First-in-Human Phase I Clinical Trial of Pharmacologic Ascorbate Combined with Radiation and Temozolomide for Newly Diagnosed Glioblastoma.

PURPOSE: Standard treatment for glioblastoma (GBM) includes surgery, radiation therapy (RT), and temozolomide (TMZ), yielding a median overall survival (OS) of approximately 14 months. Preclinical models suggest that pharmacologic ascorbate (P-AscH-) enhances RT/TMZ antitumor effect in GBM. We evaluated the safety of adding P-AscH- to standard RT/TMZ therapy. PATIENTS AND METHODS: This first-in-human trial was divided into an RT phase (concurrent RT/TMZ/P-AscH-) and an adjuvant (ADJ) phase (post RT/TMZ/P-AscH- phase). Eight P-AscH- dose cohorts were evaluated in the RT phase until targeted plasma ascorbate levels were achieved (≥20 mmol/L). In the ADJ phase, P-AscH- doses were escalated in each subject at each cycle until plasma concentrations were ≥20 mmol/L. P-AscH- was infused 3 times weekly during the RT phase and 2 times weekly during the ADJ phase continuing for six cycles or until disease progression. Adverse events were quantified by CTCAE (v4.03). RESULTS: Eleven subjects were evaluable. No dose-limiting toxicities occurred. Observed toxicities were consistent with historical controls. Adverse events related to study drug were dry mouth and chills. Targeted ascorbate plasma levels of 20 mmol/L were achieved in the 87.5 g cohort; diminishing returns were realized in higher dose cohorts. Median progression-free survival (PFS) was 9.4 months and median OS was 18 months. In subjects with undetectable MGMT promoter methylation (n = 8), median PFS was 10 months and median OS was 23 months. CONCLUSIONS: P-AscH-/RT/TMZ is safe with promising clinical outcomes warranting further investigation.

Hypoventilation disproportionate to OSAS severity in children with Prader-Willi syndrome.

OBJECTIVE: To test the hypothesis that children with Prader-Willi syndrome (PWS) and obstructive sleep apnoea syndrome (OSAS) have hypercapnia for higher proportion of total sleep time (TST) than non-syndromic children with similar obstructive apnoea-hypopnoea index (OAHI). DESIGN: Cross-sectional study. SETTING: Two tertiary care hospitals. PATIENTS: Patients with PWS and non-syndromic children with snoring who underwent polygraphy and were of similar age, body mass index (BMI) z-score and OAHI. MAIN OUTCOME MEASURE: The two groups were compared regarding %TST with transcutaneous CO2 (PtcCO2) >50 mm Hg. The interaction between PWS diagnosis and OSAS severity (OAHI <1 episode/h vs 1-5 episodes/h vs >5 episodes/h) regarding %TST with PtcCO2 >50 mm Hg was tested using multiple linear regression. RESULTS: 48 children with PWS and 92 controls were included (median age 2.3 (range 0.2-14.1) years vs 2.2 (0.3-15.1) years; BMI z-score 0.7±1.9 vs 0.8±1.7; median OAHI 0.5 (0-29.5) episodes/h vs 0.5 (0-33.9) episodes/h; p>0.05). The two groups did not differ in %TST with PtcCO2 >50 mm Hg (median 0% (0-100%) vs 0% (0-81.3%), respectively; p>0.05). However, the interaction between PWS and OSAS severity with respect to duration of hypoventilation was significant (p<0.01); the estimated mean differences of %TST with PtcCO2 >50 mm Hg between children with PWS and controls for OAHI <1 episode/h, 1-5 episodes/h and >5 episodes/h were +0.2%, +1% and +33%, respectively. CONCLUSION: Increasing severity of upper airway obstruction during sleep in children with PWS is accompanied by disproportionately longer periods of hypoventilation when compared with non-syndromic children with similar frequency of obstructive events.

O2⋠- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate.

Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H2O2; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O2⋅- and H2O2 are capable of disrupting intracellular iron metabolism, thereby selectively sensitizing non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox-active labile iron and H2O2. In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.

Sleepiness and activity in heart failure patients with reduced ejection fraction and central sleep-disordered breathing.

