Outcome of patients with malignant glioma and synchronous or metachronous non-central nervous system primary neoplasms.

Patients with malignant glioma who are also diagnosed with one or more primary neoplasms of other organs present a unique challenge in both determining prognosis and clinical management. The overlapping impact of the malignancies and their treatment result in confounding variables that may adversely affect optimal management of such patients. Additionally, the glioma-related characteristics and survival outcome of these patients is not well-defined. In this retrospective chart and data review from our longitudinal database, we identified patients with malignant glioma including anaplastic glioma and glioblastoma, diagnosed between January 2005 and June 2011, who were also diagnosed with other non-CNS primary neoplasms. Patients with known genetic syndromes were excluded. The data was analyzed to determine the clinical characteristics and glioma-related survival. A total of 204 patients with malignant glioma (165 glioblastoma and 39 anaplastic glioma) were identified. There was no significant difference in the overall survival or progression-free survival between patients with malignant glioma plus non-CNS primary neoplasm when compared with patients with malignant glioma only. In patients with glioblastoma and non-CNS malignancy, the duration between diagnosis of glioblastoma and non-CNS neoplasms did not significantly alter glioma-related survival. Patients with malignant glioma who were diagnosed with other non-CNS malignancy have survival outcome comparable to those with malignant glioma only. The duration between diagnosis of glioblastoma and diagnosis of non-CNS neoplasms did not affect survival. Further prospective studies specifically addressing survival and molecular characteristics of patients with malignant glioma plus non-CNS cancers are recommended.

Survival outcome of early versus delayed bevacizumab treatment in patients with recurrent glioblastoma.

Bevacizumab (BEV) is widely used for treatment of patients with recurrent glioblastoma. It is not known if there are differences in outcome between early versus delayed BEV treatment of recurrent glioblastoma. We examined the relationship between the time of starting BEV treatment and outcomes in patients with recurrent glioblastoma. In this retrospective chart review, we identified patients with recurrent glioblastoma diagnosed between 2005 and 2011 who were treated with BEV alone or BEV-containing regimens. Data was analyzed to determine overall survival (OS) from time of diagnosis and progression free survival (PFS) from time of starting BEV. A total of 298 patients were identified, 112 patients received early BEV, 133 patients received delayed BEV, and 53 patients were excluded because they either progressed within 3 months of radiation or received BEV at the time of diagnosis. There was no significant difference in PFS between patients that received early BEV and those that received delayed BEV (5.2 vs. 4.3 months, p = 0.2). Patients treated with delayed BEV had longer OS when compared to those treated with early BEV (25.9 vs. 20.8 months, p = 0.005). In patients with recurrent glioblastoma, there was no significant difference in PFS from the time of starting BEV between early and delayed BEV. Although patients treated with delayed BEV seemed to have longer OS, a conclusion regarding OS outcome requires further prospective trials. These results may indicate that delaying treatment with BEV is not detrimental for survival of patients with recurrent glioblastoma.

Study of the relation between serum levels of long-acting penicillin and the inflammatory markers: C-reactive protein and interleukin-6 in patients with chronic rheumatic heart disease.

BACKGROUND: There is an evidence of a chronic inflammatory state in patients with chronic rheumatic valvular heart disease (RHD) as shown by high serum levels of high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL6). Despite the efficacy of long-acting penicillin (LAP) in secondary prevention of rheumatic fever, its effect on this inflammatory state is still unknown. So, we sought to study the effect of LAP on the inflammatory markers, CRP and IL-6, in patients with chronic rheumatic heart disease. RESULTS: Eighty RHD patients coming to our hospital's outpatient clinic for rheumatic fever secondary prophylaxis by regular administration of LAP were enrolled in the study. Patients were divided into 3 groups: group A, 70 patients with RHD already on prophylactic LAP, group B, 10 patients with RHD who have not yet started prophylactic LAP, and group C, control group of 10 healthy individuals not known to have RHD. Serum levels of LAP, IL-6, and CRP were measured for the three groups. Group A had significantly lower IL-6 levels than group B (25.22 ± 33.50 vs. 126.1 ± 33.76nng/ml, respectively, p < 0.0001). IL-6 levels were significantly lower in control subjects compared to patients in group B (3.600 ± 2.319, 25.22 ± 33.50 ng/ml, respectively, p < 0.0001). However, IL-6 levels in the control group were lower but non-significantly different compared to group A. CRP level was lower in group A than group B (8419 ± 4935 vs. 14400 ± 3375 mg/dl, respectively, p = 0.0002). CRP levels were significantly lower in control subjects compared to patients in group A and group B. IL-6 values were positively correlated with CRP values (r = 0.6387, p < 0.0001). CRP values were negatively correlated with LAP values (r = -0.5277, p < 0.0001). IL-6 values were negatively correlated with LAP values (r = - 0.4401, p < 0.0001). There was a highly significant difference between LAP level in compliant and non-compliant patients (1.045 ± 1.270 vs. 0.0785 ± 0.1057 ng/ml, respectively, p value < 0.0001). There was also a highly significant difference between CRP level in compliant and non-compliant patients (7640 ± 4558 vs. 13090 ± 4717 mg/dl, respectively, p = 0.005). Moreover, there was a significant difference between IL-6 levels in compliant and non-compliant patients (21.53 ± 32.70 vs. 47.40 ± 30.91 ng/ml, respectively, p value 0.03). CONCLUSION: Serum LAP has a strong negative correlation with IL-6 and CRP levels. Regular administration of LAP strongly ameliorates the inflammatory state seen in patients with RHD.

