Conjunctivitis in dupilumab clinical trials.

BACKGROUND: Dupilumab blocks the shared receptor component for interleukin (IL)-4 and IL-13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate-to-severe atopic dermatitis (AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate-to-severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate-to-severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for dupilumab vs. placebo. OBJECTIVES: To characterize further the occurrence and risk factors of conjunctivitis in dupilumab clinical trials. METHODS: We evaluated randomized placebo-controlled trials of dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47). RESULTS: In most AD trials, dupilumab-treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis. CONCLUSIONS: Conjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab-treated patients require further study. What's already known about this topic? Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD). In most dupilumab AD trials, dupilumab-treated patients had higher conjunctivitis incidence than those receiving placebo. Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare. Conjunctivitis incidence was very low and similar for dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis. What does this study add? This analysis confirms and extends the results of the individual clinical trials. Baseline disease-related factors, including AD severity, prior conjunctivitis history and certain biomarkers (thymus and activation-regulated chemokine, IgE, eosinophils), were associated with increased incidence of conjunctivitis. Patients who responded well to dupilumab had reduced incidence of conjunctivitis. Further study is needed to elucidate the aetiology and treatment of conjunctivitis in dupilumab-treated patients with AD.

Dynamic contrast-enhanced perfusion processing for neuroradiologists: model-dependent analysis may not be necessary for determining recurrent high-grade glioma versus treatment effect.

BACKGROUND AND PURPOSE: Dynamic contrast-enhanced perfusion MR imaging has proved useful in determining whether a contrast-enhancing lesion is secondary to recurrent glial tumor or is treatment-related. In this article, we explore the best method for dynamic contrast-enhanced data analysis. MATERIALS AND METHODS: We retrospectively reviewed 24 patients who met the following conditions: 1) had at least an initial treatment of a glioma, 2) underwent a half-dose contrast agent (0.05-mmol/kg) diagnostic-quality dynamic contrast-enhanced perfusion study for an enhancing lesion, and 3) had a diagnosis by pathology within 30 days of imaging. The dynamic contrast-enhanced data were processed by using model-dependent analysis (nordicICE) using a 2-compartment model and model-independent signal intensity with time. Multiple methods of determining the vascular input function and numerous perfusion parameters were tested in comparison with a pathologic diagnosis. RESULTS: The best accuracy (88%) with good correlation compared with pathology (P = .005) was obtained by using a novel, model-independent signal-intensity measurement derived from a brief integration beginning after the initial washout and by using the vascular input function from the superior sagittal sinus for normalization. Modeled parameters, such as mean endothelial transfer constant > 0.05 minutes(-1), correlated (P = .002) but did not reach a diagnostic accuracy equivalent to the model-independent parameter. CONCLUSIONS: A novel model-independent dynamic contrast-enhanced analysis method showed diagnostic equivalency to more complex model-dependent methods. Having a brief integration after the first pass of contrast may diminish the effects of partial volume macroscopic vessels and slow progressive enhancement characteristic of necrosis. The simple modeling is technique- and observer-dependent but is less time-consuming.

CT imaging correlates of genomic expression for oral cavity squamous cell carcinoma.

BACKGROUND AND PURPOSE: Imaging correlates of genetic expression have been found for prognostic and predictive biomarkers of some malignant diseases, including breast and brain tumors. This study tests the hypothesis that imaging findings correlate with relevant genomic biomarkers in oral cavity squamous cell carcinoma. MATERIALS AND METHODS: Surplus frozen tissue from 27 untreated patients with oral cavity squamous cell carcinoma who underwent preoperative CT imaging was analyzed for gene expression. A team of neuroradiologists blinded to the genomic analysis results reviewed an extensive list of CT findings. The imaging correlated with genomic expression for cyclin D1, angiogenesis-related genes (vascular endothelial growth factor receptors and ligands), which relate to enhancement on the basis of other tumor types; and epidermal growth factor receptor, which may relate to proliferation and mass effect. RESULTS: Expression of vascular endothelial growth factor receptors 1 and 2 correlated with the enhancement of the primary tumor (P = .018 and P = .025, respectively), whereas the epidermal growth factor receptor correlated with mass effect (P = .03). Other exploratory correlations included epidermal growth factor receptor to perineural invasion (P = .05), and certain vascular endothelial growth factor receptors and ligands to mass effect (P = .03) and increased (P = .01) or decreased (P = .02) primary tumor size. CONCLUSIONS: We report that CT imaging correlates with gene expression in untreated oral cavity squamous cell carcinoma. Enhancement of the primary tumor and degree of mass effect correlate with relevant genomic biomarkers, which are also potential drug targets. Eventually, treatment decisions may be aided by combining imaging findings into meaningful phenotypes that relate directly to genomic biomarkers.