OBJECTIVE: Patients with heart failure (HF) and sleep disordered breathing (SDB) are typically not sleepy, unlike patients without heart failure. Previous work in HF patients with obstructive SDB suggested that sleepiness was associated with a reduction in daytime activity. The consequences of predominately central SDB on sleepiness in HF are less well understood. The aim of this study was to test the hypothesis that subjective sleepiness is associated with reduced daytime activity in HF patients with central SDB, compared to those without SDB. METHODS: The Epworth Sleepiness Scale (ESS), nocturnal polysomnography, and 14 days of wrist watch actigraphy were used to assess subjective daytime sleepiness, nocturnal sleep and breathing, and 24-h activity levels, respectively. RESULTS: A total of 54 patients with HF were studied, nine had obstructive SDB and were removed from further analysis. Of the patients, 23 had HF with predominantly central SDB (HF-CSA; apnea-hypopnea index (AHI) median 20.6 (IQR 12.9-40.2)/h), and 22 had noSDB (HF-noSDB; AHI 3.7 (2.5-5.9)/h). The median patient age was 68 years (range 59-73 years). There were no significant differences either in ESS score (HF-CSA; 8 [4-10] vs. HF-noSDB; 8 (6-12); p = 0.49) or in duration of daytime activity (HF-CSA 14.5 (14.1-15.2) and HF-noSDB 15.1 (14.4-15.3) hours; p = 0.10) between the groups. CONCLUSION: HF patients with predominately central SDB are not subjectively sleepy compared to those without SDB, despite reduced sleep quality. We speculate that the lack of sleepiness (based on ESS score) may be due to increased sympathetic nerve activity, although further studies are needed due to the small number (n = 5) of sleepy HF-CSA patients. Daytime activity was not different between HF-noSDB and HF-CSA patients.

Evaluation of Postharvest Washing on Removal of Silver Nanoparticles (AgNPs) from Spinach Leaves.

There is increasing use of silver nanoparticles (AgNPs) as pesticides for fruits and vegetables due to the particles' unique antimicrobial and insecticidal properties. However, residual AgNPs in harvested produce may transfer through the food chain and pose a potential risk to public health. The objective of this study is to determine whether postharvest washing can effectively remove AgNPs that had accumulated on fresh produce. Ten microliters of commercially available 40 nm citrate coated AgNPs (0.4 mg/L) was dropped to a (1 × 1 cm(2)) spot on spinach leaves, followed by washing with deionized water (DI water), Tsunami 100 (80 mg/L), or Clorox bleach (200 mg/L). Then, the AgNP removal efficiency of the three treatments was evaluated by surface-enhanced Raman spectroscopy (SERS), scanning electron microscopy (SEM)-energy dispersive spectrometry (EDS), and inductively coupled plasma mass spectrometry (ICP-MS). ICP-MS results showed that deionized water removed statistically insignificant amounts of total Ag (5%), whereas Tsunami 100 and Clorox bleach yielded 21 and 10% decreases in total Ag, respectively (P < 0.05). The increased removal efficiency resulted from AgNP dissolution and Ag(+) release upon contact with the oxidizing agents in Tsunami 100 (peroxyacetic acid, hydrogen peroxide) and Clorox bleach (sodium hypochlorite). According to the SERS results, the deionized water and Tsunami 100 treatments removed nonsignificant amounts of AgNPs. Clorox bleach decreased Ag NPs by >90% (P < 0.05); however, SEM-EDS images revealed the formation of large silver chloride (AgCl) crystals (162 ± 51 nm) on the leaf, which explained the low total Ag removal from ICP-MS. This study indicates current factory washing methods for fresh produce may not be effective in reducing AgNPs (by water and Tsunami 100) and total Ag (by all three means). This highlights the necessity to develop an efficient washing method for NP removal from food surfaces in the future.

Case report: paroxysmal cold hemoglobinuria presenting during pregnancy.

BACKGROUND: Paroxysmal cold hemoglobinuria is caused by a biphasic IgG autoantibody that triggers complement-mediated intravascular hemolysis. Paroxysmal cold hemoglobinuria has not previously been reported to occur in association with pregnancy. CASE PRESENTATION: We report a case of an 18 year old female who presented in early pregnancy with acute hemolytic anemia and a positive Donath-Landsteiner antibody test. She was diagnosed with paroxysmal cold hemoglobinuria and treated supportively. Her hemolysis resolved within 6 weeks. Because maternal IgG autoantibodies can cross the placenta, the patient was monitored closely throughout her pregnancy for recurrence. The outcome of the pregnancy was successful, with no evidence of neonatal anemia or hemolysis. CONCLUSION: This patient had a classic presentation of paroxysmal cold hemoglobinuria with rapid onset of hemolytic anemia that resolved spontaneously. To our knowledge, this is the first report of paroxysmal cold hemoglobinuria presenting during pregnancy.

Upper airway factors that protect against obstructive sleep apnoea in healthy older males.

