Safety profile of intravenous and subcutaneous siplizumab,an anti‐CD2 monoclonal antibody,for the treatment of plaque psoriasis: results of two randomized,double‐blind,placebo‐controlled studies

Several biologics targeting different cytokines and receptors, including T‐cell receptors, have been approved for psoriasis treatment. Siplizumab, a humanized anti‐CD2 monoclonal antibody, may potentially provide an alternative therapy for psoriasis. Its safety profile and immunogenicity was examined in adults with plaque psoriasis. Two multicenter phase II randomized, double‐blind, placebo‐controlled studies: one tested two intravenous (I.V.) doses (0.012 and 0.04 mg/kg) of siplizumab every 2 weeks × 8 doses (124 patients); the second study tested three subcutaneous (S.C.) dose regimens of siplizumab (5 mg × 12 weeks, 5 mg × 6 weeks + placebo × 6 weeks, 7 mg × 4 weeks + placebo × 8 weeks), and placebo × 12 weeks (420 patients). Adverse events (AEs) and laboratory values were monitored. Immunogenicity was determined by anti‐siplizumab antibodies quantification. In both studies, siplizumab exhibited an acceptable safety profile; most common AEs judged to be siplizumab related were lymphopenia, chills, and headache, reported at a higher frequency in the siplizumab‐treated vs. placebo group. Siplizumab‐related reductions in absolute lymphocyte count did not result in clinical evidence of immune suppression. Anti‐siplizumab antibodies were detected after exposure to siplizumab; however, there was no evidence of an association between antibody development and AEs. Siplizumab exhibited an acceptable safety profile in adult patients with plaque psoriasis when administered as multiple I.V. or S.C. doses. Higher, clinically relevant doses of siplizumab would need to be tested to fully assess its safety.     

Basal and residual lower esophageal pressures increase in old age in classic achalasia,but not vigorous achalasia

Background and Aim: The relationship between age and esophageal motility parameters (i.e. basal and residual pressure of the lower esophageal sphincter [LES]) remains to be established in achalasia patients, possibly because most previous studies did not distinguish between classic and vigorous achalasia patients. We investigated the relationship between age and esophageal motility parameters in both classic and vigorous achalasia patients. Methods: A retrospective review of esophageal manometry data in a single center was undertaken. Basal and residual pressure for LES was analyzed. A total of 103 achalasia patients were enrolled, comprising 84 classic and 19 vigorous types. They were subdivided into three different age groups as follows: 21–40 years old (group A), 41–60 years old (group B), and over 60 years old (group C). Results: In classic achalasia patients (M : F = 27:57, mean age = 44 ± 15 years old) the older age group showed a significantly higher basal LES pressure (49.62 ± 19.63 mmHg) than the younger age group (P < 0.0001). Moreover, the older age group also showed significantly high residual LES pressure (20.46 ± 8.61 mmHg) than the younger age group (P = 0.0006). In contrast, in vigorous achalasia patients (M : F = 12:7, mean age: 47 ± 15 years old) there were no difference between age and motility indices (all P > 0.05). Conclusion: In classic achalasia patients there appears to be a correlation between age and esophageal motility indices, especially basal and residual LES pressure. Such correlations do not appear to exist for vigorous achalasia patients.     

The clue of Interstitial Cell of Cajalopathy (ICCpathy) in human diabetic gastropathy: The ultrastructural and electrical clues of ICCpathy in human diabetic gastropathy

Recent studies of diabetic animal models suggest an important role of ICC in the pathogenesis of gastropathy. The aim of this study was to characterize the ultrastructural features of ICC and record the electrical properties in the stomach of patients with type 2 DM. Gastric specimens were obtained from 13 diabetic patients and 6 control subjects with gastric cancer that underwent gastrectomy. All specimens were taken from disease-free areas. The samples were processed for both electron microscopic and electrophysiologic examination. The characteristic ultrastructural changes of the ICC were observed in both the nucleus and cytoplasm in patients with type 2 DM. Wrinkling of the nuclear envelope and changes in the cytoplasm such as dilatation of the endoplasmic reticulum, an increase of autophagic vacuoles, were more frequently observed in the diabetic patients. Apoptosis characterized by nuclear karyorrhexis or pyknosis was observed only in the diabetic patients. Slow waves were recorded in the circular muscle of stomach. In diabetic patients, the mean resting membrane potential was higher and amplitude was lower than controls. These changes of electrical activities of slow waves were accompanied with ultrastructural changes of ICC, particularly the characteristic nuclear changes. In human diabetic patients, the characteristic ultrastructural changes of ICC such as preapoptosis, accompanied with electrical dysrhythmia of slow waves, were observed. These results show several evidence converging to support that degeneration of the ICC may be associated with the pathogenesis of diabetic gastropathy.     

Is the early cyclosporine A level predictive of the outcome of immunosuppressive therapy in severe aplastic anemia?

Immunosuppressive therapy (IST) has provided an alternative treatment option for cure of aplastic anemia patients who cannot receive bone marrow transplantation. Although there have been many recent studies on the efficacy of antithymoglobulin (ATG) combined with cyclosporine A (CsA), there is no data on the correlation between the variability of CsA levels and the response to IST. Therefore, we retrospectively assessed the factors associated with IST efficacy in patients with acquired severe aplastic anemia (SAA). Sixty‐six patients were treated with ATG combined with CsA for 6 months. In the response group, the CsA levels were increased rapidly to more than 200 ng/mL within the first 2 wk after starting the IST. However, the non‐response group had a pattern of slower increase of the CsA levels. The CsA levels, during the first and second week of treatment with IST, were significantly different in the responders and non‐responders. The factors predictive of response to IST and survival were analyzed. The univariate analysis showed that a younger age at the initiation of IST, a high absolute neutrophil count prior to starting IST, a short interval between the diagnosis and initiation of IST, and high CsA levels during the first and second week of IST treatment were positively associated with the response rate and overall survival. The multivariate analysis showed that these four factors were independent factors associated with a longer patient survival. A high response rate was associated with a short interval between diagnosis and initiation of IST as well as high CsA levels during the first and second week of IST. Therefore, early intensification of CsA levels might improve patient outcome.     