Improving imaging diagnosis of persistent nodal metastases after definitive therapy for oropharyngeal carcinoma: specific signs for CT and best performance of combined criteria.

BACKGROUND AND PURPOSE: Criteria for detection of persistent nodal metastases in treated oropharyngeal tumors are sensitive but nonspecific, leading to unnecessary nodal dissections. Developing specific imaging criteria for persistent nodal metastases could improve diagnosis while decreasing patient morbidity. MATERIALS AND METHODS: Patients with oropharyngeal squamous cell carcinoma with nodal metastases treated by definitive radiation therapy and subsequent nodal dissection were retrospectively evaluated. One hundred thirty-eight patients had pre- and posttherapy contrast-enhanced CTs evaluated by radiologists blinded to the status of pathologically proved hemineck persistent nodal metastases. Composite scoring criteria for CT, combined from individual parameters, were compared with radiologists' opinions, previous multiparameter criteria, and outcome data. RESULTS: New low-attenuation areas and a lack of size change (<20% cross sectional area) were both highly specific for persistent nodal metastases (99%; P = .0004). Extranodal disease on pretherapy imaging was moderately specific (86%; P = .001). The CSC correctly placed 29 patients in a low-risk category compared with 14 by previously reported criteria and radiologist reports. With good second-rater reliability, the CSC cutoff values stratified patients at highest risk of persistent nodal metastases, thereby improving specificity while maintaining sensitivity. CONCLUSIONS: Comparing pre- and posttherapy examinations improves specificity by discriminating focal findings and size change compared with a single time point. The CSC can categorize the risk of persistent nodal metastases more accurately than previous CT methods. This finding has the potential to improve resource use and reduce surgical morbidity.

Imaging of carotid canal sympathetic plexus schwannoma.

One case report of a schwannoma involving the sympathetic plexus in the carotid canal has been reported previously. This article presents 2 additional cases of this rare entity with associated clinical and unique radiographic findings. All patients presented with diplopia among other symptoms, and they had enhancing masses that smoothly expanded the carotid canal on cross-sectional imaging. Comparison with the index case and differential diagnosis of more common pathologies in this area are discussed.

Lifestyle influences on outcome in rheumatoid arthritis.

Functional status in rheumatoid arthritis (RA) as assessed by the HAQ is poorer in the West of Scotland than the USA or elsewhere. There is a possible link with social deprivation, which is common within the Greater Glasgow Healthboard area. Our aim was to determine if differences in lifestyle could contribute to the poorer functional outcome found in socially deprived patients.

Improved medical and surgical management of cervical spine disease in patients with rheumatoid arthritis over 10 years.

OBJECTIVES: (1) To compare clinical outcome and symptomatology of rheumatoid cervical myelopathy between patients managed conservatively and surgically. (2) To determine if surgical outcome has improved since the series published from this unit in 1987. (3) To examine the role of magnetic resonance imaging (MRI) in the diagnosis of cervical myelopathy. METHODS: Patients undergoing MRI of the cervical spine between 1991 and 1996 were identified. Case records were reviewed retrospectively. RESULTS: 111 patients with RA underwent 124 MRI scans. The median age at onset of cervical spine symptoms was 58 years (range 16-87) with median disease duration of 16 years (range 1-59). 18 (16%) required surgery immediately after MRI. 93 (84%) were managed conservatively, 9 of whom (10%) later required surgery. 2/7 deaths in the conservative group were directly related to cervical myelopathy. Patients requiring surgery were more likely to report paraesthesia, weakness, unsteadiness and to exhibit extensor plantar reflexes, gait disturbance, and reduced power. MRI findings did not correlate with clinical features. When compared with the 1974-82 cohort, fewer patients had severe myelopathy (Ranawat grade IIIB) before surgery (34% versus 7%). Early postoperative mortality improved from 9% to 0% and surgical complication rate fell from 50% to 22%. 89% of patients in the 1991-96 cohort reported subjective improvement in overall function. CONCLUSION: In this series surgical outcome has improved. The major factor in this more favourable outcome is probably that patients presenting with rheumatoid cervical myelopathy are now referred for surgery at an earlier stage of disease. Clinical findings correlate poorly with MRI findings, therefore clinical history should remain the key to determining the need for MRI.