The prevalence of obstructive sleep apnoea (OSA) increases with age, yet the risk factors for OSA in older people remain poorly understood. This study aimed to define the age-related changes in upper airway morphology in carefully matched groups of healthy older (>60 years, n=11) and younger (<40 years, n=14) males, using direct (magnetic resonance imaging (MRI)) and indirect (acoustic reflection) imaging. The median (interquartile range) combined retropalatal and retroglossal pharyngeal length was greater in older than in younger males (older 8.8 (7.8-9.0) cm, younger 7.8 (7.0-8.3) cm; p=0.03), as was the soft palate cross-sectional area (older 43.1 (36.0-48.8) cm(2), younger 35.3 (30.5-40.5) cm(2); p=0.03), parapharyngeal fat pad diameter (older 1.7 (1.4-2.2) cm, younger 1.2 (1.0-1.8) cm; p=0.03) and cross-sectional area of the fat pads (older 13.8 (9.1-17.1) cm(2); younger 7.4 (5.9-13.0) cm(2); p=0.02) as measured by MRI. Using acoustic reflection, pharyngeal calibre (older 4.8 (3.8-6.6) cm(2), younger 3.4 (2.8-4.6) cm(2); p=0.03), pharyngeal volume (older 35.1 (30.9-55.4) cm(3), younger 27.2 (22.7-44.2) cm(3); p=0.04) and glottis area (older 2.7 (2.1-3.9) cm(2), younger 1.3 (1.1-1.9) cm(2); p=0.003) were also larger in older participants compared with younger participants. There was no difference in craniofacial measures between groups, including volumetric data and hyoid bone position. The larger pharyngeal calibre observed in older males may be compensating for an age-related enlargement in pharyngeal soft tissue that predisposes to OSA.

Radiation induced adult medulloblastoma: a case report.

Adult medulloblastoma is a rare intracranial tumor. Our patient is a 61 year old woman treated with cranial irradiation 15 years previously for a low grade astrocytoma in the left posterior temporal lobe that was recently diagnosed with medulloblastoma in the right cerebellum. This is the first reported case of radiation induced adult medulloblastoma.

Burkholderia cenocepacia phage BcepMu and a family of Mu-like phages encoding potential pathogenesis factors.

We have isolated BcepMu, a Mu-like bacteriophage whose host range includes human pathogenic Burkholderia cenocepacia (formally B. cepacia genomovar III) isolates, and determined its complete 36748 bp genomic sequence. Like enteric bacteriophage Mu, the BcepMu genomic DNA is flanked by variable host sequences, a result of transposon-mediated replication. The BcepMu genome encodes 53 proteins, including capsid assembly components related to those of Mu, and tail sheath and tube proteins related to those of bacteriophage P2. Seventeen of the BcepMu genes were demonstrated to encode homotypic interacting domains by using a cI fusion system. Most BcepMu genes have close homologs to prophage elements present in the two published Salmonella typhi genomes, and in the database sequences of Photorhabdus luminescens, and Chromobacterium violaceum. These prophage elements, designated SalMu, PhotoMu and ChromoMu, respectively, are collinear with BcepMu through nearly their entire lengths and show only limited mosaicism, despite the divergent characters of their hosts. The BcepMu family of Mu-like phages has a number of notable differences from Mu. Most significantly, the critical left end region of BcepMu is inverted with respect to Mu, and the BcepMu family of transposases is clearly of a distinct lineage with different molecular requirements at the transposon ends. Interestingly, a survey of 33 B.cepacia complex strains indicated that the BcepMu prophage is widespread in human pathogenic B.cenocepacia ET12 lineage isolates, but not in isolates from the PHDC or Midwest lineages. Identified members of the BcepMu family all contain a gene possibly involved in bacterial pathogenicity, a homolog of the type-two-secretion component exeA, but only BcepMu also carries a lipopolysaccharide modification acyltransferase which may also contribute a pathogenicity factor.

Effects of intravenous amino acid administration with Y-90 DOTA-Phe1-Tyr3-Octreotide (SMT487[OctreoTher) treatment.

