Citations

Reovirus is an oncolytic virus (OV), which acts by both direct tumor cell killing and priming of antitumor immunity. A major obstacle for effective oncolytic virotherapy is effective delivery of OV to tumor cells. Ovarian cancer is often confined to the peritoneal cavity and therefore i.p. delivery of reovirus may provide the ideal locoregional delivery, avoiding systemic dissemination. However, ovarian cancer is associated with an accumulation of ascitic fluid, which may interfere with oncolytic viral therapy. Here, we investigated the effect of ascites on reovirus‐induced oncolysis against primary ovarian cancer cells and ovarian cancer cell lines. In the absence of ascites, reovirus was cytotoxic against ovarian cancer cells; however, cytotoxicity was abrogated in the presence of ascitic fluid. Neutralizing antibodies (NAb) were identified as the cause of this inhibition. Loading OV onto cell carriers may facilitate virus delivery in the presence of NAb and immune cells which have their own antitumor effector activity are particularly appealing. Immature dendritic cells (iDC), Lymphokine‐activated killer (LAK) cells and LAKDC cocultures were tested as potential carriers for reovirus for tumor cell killing and immune cell priming. Reovirus‐loaded LAKDC, and to a lesser degree iDC, were able to: (i) protect from NAb and hand‐off reovirus for tumor cell killing; (ii) induce a proinflammatory cytokine milieu (IFNɣ, IL‐12, IFNα and TNFα) and (iii) generate an innate and specific antitumor adaptive immune response. Hence, LAKDC pulsed with reovirus represent a novel, clinically practical treatment for ovarian cancer to maximise both direct and innate/adaptive immune‐mediated tumor cell killing.

AbstractBackgroundHematopoietic stem cell transplant (HSCT) recipients have increased morbidity from respiratory viral infections. Pandemic influenza A – A(H1N1)/pdm09 – in 2009–2010 was associated with increased severity of illness in patients with underlying co‐morbidities including HSCT, but the factors that contribute to severe disease in HSCT patients are not well characterized.MethodsWe conducted a multicenter review of microbiologically proven influenza A(H1N1)pdm09 in the HSCT population between April 2009 and April 2010 to determine factors that are associated with severe disease.ResultsWe identified 37 adult patients (26 allogeneic and 11 autologous HSCT recipients). Median time from transplant to diagnosis was 411 days (range 4 days–14.9 years). Three cases were hospital acquired. Twenty‐eight of 37 (75.7%) had confirmed A(H1N1)pdm09. Presumed viral lower respiratory tract infection was present in 12/37 (32.4%) patients. Antiviral therapy was given to 33/37 (89%) patients, primarily oseltamivir (n = 24) and oseltamivir before or after another antiviral (n = 8). Excluding those with nosocomial A(H1N1)pdm09, 18/34 (52.9%) were hospitalized and 6 (33%) required admission to an intensive care unit. Mortality within 30 and 60 days of symptom onset was 7/37 (18.9%) and 11/37 (29.7%), respectively. Factors associated with mortality included nosocomial acquisition (P = 0.023), receipt of mycophenolate mofetil (P = 0.001), or antilymphocyte antibody (P = 0.005) within the past 6 months, reduced‐intensity conditioning (P = 0.027), and bacteremia (P = 0.021).ConclusionsA(H1N1)pdm09 infection was particularly severe in HSCT recipients, specifically among those receiving augmented immunosuppression for graft‐versus‐host disease. The high mortality of the nosocomial cases highlights the need for strict infection‐control measures in hospitals during influenza outbreaks.

Transaortic valve implantation via direct aortic puncture has been shown to be useful alternative to more traditional access routes. In patients with previously placed ascending aorta saphenous vein grafts, access to the aortic valve may be limited. We therefore sought to detail the utility of a new approach for accessing the ascending aorta during transcatheter aortic valve implantation via the hood of previously placed saphenous vein grafts. © 2013 Wiley Periodicals, Inc.

