participants taking salmeterol experienced fewer adverse events than those using theophylline (Parallel studies: Relative Risk 0.44; 95% CI 0.30 to 0.63, Risk Difference -0.11; 95% CI -0.16 to -0.07, Numbers Needed to Treat (NNT) 9; 95% CI 6 to 14). Significant reductions were reported for central nervous system adverse events (Relative Risk 0.50; 95% CI 0.29 to 0.86, Risk Difference -0.07; 95% CI -0.12 to -0.02, NNT 14; 95% CI 8 to 50) and gastrointestinal adverse events (Relative Risk 0.30; 95% CI 0.17 to 0.55, Risk Difference -0.11; 95% CI -0.16 to -0.06, NNT 9; 95% CI 6 to 16). AUTHORS' CONCLUSIONS: Long-acting beta-2 agonists, particularly salmeterol, are more effective than theophylline in improving morning and evening PEF, but are not significantly different in their effect on FEV1. There is evidence of decreased daytime and nighttime short-acting beta-2 agonist requirement with salmeterol. Fewer adverse events occurred in participants using long-acting beta-2 agonists (salmeterol and formoterol) as compared to theophylline.

Inhaled corticosteroids compared to placebo for prevention of exercise induced bronchoconstriction.

BACKGROUND: The pathogenesis of exercise induced bronchoconstriction is likely multifactorial and is not completely understood. Inflammation plays an important role in the pathogenesis of exercise induced bronchoconstriction in asthmatic subjects but the evidence seems less strong in non-asthmatic subjects. The management of exercise induced bronchoconstriction focuses on prevention, through both pharmacologic and non-pharmacologic interventions. OBJECTIVES: The objectives of this review were to evaluate the use of inhaled corticosteroids in the treatment of exercise induced bronchoconstriction in a systematic way. Specifically, the review was designed to: determine whether inhaled corticosteroids (compared to placebo) has an attenuating effect on exercise induced bronchoconstriction in adult and pediatric asthmatic patients; estimate the magnitude of the attenuating effect. SEARCH STRATEGY: We searched the Cochrane Airways Review Group Specialised Register of trials, the Cochrane Central Register of Controlled Trials, review articles, textbooks and reference list of articles. SELECTION CRITERIA: Randomised trials in adults or children comparing inhaled corticosteroids with placebo to prevent bronchoconstriction in patients with exercise induced bronchoconstriction. DATA COLLECTION AND ANALYSIS: Trial quality assessment and data extraction were conducted independently by two reviewers. MAIN RESULTS: The results from six randomised controlled trials involving 123 participants were analyzed (two trials involving adults and four involving children). Combining results from the two parallel studies with at least 4 weeks duration of inhaled corticosteroids, the use of inhaled corticosteroids significantly attenuated the percent fall index in forced expiratory volume in 1 second (WMD = 14.07%; 95% CI: 11.62% to 16.52%). The result from one crossover study with duration of inhaled corticosteroids of 4 weeks revealed significant attenuation of percent fall in forced expiratory volume in 1 second ( WMD = 6.90%; 95% CI: 1.40% to 12.40%) and the percent fall in peak expiratory flow ( WMD =11.50%; 95% CI: 6.31% to 16.69%). The small amount of data from placebo-controlled trials using a single treatment do not currently allow conclusions to be drawn. AUTHORS' CONCLUSIONS: Inhaled corticosteroids used for 4 weeks or more before exercise testing significantly attenuated exercise-induced bronchoconstriction. The relative benefits of inhaled corticosteroids compared to other forms of exercise induced bronchoconstriction treatment (sodium cromoglycate, nedocromil sodium, salbutamol, and other anti-inflammatory agents) remains unclear.

The natural history of asthma from childhood to adulthood.

Medical Practitioners are often questioned regarding the prognosis of a child with asthma. We have performed a literature review of the natural history of childhood asthmatics. Factors which affect the natural history and prognosis of childhood asthma are discussed. Current evidence suggests that evolution of asthma severity is fairly predictable. Features of childhood asthma such as severity, duration, atopy, bronchial hyperresponsiveness and exposure to smoking can predict the course of asthma into adulthood. Most children with mild intermittent asthma will outgrow their asthma, or have mild episodic asthma. Early commencement of anti-inflammatory therapy, such as inhaled corticosteroids may prevent the progression of the disease. Most patients with mild asthma have good functional outcome and low healthcare utilisation.

Evidence-based pharmacologic treatment for mild asthma.

