Strongyloides stercoralis hyperinfection in systemic lupus erythematosus and the antiphospholipid syndrome

OBJECTIVE: The Strongyloides stercoralis hyperinfection syndrome (SHS) may develop in individuals with asymptomatic infection receiving immunosuppressive treatment. This report summarizes current knowledge regarding SHS in patients with systemic lupus erythematosus (SLE) and associated antiphospholipid syndrome (APS). METHODS: Two patients with active SLE and associated APS presenting with SHS are reported. Additional cases of strongyloidiasis in SLE were identified and reviewed. RESULTS: Patient 1: A 34-year-old woman with SLE and APS characterized by active glomerulonephritis, stroke, and several hospital-acquired infections presented with vomiting and diffuse abdominal pain. Intestinal vasculitis was suspected, and treatment with methylprednisolone and cyclophosphamide was given. Response was partial. A gastric biopsy revealed S. stercoralis larvae. She received ivermectin and eventually recovered. Patient 2: A 37-year-old man with active glomerulonephritis and APS with recurrent thrombosis presented with digital necrosis. Necrotizing vasculitis was suspected and treated with immunosupressants. He suddenly developed respiratory failure secondary to alveolar hemorrhage and bronchoalveolar lavage was performed. The patient developed Gram-negative septic shock and died. The postmortem result of bronchoalveolar lavage yielded Strongyloides larvae. Nine cases of strongyloidiasis and the SHS in SLE patients reported in the literature were identified and reviewed. Five of these patients died; none had associated APS. CONCLUSIONS: These cases suggest that the SHS can exacerbate SLE and APS, predisposing to Gram-negative sepsis and death. Immunocompromised patients need an early diagnosis and specific treatment of parasitic diseases and their complications. The SHS should be considered in the differential diagnosis of lupus complications in patients from endemic areas.     

First-line cetuximab plus capecitabine in elderly patients with advanced colorectal cancer: clinical outcome and subgroup analysis according to KRAS status from a Spanish TTD Group Study

Single-agent cetuximab is safe and active in elderly patients with advanced colorectal cancer (CRC). A cetuximab–capecitabine combination has not previously been tested in elderly patients with advanced CRC.

Material and Methods.

Sixty-six patients with advanced CRC were treated with cetuximab as a 400 mg/m² i.v. infusion followed by 250 mg/m² i.v. weekly plus capecitabine at a dose of 1,250 mg/m² every 12 hours. After the inclusion of 27 patients, the protocol was amended for safety reasons, reducing the dose of capecitabine to 1,000 mg/m² every 12 hours. Thirty-nine additional patients were treated with the reduced dose of capecitabine.

Results.

The overall response rate was 31.8%. KRAS status was determined in 58 patients (88%). Fourteen of 29 patients with wild-type KRAS tumors responded (48.3%; 95% confidence interval [CI], 29.4%–67.5%), compared with six of 29 patients with mutant KRAS tumors (20.7%; 95% CI, 8.0%–39.7%). The median progression-free survival (PFS) interval was 7.1 months. The median PFS interval for patients whose tumors were wild-type KRAS was significantly longer than for those with mutant KRAS tumors (8.4 months versus 6.0 months; p = .024). The high incidence of severe paronychia (29.6%) declined (7.7%) after capecitabine dose adjustment.

Conclusions.

Cetuximab plus capecitabine at a dose of 1,000 mg/m² every 12 hours may be an alternative to more aggressive regimens in elderly patients with advanced wild-type KRAS CRC.     

Stromal Cell-Derived Factor 1�� Mediates Resistance to mTOR-Directed Therapy in Pancreatic Cancer

Purpose

The factors preventing the translation of preclinical findings supporting the clinical development mTOR-targeted therapy in pancreatic cancer therapy remain undetermined. Stromal cell.derived factor 1α (SDF-1α)-CXCR4 signaling was examined as a representative microenvironmental factor able to promote mTOR-targeted therapy resistance in pancreatic cancer.

Experimental Design

Primary pancreas explant xenografts and in vitro experiments were used to perform pharmacodynamic analyses of SDF-1α-CXCR4 regulation of the mTOR pathway. Combinatorial effects of CXCR4, EGFR, and mTOR pharmacologic inhibition were evaluated in temsirolimus-resistant and -sensitive xenografts. Intratumoral gene and protein expressions of mTOR pathway effectors cyclin D1, c-Myc, and VEGF were evaluated.

Results

Baseline intratumoral SDF-1α gene expression correlated with temsirolimus resistance in explant models. SDF-1α stimulation of pancreatic cells resulted in CXCR4-mediated PI3-kinase-dependent S6-RP phosphorylation (pS6-RP) on exposure to temsirolimus. Combinatorial therapy with AMD3465 (CXCR4 small-molecule inhibitor) and temsirolimus resulted in effective tumor growth inhibition to overcome temsirolimus resistance. In contrast, SDF-1α exposure induced a temsirolimus-resistant phenotype in temsirolimus-sensitive explants. AMD3465 inhibited CXCR4-mediated intratumoral S6-RP phosphorylation and cyclin D and c-myc gene expression. Next, CXCR4 promoted intratumoral EGFR expression in association with temsirolimus resistance. Treatment with AMD3465, temsirolimus- and erlotinib-mediated tumor growth inhibition to overcome temsirolimus resistance in the explant model. Lastly, SDF-1α-CXCR4 signaling increased intratumoral VEGF gene and protein expression.