Impact of adverse events of bevacizumab on survival outcomes of patients with recurrent glioblastoma.

BACKGROUND: Bevacizumab is widely used for treatment of recurrent glioblastoma (rGB). It is well known that adverse events (AEs) due to bevacizumab can cause early discontinuation of treatment. However, the association between AEs and survival outcomes is not well defined. METHODS: We retrospectively identified patients with rGB, who were treated with single-agent bevacizumab or bevacizumab-based combination regimens from 07/2005 through 07/2014, and who discontinued bevacizumab due to either AEs or physician's decision. Those who discontinued bevacizumab because of tumor progression were excluded. Demographic, treatment, and survival data were collected from the database. RESULTS: Of 298 adults with rGB treated with bevacizumab in our database, 65 patients discontinued bevacizumab due to AEs (n = 39, 60%) or physician's decision (n = 26, 40%). There were no statistically significant differences in regards to age, performance status, extent of resection, number of lesions, the time between diagnosis and first recurrence, time between diagnosis and initiation of bevacizumab, number of recurrences before bevacizumab initiation, and duration of bevacizumab treatment between the two groups. Interestingly, patients who discontinued bevacizumab because of AEs progressed earlier after bevacizumab discontinuation (3.9 months vs 5.7 months; p = 0.02), had significantly shorter progression-free survival (PFS) (10.4 months vs 14.2 months; p = 0.01) and shorter overall survival (OS) from bevacizumab initiation (13.9 months vs 32.5 months; p = 0.01) as well as shorter OS from tumor diagnosis (20 months vs 49.3 months; p = 0.007) when compared to patients who discontinued bevacizumab due to a physician's decision. CONCLUSIONS: Our results indicate that the development of AEs to bevacizumab or bevacizumab-containing regimens is associated with unfavorable glioma-related survival outcomes in patients with rGB.

Herpes simplex virus type-1 latency-associated transcript-induced immunoreactivity of substance P in trigeminal neurons is reversed by bone morphogenetic protein-7.

Herpes simplex virus type-1 (HSV-1) primarily infects mucoepithelial tissues of the eye and the orofacial region. Subsequently, the virus is retrogradely transported through the axons of the trigeminal sensory neurons to their nuclei, where the virus establishes a life-long latent infection. During this latency period, the viral genome is transcriptionally silent except for a single region encoding the latency-associated transcript (LAT). To understand how HSV-1 latency might affect the expression of substance P in sensory neurons, we transfected primary cultures of trigeminal neurons obtained from rat embryos, with LAT expressing plasmids. The expression of LAT increased the percentage of substance P-immunoreactive neurons by two thirds. To examine the effect of bone morphogenetic protein-7 (BMP7) on the LAT-induced increase in substance P expression in trigeminal neurons, cultures transfected with LAT were treated with BMP7. Treatment with BMP7 reversed the effects of LAT on substance P expression in trigeminal neurons. Our data show for the first time that LAT increases substance P expression in trigeminal neurons and BMP7 can reverse these effects of LAT.

The use of oral granisetron versus intravenous ondansetron for antiemetic prophylaxis in patients undergoing laparoscopic surgery: the effect on emetic symptoms and quality of recovery.