BACKGROUND: Although mild asthmatics form the majority of asthma sufferers, there is a relative paucity of evidence-based treatment compared with severe asthmatics. OBJECTIVE: We have performed an up-to-date review of the literature on therapy in this group of patients who form an overlooked but important majority. Potential trials were identified through MEDLINE (1965-2007) and Cochrane library (up to February 2007). DISCUSSION: Recent trials have shown that inhaled corticosteroids (ICS) remain the cornerstone of treatment for patients with mild persistent asthma. Early intervention with ICS decreases the risk of severe exacerbations and improves asthma control in patients with mild persistent asthma of recent onset. ICS are superior to leukotriene receptor antagonists and xanthines for control of asthma and in the improvement of lung functions. The addition of long-acting beta2-agonist may be considered in those with moderately persistent asthma or whom asthma is not well controlled with low doses of ICS.

Cavitating cryptococcal pneumonia in the immunocompetent host.

INTRODUCTION: Isolated cryptococcal pneumonia in the immunocompetent host is a rare infection. Indications for treatment and its duration are currently not defined. CLINICAL PICTURE: Three patients presented with cavitating cryptococcal pneumonia. TREATMENT: They were treated with oral fluconazole. OUTCOME: Improvement was evident clinically, radiologically and serologically. Fluconazole was continued until serum cryptococcal antigen (SCA) levels were negative in our patients as they had manifestations such as haemoptysis, cavitating or multi-lobar pneumonia and relatively high antigen levels, suggesting potentially serious disease. CONCLUSIONS: Fluconazole is effective and safe for the treatment of cryptococcal pneumonia in the immunocompetent host. Although the role of monitoring SCA levels in the immunocompetent host is currently unclear, it may be an indication of infective burden and the benefits of longer treatment seem to outweigh the risks.

Simple aspiration versus chest-tube insertion in the management of primary spontaneous pneumothorax: a systematic review.

BACKGROUND: The initial treatment of a primary spontaneous pneumothorax (PSP) is controversial. Guidelines of the British Thoracic Society recommend simple aspiration for all PSP requiring intervention. The placement of chest tubes is only advocated for patients who fail simple aspiration. However, the American College of Chest Physicians Delphi Consensus Statement found simple aspiration to be rarely appropriate in the management of PSP. AIMS: To compare simple aspiration with chest-tube drainage in the initial management of PSP. METHODS: Meta-analysis of randomized controlled trials (RCTs). OUTCOME MEASURES: Reductions in duration of hospital stay, recurrence rate and pain or dyspnoea score were classified as benefits, whereas reductions in successful events were classified as risks. DATA COLLECTION AND ANALYSIS: For dichotomous data, the relative risk (RR) and 95% confidence intervals were calculated. For continuous data, weighted mean differences (WMD) were used. RESULTS: Three RCTs were identified with a combined total of 194 patients. Simple aspiration was associated with shorter hospitalization (WMD -1.30 days [-2.20 to -0.39]). The results for success rate could not be combined because of differences in outcome definitions. However, a pooled result for "success at 1 week or more" showed no significant difference between either intervention (RR 0.86 [0.67, 1.11]). Results of recurrence at 1 year were also not significantly different (RR 0.73 [0.39-1.38]). Different reporting systems for pain scores meant that data could not be pooled. Only one trial reported dyspnoea scores. CONCLUSION: RCT evidence in this field is limited, and the total sample size is too small to make any firm conclusion. On the basis of current available evidence, simple aspiration is advantageous in the initial management of PSP because of shorter hospitalization. There is no significant difference in recurrence at 1 year using either modality, and the efficacy data are inconclusive.

An unusual cause of pulmonary haemorrhage in a patient with rheumatoid arthritis.

INTRODUCTION: Pulmonary haemorrhage is a rare presentation of strongyloides hyperinfection. CLINICAL PICTURE: A 69-year-old female patient with rheumatoid arthritis on methotrexate and prednisolone presented with severe community acquired pneumonia. Intravenous trimethoprim/ sulfamethoxazole (bactrim) and high dose hydrocortisone for Pneumocystis carinii pneumonia were commenced. She developed pulmonary haemorrhage 2 weeks later and bronchoalveolar lavage cytology revealed helminthic larvae identified as strongyloides. TREATMENT AND OUTCOME: Despite treatment with ivermectin and albendazole with rapid tailing down of hydrocortisone, she succumbed to her illness. CONCLUSIONS: Strongyloides hyperinfection should be considered in an immunocompromised patient on high dose corticosteroid presenting with pulmonary haemorrhage. Prognosis remains dismal as supported by our case report and current literature.