Y-90-DOTA-Phe1-Tyr3-Octreotide (90Y-SMT 487, OctreoTher) has shown potential for effectively treating patients with neuroendocrine tumors. The dose-limiting organ for this agent is the kidney. The purpose of this work is to assess the effectiveness of a commercially available amino acid solution on reducing renal uptake of 90Y-SMT 487 and determine the safety profile of this solution. Subjects with In-111 pentetreotide positive tumors and normal creatinine levels were treated with 3 cycles of 90Y-SMT 487, 120 mCi/cycle, at 6-9 week intervals. During each treatment two liters of an amino acid solution containing arginine and lysine (Aminosyn II 7%, Abbott Laboratories, Abbott Park, IL) were infused IV over 4 hours. Adverse events were recorded. To assess the effect of Aminosyn II on renal uptake of 90Y-SMT 487, a subgroup of subjects underwent bremsstrahlung imaging 24 hours following infusion. Kidney to liver (K/L) count density ratios were generated from the baseline In-111 pentetreotide images (performed without amino acid infusion) and the 90Y bremsstrahlung images. Follow-up creatinine levels were obtained. Thirty-seven subjects received a total of 89 90Y-SMT 487 treatments. The number of amino-acid infusions associated with one or more episodes of emesis was 53 (62%). During 13 (15%) of these infusions, the Aminosyn II rate had to be reduced because of severe nausea and vomiting. Symptomatic flushing occurred during 16 (18%) of the infusions. One subject experienced a near syncopal event shortly after completing the infusion. Creatinine levels remained normal in 34 of 36 subjects during a mean follow-up period of 9.8 months. Fourteen subjects underwent bremsstrahlung imaging following infusion of 90Y-SMT 487. Kidney uptake appeared to decrease with administration of the amino acid solution in 13 of 14 subjects. For the 28 individual kidneys, the mean percent decrease in the Kidney/Liver uptake ratio with the amino acid solution was found to be 32%. We conclude that 2 L of Aminosyn II 7% infused over 4 hours appears to notably reduce renal uptake of 90Y-SMT 487. Aminosyn is generally well tolerated, particularly at lower infusion rates with occasional moderate to severe nausea and vomiting at higher rates.

Evaluating the clinical effectiveness of 90Y-SMT 487 in patients with neuroendocrine tumors.

UNLABELLED: Because of the presence of cell membrane somatostatin receptors (SSTRs), many neuroendocrine tumors will bind analogs of somatostatin. (90)Y-Dodecanetetraacetic acid-Phe1-Tyr3-octreotide (SMT 487) is an SSTR radiopharmaceutical currently under investigation as a therapeutic option for neuroendocrine tumors. Although there are a variety of methods for evaluating response to a given cancer therapy, an important indicator of success is the impact on the clinical status of the patient. The purpose of this work was to develop a semiquantitative method and assess the clinical effectiveness of (90)Y-SMT 487 therapy in patients with neuroendocrine tumors. METHODS: A scoring system was developed to evaluate clinical response that included the following parameters: weight, health status score (determined by the patient), Karnofsky score, and tumor-related symptoms. RESULTS: We applied this scoring system to 21 patients who had completed 3 cycles of therapy with (90)Y-SMT 487. Fourteen of the 21 showed a favorable clinical response, whereas 5 were clinically stable after treatment and 2 showed evidence of clinical progression. There was also a significant reduction in the amount of octreotide being used after completion of (90)Y-SMT 487 therapy in the 20 patients who were on this medication. CONCLUSION: Using this scoring method, (90)Y-SMT 487 appears effective in improving the clinical status of patients with (111)In-pentetreotide-positive neuroendocrine tumors.

Assessment of hepatic toxicity from treatment with 90Y-SMT 487 (OctreoTher(TM)) in patients with diffuse somatostatin receptor positive liver metastases.

The purpose of this study was to determine whether there is evidence for hepatocellular radiation injury following treatment with (90)Y-SMT487 ((90)Y-DOTA-tyr3-octreotide, OctreoTher(TM)) in patients with extensive liver metastases from neuroendocrine tumors. Patients reported in this study participated in a Phase II trial of efficacy and safety of (90)Y-SMT487. The trial design called for three treatment cycles of 120 mCi each (4400 MBq) of (90)Y-SMT487. (111)In-pentetreotide SPECT images were used to determine the extent of liver metastases. Serum AST, ALT, and alkaline phosphatase levels were obtained at baseline and following each cycle of therapy. Least squares fit was applied to the serial liver enzyme measurements in patients with extensive liver metastases. Post-therapy liver enzyme measurements were also evaluated using WHO common toxicity criteria. Repeated-measures ANOVA and paired t-test were applied to the serial enzyme measures. There were 21 subjects. Fifteen of these had hepatic metastases with 12 demonstrating extensive (defined as 25% or more) liver involvement. In only 4 of these 15 did any of the three enzyme levels increase in WHO toxicity grade from baseline to final follow-up. We conclude that patients with diffuse SSTR positive hepatic metastases can be treated with a cumulative administered activity of 360 mCi (90)Y-SMT487 with only a small chance of developing mild acute or subacute hepatic radiation injury.