Acute exacerbation of chronic obstructive pulmonary disease: Influence of social factors in determining length of hospital stay and readmission rates

BACKGROUND:

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is the leading reason for hospitalization in Canada and a significant financial burden on hospital resources. Identifying factors that influence the time a patient spends in the hospital and readmission rates will allow for better use of scarce hospital resources.

OBJECTIVES:

To determine the factors that influence length of stay (LOS) in the hospital and readmission for patients with AECOPD in an inner-city hospital.

METHODS:

Using the Providence Health Records, a retrospective review of patients admitted to St Paul’s Hospital (Vancouver, British Columbia) during the winter of 2006 to 2007 (six months) with a diagnosis of AECOPD, was conducted. Exacerbations were classified according to Anthonisen criteria to determine the severity of exacerbation on admission. Severity of COPD was scored using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. For comparative analysis, severity of disease (GOLD criteria), age, sex and smoking history were matched.

RESULTS:

Of 109 admissions reviewed, 66 were single admissions (61%) and 43 were readmissions (39%). The number of readmissions ranged from two to nine (mean of 3.3 readmissions). More than 85% of admissions had the severity of COPD equal to or greater than GOLD stage 3. The significant indicators for readmission were GOLD status (P<0.001), number of related comorbidities (OR 1.47, 95% CI 1.10 to 1.97; P<0.009) and marital status (single) (OR 4.18, 95% CI 1.03 to 17.02; P<0.046). The requirement for social work involvement during hospital admission was associated with a prolonged LOS (P<0.05).

CONCLUSIONS:

The results of the present study show that disease severity (GOLD status) and number of comorbidities are associated with readmission rates of patients with AECOPD. Interestingly, social factors such as marital status and the need for social work intervention are also linked to readmission rates and LOS, respectively, in patients with AECOPD.     

Clinicopathological significance of vascular endothelial growth factor-C and cyclooxygenase-2 in esophageal squamous cell carcinoma

BACKGROUND: Vascular endothelial growth factor-C (VEGF-C) is a specific growth factor of lymphatics, which is known to play some role in tumor growth and metastasis to lymph nodes and distant organs in various malignancies. The purpose of the present study was to investigate the expression of VEGF-C in human esophageal squamous cell carcinomas (ESCC) to elucidate its role in tumor progression and lymph node metastasis. Another aim of the study was to investigate the relation between VEGF-C and cyclooxygenase-2 (COX-2) in ESCC. METHODS: The expression of VEGF-C and COX-2 in ESCC was evaluated in 13 endoscopic mucosal resection specimens and in 21 surgical specimens by immunohistochemical staining. Clinical data were obtained from medical records. RESULTS: The degree of VEGF-C expression increased as the depth of primary tumor progressed (r = 0.521, P = 0.002), the stage progressed (r = 0.572, P < 0.001), and the degree of COX-2 expression increased (r = 0.387, P = 0.024). The VEGF-C positive rate was different between early cancers in which regional lymph node metastasis was thought to be absent and advanced cancers in which regional lymph node metastases were confirmed after surgery (20.0% vs 100.0%; P < 0.001). CONCLUSIONS: The VEGF-C expression in ESCC is related to COX-2 expression, and VEGF-C is also associated with the depth of primary tumor, the stage, and probably lymph node metastasis. Thus the investigation of VEGF-C expression in ESCC may assist in management planning.     

Drug use patterns and infection with sexually transmissible agents among young adults in a high-risk neighbourhood in New York City

Aims To determine relationships between drug use ‘hardness’ (defined in increasing order of hardness as no drug use, marijuana use, non‐injected heroin or cocaine use, crack smoking and injection drug use) and prevalences of several sexually transmissible infections among young adults in a high‐risk neighbourhood. Drug users, particularly injection drug users and crack smokers, may be a core group for some sexually transmitted infections. Design Cross‐sectional survey and assays of young adults from (a) a household probability sample and (b) a targeted sample of youth who have used injected drugs, crack, other cocaine or heroin. Setting Bushwick, an impoverished New York City minority neighbourhood with major drug markets. Participants A total of 363 18–24‐year‐olds from a household probability sample; 165 Bushwick 18–24‐year‐olds who have used injected drugs, crack, other cocaine or heroin. Measurements Drug use by self‐report; serum‐ and urine‐based assays for HIV, hepatitis B and C, syphilis, gonorrhoea, chlamydia and herpes simplex (type 2). Findings Household‐sample prevalences: HIV, hepatitis C and syphilis, 1%; gonorrhoea 3%; chlamydia 5%; past or present hepatitis B infection 8%; herpes simplex (type 2) 18%. In combined household and targeted samples, hepatitis C and HIV were concentrated among drug injectors. Herpes simplex (type 2), syphilis and hepatitis B increased among women with ‘hardest drug ever used’. Conclusions Using ‘harder’ drugs is associated with some but not all of these infections. Prevention efforts should help youth avoid unsafe sex and higher‐risk drugs.