Cerebral infarct mimicking glioma in Sjogren's syndrome.

A 50-year-old Chinese woman with a chronic 20-year history of ataxic gait associated with dry eyes and mouth, was admitted to hospital after a single episode of syncope. Magnetic resonance imaging scans showed a large left frontal hypodense lesion suggestive of a glioma. Craniotomy was performed and the lesion excised, with histology showing only infarcted tissue and no malignant cells. Further diagnostic evaluation revealed that the patient had primary Sjogren's syndrome, with demyelinating polyneuropathy. In the absence of risk factors for stroke, it was considered likely that the cerebral infarct was secondary to autoimmune-related vasculitis. Functional neuroimaging, such as magnetic resonance spectroscopy, should be considered in evaluating doubtful or unusual brain lesions in patients with autoimmune disease.

Isocitrate dehydrogenase as a marker of centrilobular hepatic necrosis in the experimental model of rats.

BACKGROUND AND AIMS: Serum alanine aminotransferase (ALT) and aspartate aminotransferase may not detect centrilobular hepatic necrosis (CLN) of a mild degree because these enzymes are known to be located predominantly in the periportal area. The aim of this study was to evaluate the usefulness of plasma isocitrate dehydrogenase (ICDH), which is located predominantly in the centrilobular zone, as a marker of CLN. METHODS: In 56 adult male rats, centrilobular (n = 21) and periportal hepatic necrosis (PPN; n = 21) were induced experimentally by the intraperitoneal injection of bromobenzene and allylalcohol, respectively. Seven rats were used as solvent controls in both groups. Isocitrate dehydrogenase and ALT activities were measured in the plasma of rats with mild to moderate hepatic necrosis (17 CLN and 19 PPN). Isocitrate dehydrogenase and ALT were compared according to the sampling time (12, 24 and 48 h) and the location of hepatic necrosis. Ratios of ICDH/ALT were also calculated and compared between CLN and PPN groups at any time points. RESULTS: Plasma ICDH activities were higher in rats with CLN than in those with PPN. In contrast, plasma ALT levels were higher in rats with PPN than in those with CLN at 12 h and were similar in both groups after 12 h. The ICDH/ALT ratios were much higher in rats with CLN compared to those with PPN (P< 0.001). The ratios were above 1.0 in 13 of 17 rats (77%) with CLN in contrast to none of the 19 rats with PPN. CONCLUSIONS: Our data suggested that the plasma ICDH/ALT ratio might be useful to differentiate between mild to moderate degrees of CLN from PPN, at least in the experimental model of rats.

Hepatitis C virus core protein potentiates c-Jun N-terminal kinase activation through a signaling complex involving TRADD and TRAF2.

The hepatitis C virus (HCV) core protein is a multifunctional viral nucleocapsid protein. Previously, it has been demonstrated that the HCV core protein interacts with the cytoplasmic domain of tumor necrosis factor receptor 1 (TNFR1). Since the TNFR1 is engaged in stimulation of transcriptional factor NF-kappaB and AP-1 through activation of IkappaB kinase and c-Jun N-terminal kinase (JNK, or stress-activated protein kinase), respectively, we have examined whether the interaction between core protein and TNFR1 can modulate JNK. In this study, we demonstrate that the HCV core protein synergistically activates TNFalpha-induced JNK at a core concentration dependent manner in human embryonic kidney (HEK) 293 cells. HCV core-mediated synergism of JNK activation was also detected in stable cells expressing HCV core protein. Furthermore, we demonstrate that HCV core protein does not compete with TNF receptor-associated death domain (TRADD) for its interaction with the death domain of TNFR1. Our in vivo data show that HCV core and TRADD form a ternary complex with TNFR1. These findings suggest that the HCV core protein modulates TNFR1 signaling and may, thus, play a role in chronic infection of HCV patients.

Expression of transforming growth factor-alpha mRNA in livers of patients with chronic viral hepatitis and hepatocellular carcinoma.