Conclusions

SDF-1α-CXCR4 signaling represents a microenvironmental factor that can maintain mTOR pathway fidelity to promote resistance to mTOR-targeted therapy in pancreatic cancer by a variety of mechanisms such as recruitment of EGFR signaling and angiogenesis.     

Breast cancer proteomics reveals a positive correlation between glyoxalase 1 expression and high tumor grade

Breast cancer is the neoplasia with the highest incidence in women worldwide. Proteomics approaches have accelerated the discovery of diagnostic and prognostic biomarkers. Here, we compared the proteomic profiles of breast tumors versus non-tumoral tissues in order to identify modulated proteins, which could represent potential markers associated to clinical features. By two-dimensional electrophoresis, we detected 28 differentially expressed proteins. Among these, 21 proteins were up-regulated and 7 were down-regulated in tumors (p<0.05). Proteins were identified using LC/ESI-MS/MS tandem mass spectrometry. One protein was identified as glyoxalase 1 (GLO1), an enzyme involved in detoxification of methylglyoxal, a cytotoxic product of glycolysis. GLO1 overexpression was confirmed by western blot assays in paired normal and tumor breast tissues in clinical stages I-III, and by immunohistochemistry on tissue microarrays (TMA) comprising a cohort of 98 breast tumors and 20 healthy specimens. Results from TMA demonstrated that GLO1 is overexpressed in 79% of tumors. Interestingly, GLO1 up-regulation correlates with advanced tumor grade (p<0.05). These findings demonstrate the association of GLO1 overexpression with tumor grade and pointed out for additional studies to establish the importance of GLO1 in breast cancer.     

Organizational socialization of volunteers: the effect on their intention to remain

Identifying the factors affecting the retention of volunteers in their activities is one of the main objectives for researchers and volunteer managers. There have been many studies with this aim and many factors affecting sustained volunteerism have been identified. However, one of the limits of these models is the low percentage of explained variance, which indicates that there are other additional factors, yet unidentified, which may have an important influence in the prediction of durability as a volunteer. In our study, we intend to analyze the effect that some factors of organizational socialization of volunteers have on their intention to remain volunteers. In particular, we will focus on the level of integration in the organization, evaluated from five variables: social networks, training, understanding, social support inside the organization, and characteristics of the job they perform. The statistical analysis shows that social networks, organizational support, positive task, and formation are highly significant predictors of the intention to remain a volunteer. These four variables explain 29% of the variability of the dependent variable, while the variables understanding and social support of the volunteers were excluded from the regression equation. © 2009 Wiley Periodicals, Inc.     

Prospective evaluation of esophageal motor dysfunction in Down''s syndrome

OBJECTIVE: The aim of this study was to determine the prevalence and way of presentation of esophageal motor dysfunction in a nonselected population of subjects with Down's syndrome. METHODS: The study was conducted in 58 Down's syndrome patients and 38 healthy controls. A global symptom score and individual scores for dysphagia for liquids and solids, heartburn, vomiting/regurgitation, and chest pain were obtained. Esophageal function was evaluated initially by scintigraphy using liquid and semisolid bolus. Time-activity curves based on the mean condensed images were used to calculate residual activity at 100 s after swallowing. According to both scintigraphy and clinical evaluation results, participants underwent a radiological and manometric study. RESULTS: The most frequent symptoms in Down's syndrome patients were: dysphagia for liquids (n = 9), dysphagia for solids (n = 10), vomiting/regurgitation (n = 8), and chest pain (n = 2). Liquid and semisolid retention of the tracer was significantly higher in Down's syndrome patients than in controls (p < 0.05). In 15 participants with Down's syndrome, tracer retention was higher than the 95 percentile of controls' retention. No correlation was found between the global or individual symptom score and esophageal retention quantified by scintigraphy. Hypothyroidism was unrelated to esophageal symptoms or retention. Five of the 15 esophagograms performed were abnormal, showing barium retention and/or esophageal dilation. Manometry showed achalasia in two subjects, total body aperistalsis in one, and nonspecific esophageal motor disorder in two. CONCLUSION: Esophageal motor disorders, particularly achalasia, are frequent in individuals with Down's syndrome. Awareness of esophageal dysmotility in this population is important, even though symptoms are not evident, to avoid potential complications.     

Intermittent small bowel obstruction caused by Meckel’s enterolith

A 56-year-old man presented with small bowel obstruction after a 6-week history of intermittent resolving subacute small bowel obstruction. After investigations, he underwent laparotomy. A mobile, narrow-necked Meckel’s diverticulum packed with enteroliths pressing against proximal small bowel was discovered. A small bowel resection was performed.