An analysis of the causes of adverse events from the Quality in Australian Health Care Study.

OBJECTIVE: To examine the causes of adverse events (AEs) resulting from healthcare to assist in developing strategies to minimise preventable patient injury. DESIGN: Descriptions of the 2353 AEs previously reported by the Quality in Australian Health Care Study (QAHCS) were reviewed. A qualitative approach was used to develop categories for human error and for prevention strategies to minimise these errors. These categories were then used to classify the AEs identified in the QAHCS, and the results were analysed with previously reported preventability and outcome data. RESULTS: 34.6% of the causes of AEs were categorised as "a complication of, or the failure in, the technical performance of an indicated procedure or operation", 15.8% as "the failure to synthesise, decide and/or act on available information", 11.8% as "the failure to request or arrange an investigation, procedure or consultation", and 10.9% as "a lack of care and attention or failure to attend the patient". AEs in which the cause was cognitive failure were associated with higher preventability scores than those involving technical performance. The main prevention strategies identified were "new, better, or better implemented policies or protocols" (23.7% of strategies), "more or better formal quality monitoring or assurance processes" (21.2%), "better education and training" (19.2%), and "more consultation with other specialists or peers" (10.2%). CONCLUSION: The causes of AEs or errors leading to AEs can be characterised, and human error is a prominent cause. Our study emphasises the need for designing safer systems for care which protect the patient from the inevitability of human error. These systems should provide new policies and protocols and technological support to aid the cognitive activities of clinicians.

Race and stress in the incidence of herpes zoster in older adults.

OBJECTIVES: To examine the effect of black race and acute (negative life events) and chronic (lack of social support) psychological stress on the risk of herpes zoster in late life. DESIGN: A population-based, prospective cohort study. SETTING: Central North Carolina. PARTICIPANTS: Duke Established Populations for Epidemiological Studies of the Elderly, a stratified probability sample of community-dwelling persons more than 65 years of age. MEASUREMENTS: Interviewers administered a comprehensive health survey to the participants in 1986-1987 (P1, n = 4162), 1989-1990 (P2, n = 3336), and 1992-1994 (P3, n = 2568). Incident cases of zoster between P1 and P2 and P2 and P3 served as the dependent variable. Hypothesis-testing variables included race, negative life events, and five measures of social support. Control variables included age, sex, education, cancer, chronic diseases, basic ADLs, instrumental ADLs, depression, self-rated health, hospitalization, and cigarette smoking. Statistical analyses employed chi-square tests and proportional hazards model. RESULTS: At baseline, the sample had a mean age of 73.6 years and was 55% black, 45% white, and 65% female. There were 65 cases of zoster between P1 and P2 and 102 cases of zoster between P2 and P3. From P1 to P2, 1.4% of blacks and 3.4% of whites developed zoster (P < .001). From P2 to P3, 2.9% of blacks and 7.5% of whites developed zoster (P < .001). After controlling for the above variables, blacks were significantly less likely to develop zoster (adjusted risk ratio = 0.35; 95% confidence interval (CI), 0.24-0.51; P < .001). Negative life events increased the risk of zoster, but the result was borderline for statistical significance (adjusted RR = 1.38, 95% CI 0.96-1.97; P = .078). No measures of social support were significantly associated with zoster. CONCLUSION: Black race decreased the risk of zoster in late life significantly. Measures of stress were not significantly related to zoster, but study limitations preclude definitive conclusions. Future research should focus on these factors in larger samples and different populations.

Hepatitis C.

OBJECTIVES: To review the virology, epidemiology, pathogenesis, natural history, clinical manifestations, and current treatment of hepatitis C virus (HCV) infection. DATA SOURCES: The MEDLINE database (1966 to 1996) was searched for English-language articles and abstracts on HCV and non-A, non-B hepatitis. Papers cited in relevant primary articles were also reviewed. STUDY SELECTION: More than 500 original and review articles were evaluated, and the most relevant were selected. DATA EXTRACTION: Data were extracted and reviewed by all authors. DATA SYNTHESIS: In most patients, HCV infection results in chronic hepatitis. The disease is insidious and subclinical but may progress over decades into end-stage liver disease and hepatocellular carcinoma, which makes HCV cirrhosis a leading indication for orthotopic liver transplantation. Current diagnostic methods are highly sensitive and specific, and quantitative assessment of viral load may help to predict and monitor response to treatment. The only available therapeutic option is interferon, and this agent is effective in only a small subset of patients. CONCLUSIONS: Infection with HCV is a significant public health problem that has important clinical and financial consequences. The tailoring of specific therapy according to viral load or genotype, better patient selection, and use of combination drug regimens may improve the chance of viral clearance and sustained biochemical and histologic response. Further understanding of the basic virology of HCV and the exact mechanisms of viral persistence and tissue injury is needed to help define future therapeutic and preventive strategies.