BACKGROUND: Transforming growth factor-alpha (TGFalpha) is an important autocrine growth factor of hepatocytes. The authors evaluated the roles of TGFalpha in chronic viral hepatitis (CVH) and hepatocellular carcinoma (HCC). METHODS: The authors measured the amounts of TGFalpha mRNA in liver tissues from 18 patients with HCC, 31 patients with CVH, and 7 normal controls. " Hot-start" reverse transcription-polymerase chain reaction (RT-PCR) using oligo-dT and specific primers detected TGFalpha mRNA in total cellular RNA extracted from liver tissues. The levels of TGFalpha mRNA were determined by the end point titers of serial, two-fold dilutions of cDNA. The amounts of hepatitis B virus RNA (HBV-RNA) in livers of patients with chronic hepatitis B also were measured by Northern blot hybridization. RESULTS: TGFalpha mRNA levels were extremely higher in patients with HCC compared with patients with CVH and normal controls, and the levels in patients with CVH also were elevated compared with normal controls. The levels of TGFalpha mRNA were overexpressed in the underlying livers of patients with HCC compared with patients with CVH, although they were lower than those found in HCC tissues. The levels of TGFalpha mRNA were higher in samples from patients with chronic hepatitis B than in samples from patients with chronic hepatitis C. The levels of TGFalpha mRNA were not correlated with serum alanine aminotransferase or HBV-RNA levels in liver tissues in patients with chronic hepatitis B. However, the expression of TGFalpha mRNA tended to be higher in the livers of patients with raised serum alpha-fetoprotein levels. CONCLUSIONS: The overexpression of TGFalpha mRNA in the liver seems to be associated with the regeneration of hepatocytes rather than hepatic necrosis or viral replication. Also, it may be related closely to the development or progression of HCC, especially in the livers of patients with chronic hepatitis B.

Combined therapy consisting of intraarterial cisplatin infusion and systemic interferon-alpha for hepatocellular carcinoma patients with major portal vein thrombosis or distant metastasis.

BACKGROUND: Hepatocellular carcinoma (HCC) patients with major vascular involvement or extrahepatic metastasis are not good candidates for surgery or transarterial chemoembolization (TACE). In this study, the authors evaluated the efficacy of combined therapy with intraarterial cisplatin infusion and systemic administration of interferon-alpha (IFN-alpha) as a palliative treatment for these patients. METHODS: Sixty-eight HCC patients with major portal vein thrombosis (n = 47) or distant metastasis (n = 27) were randomly allocated to 1 of 3 groups. Group I (n = 19) received combined therapy consisting of intraarterial cisplatin infusion and systemic IFN-alpha, Group II (n = 23) received intraarterial cisplatin infusion, and Group III (n = 26) was managed with only supportive care. Cisplatin 2 mg/kg was infused through the proper hepatic artery every 8 weeks, and IFN-alpha 3 million IU/m2 was administered subcutaneously 3 times a week. RESULTS: The partial response (defined as a 50% or greater reduction in the product of the 2 longest perpendicular tumor measurements) rate of Group I was significantly higher than that of Group II (33% vs. 14%; P < 0.05). Also, the 1-year survival rate of Group I (27%) was higher than that of Group II (9%) or Group III (0%) (P < 0.05 and P < 0.01, respectively). The median survival period of Group I was 19 weeks, which was significantly longer than that of Group II (11 weeks) or Group III (5 weeks) (P < 0.05 and P < 0.01, respectively). CONCLUSIONS: These results suggest that combined therapy consisting of intraarterial cisplatin infusion and systemic IFN-alpha may be useful as a palliative treatment for HCC patients with major vascular involvement or extrahepatic metastasis.

Is decompressive craniectomy for acute cerebral infarction of any benefit?

BACKGROUND: Acute occlusion of the major cerebral arteries results in ischaemic changes to the brain, without time for reperfusion by the collateral circulation. The subsequent cellular events lead to a breakdown of the blood-brain barrier, causing malignant cerebral edema manifested clinically by a rapid neurological deterioration. The aim of this study was to determine the value of surgical decompression in patients who present with acute cerebral infarction. METHODS: Retrospective review of patients with deteriorating consciousness level from massive cerebral ischemia and secondary edema, treated by decompressive craniectomy. RESULTSThere were 10 patients over a 2-year period from 1997-99, consisting of seven male and three female patients (mean age 47.56 years) with a mean preoperative Glasgow Coma Scale (GCS) score of 6/15. Three patients had dominant middle cerebral artery (MCA) infarction, four had nondominant MCA infarction, one had posterior cerebral artery infarction, and the remaining two had cerebellar infarction. At a mean follow-up period of 7 months, two patients had died (20% mortality), four patients (40%) were vegetative or severely disabled, and the remaining four patients (40%) had mild disability or good outcome. Favorable prognostic factors were younger age (less than 50 years) and good initial GCS score (14 or better). CONCLUSION: Decompressive craniectomy in the setting of acute brain swelling from cerebral infarction is a life-saving procedure and should be considered in younger patients who have a rapidly deteriorating neurologic status.