BackgroundVancomycin treatment failure has been associated with low serum vancomycin trough concentrations, prompting recommendations to increase the daily doses in adults and children. Despite more aggressive vancomycin dosing, there continues to be significant variability in vancomycin trough concentrations in pediatric patients.MethodsTo determine if vancomycin trough concentrations in pediatric patients differ by age and weight, we reviewed records of hospitalized patients who received vancomycin between 2008 and 2012. Patients were divided into groups that received vancomycin 40 mg/kg/day (2008–2009) or 60 mg/kg/day (2010–2012). Vancomycin trough concentrations were compared between groups and within the 60 mg/kg/day group, stratified by patient age and weight.ResultsAfter increasing the vancomycin dose from 40 to 60 mg/kg/day, initial trough concentrations increased significantly in patients younger than 2 and greater than 6 years of age, but not in patients between the ages of 2 and 5 years. In the 60 mg/kg/day group, only 16.7% of patients between 2 and 5 years of age had initial trough concentrations in the therapeutic range (10–20 μg/ml). Initial trough concentrations were therapeutic in a greater proportion of patients ages 6–12 years (38.7%) and 13–18 years (63.0%). Patients between the ages of 13 and 18 had the highest proportion of supratherapeutic initial vancomycin trough concentrations (14.8%). Patients weighing over 50 kg had significantly higher trough concentrations than patients 50 kg or less (17.1 μg/ml vs 9.3 μg/ml, p<0.001).ConclusionAlthough increasing the vancomycin dose from 40 to 60 mg/kg/day led to a significant increase in vancomycin trough concentrations, a large proportion of patients receiving 60 mg/kg/day of vancomycin had trough concentrations outside of the therapeutic range. Specifically, patients younger than 6 years tended to have low trough concentrations, whereas adolescents and children over 50 kg were more likely to have elevated trough concentrations. Vancomycin dosing strategies in pediatric patients should consider age and weight as well as renal function and indication.

Background Acetazolamide induces cerebral vasodilatation and may be used to measure cerebrovascular reserve in patients with cerebral arteriopathy. While acetazolamide is known to induce transient neurologic deficits as a result of “steal phenomenon,” prolonged deficits have rarely been described. Methods Retrospective, single-centre case review from 2011 to 2012. Results We describe 3 patients ages 41, 60 and 65 years (2 women; 1 man) who developed prolonged neurological deterioration following administration of acetazolamide in the acute phase following presentation for evaluation of cerebrovascular reserve. Two patients presented with hemispheric ischaemic symptoms; one presented with headache and parietal convexity subarachnoid haemorrhage. One patient had extensive intracranial vascular disease consistent with a moyamoya-like syndrome with left middle cerebral artery (MCA) occlusion and severe left supraclinoid internal carotid artery (ICA) stenosis. Another had 50% left MCA stenosis as well as > 70% stenosis of the left ICA. She failed medical therapy, L CAS, L MCA angioplasty, and left EC-IC bypass. A third patient had occlusion of the right ICA and severe left ICA stenosis. In every case, acetazolamide challenge was carried out in the acute phase following presentation. All three patients developed significant prolonged worsening of neurologic deficits following the administration of acetazolamide (1 g). Patients received aggressive intravenous hydration. Two of the patients regained pre-acetazolamide neurological status within 18 hours. The third patient recovered several days after emergency left carotid artery stenting. Imaging studies (CT in 2 cases; MRI in 1) did not reveal interval haemorrhage or additional ischaemic changes in any case. Conclusion Administration of acetazolamide has the potential to induce decline in neurological function after administration in the acute phase and may be persistent for several hours or days. A steal phenomenon is a possible mechanism. The combination of severe extracranial and intracranial vascular disease may predispose to prolonged deficits and may be a contraindication to diagnostic use of acetazolamide. Disclosures R. Tawk: None. B. Eidelman: None. R. Hanel: None. J. Meschia: None. K. Barrett: None.

BACKGROUNDPatients diagnosed with primary sclerosing cholangitis (PSC) and dominant strictures often undergo endoscopic retrograde cholangiopancreatography with brush cytology to exclude or confirm the development of malignancy. Equivocal (atypical or suspicious) routine cytologic results may confound patient management decisions, especially in the absence of a mass on imaging. The objective of the current study was to identify independent predictors of malignancy in patients with PSC with an equivocal cytology diagnosis.METHODSPatients with PSC underwent brush cytology for routine cytology and fluorescence in situ hybridization (FISH) during endoscopy as per standard care. FISH slides were classified as polysomy if at least 5 cells displayed a gain of ≥ 2 probes. A retrospective search identified 102 patients without a mass lesion noted on initial imaging studies, an equivocal routine cytology, and ≥ 2 years of follow‐up.RESULTSOf 102 patients, 30 (29%) with an equivocal cytology result developed cancer within 2 years. Serum carbohydrate antigen 19‐9 (CA 19‐9) levels ≥ 129 U/mL (hazard ratio [HR] 3.19; P = .001) and polysomy (HR 8.70; P < .001) were each found to be predictive of cancer. Of 10 patients who had elevated CA 19‐9 levels and polysomy, all went on to develop cancer (9 within 2 years). Although only 10 patients were included in this subset, the combination of elevated CA 19‐9 and polysomy was found to be predictive of cancer (HR 10.92; P < .001).CONCLUSIONSPolysomy by FISH identified those patients most likely to have or develop malignancy in the challenging clinical scenario of PSC with no mass at baseline and equivocal cytology. The combination of an elevated serum CA 19‐9 level with polysomy is highly suspicious for the presence of malignancy. Cancer (Cancer Cytopathol) 2013;121:708–717. © 2013 American Cancer Society.