Racial differences in the occurrence of herpes zoster.

The purpose of this study was to determine if there are racial differences in the occurrence of herpes zoster (shingles). The study population was the Duke Established Populations for Epidemiologic Studies of the Elderly, a probability sample of community-dwelling persons > 64 years old in North Carolina. Interviewers administered a comprehensive health survey to the participants that included questions about lifetime occurrence of shingles. Of the 3206 subjects, 316 (9.9%) had had zoster: 81 (4.5%) of 1754 blacks and 235 (16.1%) of 1452 whites had had shingles (P < .0001). After controlling for age, cancer, and demographic factors, blacks remained one-fourth as likely as whites (adjusted odds ratio 0.25, 95% confidence interval 0.18-0.35; P = .0001) to have experienced zoster. In summary, blacks had a significantly lower risk of developing herpes zoster than whites, a new finding in herpes zoster epidemiology.

Zidovudine resistance, syncytium-inducing phenotype, and HIV disease progression in a case-control study. The VA Cooperative Study Group.

A case-control study of patients with progressive (cases) or nonprogressive (controls) disease was designed to determine the association among disease progression, zidovudine sensitivity, and syncytium-inducing phenotype. Viral isolates were screened for sensitivity to zidovudine using a peripheral blood mononuclear cell-based assay and for syncytium-inducing (SI) phenotype in MT2 cell culture. Thirty-four patients, whose disease progressed to AIDS or whose CD4 cell numbers fell < 200 cells/mm3, were matched with 34 patients whose conditions had not progressed or whose CD4 cell numbers remained > 200 cells/mm3. Virus was successfully cultured from both the progressor and the nonprogressor in 17 of these 34 matched case-control pairs. In six of the 17 pairs, virus isolated from the progressor had an IC50 (50% inhibitory concentration) for zidovudine > 1 microM and at least threefold greater than the IC50 of virus isolated from the matched nonprogressor (p = 0.04). In 16 of these 17 pairs the virus isolated from the progressor had the SI phenotype, indicative of high cytopathogenicity, while the virus from the matched nonprogressor had a non-syncytium-inducing phenotype (p < 0.0001). Zidovudine therapy did not appear to select for the SI phenotype in this patient population. A statistically significant association between high-level zidovudine resistance and clinical disease progression was demonstrated. A statistically significant association between the SI phenotype and disease progression was demonstrated. The results suggest that disease progression while being treated with zidovudine therapy may be more closely associated with the SI phenotype than with zidovudine resistance.

Aging and reactivation of latent murine cytomegalovirus.

BALB/c mice were experimentally infected with murine cytomegalovirus (MCMV) to discover whether latent MCMV persisted in aging mice and to examine the effect of aging on MCMV reactivation. Latently infected mice received saline, cyclophosphamide, or allogeneic blood at 6 and 18 months of age. MCMV DNA was detected by polymerase chain reaction in submaxillary salivary gland biopsy specimens from saline-treated young and old mice. Evidence of MCMV reactivation was sought by culture of biopsy specimens and by MCMV IgG ELISA of pre- and posttreatment sera from all animals. Very few cyclophosphamide- or saline-treated mice reactivated MCMV at either age, but young transfused mice reactivated MCMV significantly more often than did old transfused mice. These experiments indicate that MCMV DNA persists in the salivary gland of aging mice but that the likelihood of MCMV reactivation does not increase with age.

Murine cytomegalovirus gene amplification and culture after submaxillary salivary gland biopsy.

