Carbonic Anhydrase 9 Expression Increases with Vascular Endothelial Growth Factor-Targeted Therapy and Is Predictive of Outcome in Metastatic Clear Cell Renal Cancer

AbstractBackgroundThere is a lack of biomarkers to predict outcome with targeted therapy in metastatic clear cell renal cancer (mccRCC). This may be because dynamic molecular changes occur with therapy.ObjectiveTo explore if dynamic, targeted-therapy-driven molecular changes correlate with mccRCC outcome.Design, setting, and participantsMultiple frozen samples from primary tumours were taken from sunitinib-naïve (n=22) and sunitinib-treated mccRCC patients (n=23) for protein analysis. A cohort (n=86) of paired, untreated and sunitinib/pazopanib-treated mccRCC samples was used for validation. Array comparative genomic hybridisation (CGH) analysis and RNA interference (RNAi) was used to support the findings.InterventionThree cycles of sunitinib 50mg (4 wk on, 2 wk off).Outcome measurements and statistical analysisReverse phase protein arrays (training set) and immunofluorescence automated quantitative analysis (validation set) assessed protein expression.Results and limitationsDifferential expression between sunitinib-naïve and treated samples was seen in 30 of 55 proteins (p<0.05 for each). The proteins B-cell CLL/lymphoma 2 (BCL2), mutL homolog 1 (MLH1), carbonic anhydrase 9 (CA9), and mechanistic target of rapamycin (mTOR) (serine/threonine kinase) had both increased intratumoural variance and significant differential expression with therapy. The validation cohort confirmed increased CA9 expression with therapy. Multivariate analysis showed high CA9 expression after treatment was associated with longer survival (hazard ratio: 0.48; 95% confidence interval, 0.26–0.87; p=0.02). Array CGH profiles revealed sunitinib was associated with significant CA9 region loss. RNAi CA9 silencing in two cell lines inhibited the antiproliferative effects of sunitinib. Shortcomings of the study include selection of a specific protein for analysis, and the specific time points at which the treated tissue was analysed.ConclusionsCA9 levels increase with targeted therapy in mccRCC. Lower CA9 levels are associated with a poor prognosis and possible resistance, as indicated by the validation cohort.Patient summaryDrug treatment of advanced kidney cancer alters molecular markers of treatment resistance. Measuring carbonic anhydrase 9 levels may be helpful in determining which patients benefit from therapy

Long-Term Follow-Up in Children with Anisocoria: Cocaine Test Results and Patient Outcome

Background Evaluation of anisocoria including pharmacological testing for Horner's syndrome in the pediatric population is challenging in view of potential serious underlying disease. We describe cocaine test results, outcome of systemic investigation, and long-term follow-up in children with anisocoria. Methods Retrospective review of medical records and phone interview of consecutive pediatric patients (<18 years old) who underwent cocaine testing from August 2007 to July 2015 at a tertiary referral centre. Results A total of 35 patients were included with a positive, negative, or inconclusive cocaine test in 12/35, 19/35, and 4/35, respectively. Systemic investigation was performed in 11 of the patients with a positive and in 2 of the patients with an inconclusive cocaine test result. Mediastinal Hodgkin lymphoma was found in one patient with an inconclusive cocaine test result. Two other cases were presumably related to birth trauma and surgical trauma. None of the other children further developed any pathology during the follow-up period of 34.8 months (range 0-106.6). Conclusions In most children with anisocoria and a positive cocaine test result, systemic investigation did not reveal any underlying etiology. The only malignant disease was diagnosed in a patient with a suspicion of Horner's syndrome but with an inconclusive cocaine test result in our cohort

Die Neuritis nervi optici

The diagnosis of optic neuritis (ON) is made clinically based on typical signs and symptoms such as reduced vision and painful eye movements. Very often, ON is part of or associated with a systemic disease, in particular, multiple sclerosis (MS). Differential diagnosis is necessary in untypical cases with bilateral involvement, unusual age at manifestation or associated systemic and/or neurological symptoms. Neurological examination and cerebral MRI are standard in ON work-up. CSF analysis together with MRI scans allows MS risk assessment in ON patients. Further work-up is necessary in suspected systemic autoimmune disorders, sarcoidosis or infectious causes of ON such as borreliosis. © Georg Thieme Verlag KG Stuttgart · New York. Zusammenfassung: Die akute Neuritis nervi optici ist eine klinische Diagnose und typischerweise durch eine vor allem bei Augenbewegung schmerzhafte Sehminderung charakterisiert. Häufig ist sie Ausdruck einer entzündlichen Systemerkrankung, insbesondere der Multiplen Sklerose. Untypische Verläufe wie das beidseitige Auftreten, ein ungewöhnliches Erkrankungsalter oder klinische Präsentation wie auch systemische und neurologische Begleitsymptome erfordern differenzialdiagnostische Überlegungen. Neben der routinemäßigen neurologisch-klinischen Untersuchung hat sich die MRT des Kopfes als Standarddiagnostik etabliert. Die Bildgebung ermöglicht neben der Lumbalpunktion eine Aussage über das Multiple-Sklerose-Risiko. Die Zusatzdiagnostik bei akuter Neuritis nervi optici hat in den letzten Jahren in der Entscheidung über die immunmodulatorische Frühbehandlung des klinisch isolierten Syndroms an Bedeutung gewonnen. Weitere serologische und bildgebende Untersuchungen im Zusammenhang mit einer Neuritis nervi optici haben bei Verdacht auf eine infektiöse Ursache, eine Sarkoidose oder systemische Autoimmunerkrankung ihren differenzialdiagnostischen Stellenwert

Optic neuritis

The diagnosis of optic neuritis (ON) is made clinically based on typical signs and symptoms such as reduced vision and painful eye movements. Very often, ON is part of or associated with a systemic disease, in particular, multiple sclerosis (MS). Differential diagnosis is necessary in untypical cases with bilateral involvement, unusual age at manifestation or associated systemic and/or neurological symptoms. Neurological examination and cerebral MRI are standard in ON work-up. CSF analysis together with MRI scans allows MS risk assessment in ON patients. Further work-up is necessary in suspected systemic autoimmune disorders, sarcoidosis or infectious causes of ON such as borreliosis. © Georg Thieme Verlag KG Stuttgart · New York. Zusammenfassung: Die akute Neuritis nervi optici ist eine klinische Diagnose und typischerweise durch eine vor allem bei Augenbewegung schmerzhafte Sehminderung charakterisiert. Häufig ist sie Ausdruck einer entzündlichen Systemerkrankung, insbesondere der Multiplen Sklerose. Untypische Verläufe wie das beidseitige Auftreten, ein ungewöhnliches Erkrankungsalter oder klinische Präsentation wie auch systemische und neurologische Begleitsymptome erfordern differenzialdiagnostische Überlegungen. Neben der routinemäßigen neurologisch-klinischen Untersuchung hat sich die MRT des Kopfes als Standarddiagnostik etabliert. Die Bildgebung ermöglicht neben der Lumbalpunktion eine Aussage über das Multiple-Sklerose-Risiko. Die Zusatzdiagnostik bei akuter Neuritis nervi optici hat in den letzten Jahren in der Entscheidung über die immunmodulatorische Frühbehandlung des klinisch isolierten Syndroms an Bedeutung gewonnen. Weitere serologische und bildgebende Untersuchungen im Zusammenhang mit einer Neuritis nervi optici haben bei Verdacht auf eine infektiöse Ursache, eine Sarkoidose oder systemische Autoimmunerkrankung ihren differenzialdiagnostischen Stellenwert