Based on comparative studies in patients receiving emetogenic chemotherapy, it has been suggested that granisetron would be more effective than ondansetron for the prevention of postdischarge nausea and vomiting (PDNV). However, there have been no direct comparisons of these two popular 5-HT3 antagonists with respect to PDNV and quality of recovery. We designed this randomized, double-blind study to compare the antiemetic efficacy of oral granisetron (1 mg) to a standard IV dose of ondansetron (4 mg) when administered for antiemetic prophylaxis as part of a multimodal regimen in a laparoscopic surgical population. A total of 220 patients undergoing laparoscopic surgery with a standardized general anesthetic technique were enrolled in this prospective study at two major medical centers. Patients were randomly assigned to one of two prophylactic treatment groups: the control (ondansetron) group received an oral placebo 1 h before surgery and ondansetron, 4 mg IV, at the end of the surgery, and the granisetron group received granisetron, 1 mg per os, 1 h before surgery, and normal saline, 2 mL IV, at the end of the surgery. The early recovery profiles, requirement for rescue antiemetics, incidence of PDNV, and the side effects were recorded over the 48 h study period. In addition, nausea scores were assessed using an 11-point verbal rating scale at specific intervals in the postoperative period. The quality of recovery and patient satisfaction scores were recorded at 48 h after surgery. The demographic characteristics were similar in the two prophylaxis treatment groups, as well as the recovery times to patient orientation, oral intake, and hospital discharge. The incidences of PDNV, requirements for rescue antiemetics, and quality of recovery did not differ between the two study groups. The antiemetic drug acquisition costs to achieve comparable patient satisfaction with ondansetron and granisetron were US 25.65 dollars and 47.05 dollars, respectively. Therefore, ondansetron (4 mg IV) was more cost-effective than granisetron (1 mg per os) for routine antiemetic prophylaxis as part of a multimodal regimen in patients undergoing either outpatient or inpatient laparoscopic surgery.

Intracoronary Eptifibatide During Primary Percutaneous Coronary Intervention in Early Versus Late Presenters with ST Segment Elevation Myocardial Infarction: A Randomized Trial.

INTRODUCTION: The role of intracoronary (IC) eptifibatide in primary percutaneous coronary intervention (PPCI) for ST segment elevation myocardial infarction (STEMI) and whether time of patient presentation affects this role are unclear. We sought to evaluate the benefit of IC eptifibatide use during primary PCI in early STEMI presenters compared to late STEMI presenters. METHODS: We included 70 patients who presented with STEMI and were eligible for PPCI. On the basis of symptom-to-door time, patients were classified into two arms: early (<3 h, n = 34) vs late (≥3 h, n = 36) presenters. They were then randomized to local IC eptifibatide infusion vs standard care (control group). The primary end point was post-PCI myocardial blush grade (MBG) in the culprit vessel. Other end points included corrected TIMI frame count (cTFC), ST segment resolution (STR) ≥70%, and peak CKMB. RESULTS: In the early presenters arm, no difference was observed in MBG results ≥2 in the IC eptifibatide and control groups (100% vs 82%; p = 0.23). In the late presenters arm, the eptifibatide subgroup was associated with improved MBG ≥2 (100% vs 50%; p = 0.001). IC eptifibatide in both early and late presenters was associated with less cTFC (early presenters 19 vs. 25.6, p = 0.001; late presenters 20 vs. 31.5, p < 0.001) and less peak CKMB (early presenters 210 vs 260 IU/L, p = 0.006; late presenters 228 vs 318 IU/L, p = 0.005) compared with the control group. No difference existed between both groups in STR index in early and late presenters. CONCLUSION: IC eptifibatide might improve the reperfusion markers during PPCI for STEMI patients presenting after 3 h from onset of symptoms. A large randomized study is recommended to ascertain the benefits of IC eptifibatide in late presenters on clinical outcomes.

Heated and humidified insufflation during laparoscopic gastric bypass surgery: effect on temperature, postoperative pain, and recovery outcomes.