An important target tissue for murine cytomegalovirus (CMV) infection is the submaxillary salivary gland. Submaxillary salivary gland biopsy specimens from BALB/c mice latently infected with murine CMV were examined for murine CMV DNA by in vitro enzymatic amplification using the polymerase chain reaction preceding oligonucleotide hybridization. The amplified sequence was a 152-base pair segment from within the immediate early gene of murine CMV. Biopsy and whole gland specimens from acutely infected BALB/c mice and latently infected, immunosuppressed BALB/c mice were compared for active murine CMV infection. After acute infection with murine CMV, virus was recovered in all cultures of both biopsy and whole salivary gland specimens but from none of the latently infected animals. Reactivated virus was detected by culture of both biopsy (90%) and whole salivary gland specimens (100%) from latently infected mice that received antithymocyte serum. Viral nucleic acid was detected in 90% of biopsy specimens from latently infected animals. Hence, active murine CMV infection can be detected in biopsy specimens from mice with acute and reactivated infection and murine CMV DNA can be amplified and detected in salivary gland biopsy specimens from latently infected animals. Biopsy of this or other target tissues can be useful for obtaining tissue for viral studies where the survival of the animal is important and it is useful to distinguish latent from acute or reactivated infection.

Medical education in the community: a Nigerian experience.

PIP: Central to the curriculum of the University of Ilorin's medical school is the Community-Based Education and Service (COBES) program. This program is consistent with the emphasis of the government health care system on primary health care services targeted at problems such as poor nutrition, parasitic disease, and infection, especially among mothers and children. The CORES program, instituted in 1978, places medical students in both urban and rural clinics to impart awareness of the unique problems in each setting. In their 1st COBES posting, students study the demographic structure of the community and make a "community diagnosis." They organize a health education day and a public health action (e.g. immunization). At the end of this posting, students present suggestions for action to village leaders. The 2nd posting is centered around the World Health Organization's theme for that year. Postings 3 and 4 emphasize the development of clinical skills in basic primary care. At all times, students are taught to understand the impact of the local culture on the interpretation and treatment of illness. The COBES experience has stimulated numerous related developments, including establishment of an African Chapter of the Network of Community Oriented Institutions for Health Sciences, proposals for reforms in medical education by the 1989 African Inter-Ministerial Conference, and the introduction of similar programs at Ogun State and Bayero Universities.^ieng

Cytomegalovirus pneumonia.

Cytomegalovirus (CMV) is a common virus that asymptomatically infects the majority of the population by early adulthood. After initial infection, the virus remains in a latent state in the host and can be reactivated under a variety of conditions. In contrast to the normal host, both primary and reactivated symptomatic CMV infections are common in certain immunocompromised patients including organ transplant recipients and patients with the acquired immunodeficiency syndrome (AIDS). One of the more common manifestations of the virus in this setting is a severe and often fatal interstitial pneumonitis. In transplant patients, this predictably occurs in the second or third month after transplantation and is characterized by severe hypoxemia and bilateral, symmetric interstitial infiltrates on chest x-ray. While the most direct and specific means of diagnosing CMV pneumonia is isolation of the virus from lung tissue homogenates cultured on human fibroblasts, techniques have recently been introduced using specific monoclonal antibodies or CMV DNA probes to rapidly identify the virus in tissue biopsy, cytologic specimens, or in tissue culture. These rapid techniques will become particularly important as antiviral agents with activity against CMV become available.

Brain abscess caused by a variety of cladosporium trichoides.

A brain abscess caused by a new variety of Cladosporium trichoides occurred in a previously healthy man. A reversed T-suppressor/helper cell ratio was noted as the only immunologic abnormality. He required three surgical procedures, the last an occipital lobectomy, and antifungal chemotherapy to control his disease. He received 2,068 mg of amphotericin B and one year of flucytosine at 6 g per day. Ten months after the last surgery he is without evidence of disease. C. trichoides var. chlamydosporum was isolated from the abscess. It differed from C. trichoides by producing chlamydospores in vitro and only hyphae in the brain abscess. On modified Sabouraud agar, the fungus did not grow at 25 degrees C and grew poorly at 30 degrees C and 37 degrees C. Histologic sections revealed necrosis, no encapsulation, and no epitheliod cells.

Acquired cytomegalovirus retinitis. Four new cases and a review of the literature with implications for management.

49 cases of acquired cytomegalovirus retinitis were reviewed including three new cases in renal allograft recipients and one in a patient with Hodgkin's Disease. Diagnosis in over 90% of cases was based on the distinctive funduscopic appearance of cytomegalovirus (CMV) retinitis. When performed, urine, subretinal fluid, and blood buffy coat cultures were positive for CMV in 97, 67 and 39% of cases, respectively. More than two-thirds of these patients were organ transplant recipients who received chronic immunosuppressive therapy. Attempted therapy of CMV retinitis with a variety of regimens has not been proven to be effective. At present, no specific treatment is recommended unless it is given under a controlled therapeutic trial.