BACKGROUND: Controversy exists regarding the efficacy of heated and humidified intraperitoneal gases in maintaining core body temperature. We performed a sham-controlled study to test the hypothesis that active warming and humidification of the insufflation gas reduces intraoperative heat loss and improves recovery outcomes. PATIENTS AND METHODS: Fifty morbidly obese patients undergoing laparoscopic Roux-en-Y gastric bypass procedures using a standardized anesthetic technique were randomly assigned to either a control (sham) group receiving room temperature insufflation gases with an inactive Insuflow (Lexion Medical, St. Paul, MN) device, or an active (Insuflow) group receiving warmed and humidified intraperitoneal gases. Esophageal and/or tympanic membrane temperature was measured perioperatively. Postoperative pain was assessed at 15 minute intervals using an 11-point verbal rating scale, with 0 = none to 10 = maximal. In addition, postoperative opioid requirements, incidence of nausea and vomiting, as well as the quality of recovery, were recorded. RESULTS: Use of the active Insuflow device was associated with significantly higher mean +/- standard deviation (SD) intraoperative core body temperatures (35.5 +/- 0.5 vs. 35.0 +/- 0.4 degrees C). Postoperative shivering (0 vs. 19%) and the requirement for morphine in the postanesthesia care unit (5 +/- 4 vs. 10 +/- 5 mg) were both significantly lower in the Insuflow vs. control groups. Patients in the Insuflow group also reported a higher quality of recovery 48 hours after surgery (15 vs. 13, P < 0.05). CONCLUSION: The Insuflow device modestly reduced shivering and heat loss, as well as the need for opioid analgesics in the early postoperative period. However, it failed to improve laparoscopic visualization due to fogging, and provided improvement in the quality of recovery only on postoperative day 2.

Local Intracoronary Eptifibatide versus Mechanical Aspiration in Patients with Acute ST-Elevation Myocardial Infarction.

Objectives. We compared local delivery of intracoronary eptifibatide via perfusion catheter to thrombus aspiration in primary PCI. Background. Perfusion catheter increases local concentration of the drugs at the culprit site and prolongs their residency time. Methods. 75 patients with acute STEMI were randomized to three groups: 25 received local intracoronary eptifibatide and verapamil via perfusion catheter; 25 patients were managed by Diver CE thrombectomy device and 25 patients by primary PCI without thrombus aspiration. Primary end point was assessment of postprocedural TIMI flow, MPG, and corrected TIMI frame count (cTFC) in the culprit vessel. Results. Perfusion catheter was superior to thrombus aspiration and conventional PCI as regards MBG (68% versus 36% in Diver CE and 20% in the control arm; P value = 0.002), with shorter cTFC rates than thrombectomy and control groups (20.76 ± 4.44 versus 26.68 ± 8.40 and 28.16 ± 5.96, resp.; P = 0.001). TIMI flow was not different between the 3 groups. Eptifibatide led to less time to peak CK (13.12 hours versus 16.5 and 19.5 hours, respectively, P value = 0.001). Conclusion. Local intracoronary eptifibatide by perfusion catheter reduces thrombus burden with better results in microvascular perfusion assessed by cTFC and MBG compared to aspiration device or conventional PCI.

Implications of bevacizumab discontinuation in adults with recurrent glioblastoma.

BACKGROUND: Patients with recurrent glioblastoma benefiting from bevacizumab are often treated indefinitely due to concerns regarding rebound tumor recurrence upon discontinuation. However, treatment is discontinued for reasons other than disease progression in a subset of these patients, the characteristics and outcomes of which are poorly defined. METHODS: Of 342 adults with recurrent glioblastoma in our database treated with bevacizumab, 82 received treatment for ≥ 6 months; of these, bevacizumab was discontinued for reasons other than tumor progression in 18 patients (Bev-D) and for disease progression in the remainder (Bev-S). The impact of discontinuation on outcome was assessed with discontinuation as a time-dependent covariate in a Cox hazards model for progression-free survival. RESULTS: There was no difference in hazard rates for progression between Bev-D and Bev-S groups; the adjusted hazard ratio for progression using discontinuation as a time-dependent covariate was 0.91 (95% CI:0.47, 1.78). The median PFS after bevacizumab-discontinuation was 27 weeks (95% CI:15-NR). At progression, a higher proportion of Bev-D patients had local progression compared with the Bev-S patients. Salvage therapy in Bev-D patients yielded a PFS-26 weeks of 47% (95% CI:23%-94%) with a median PFS of 23 weeks (95% CI:12-NR), vs. 5% (95% CI: 1%-21%) and 9 weeks (95% CI: 6-11) in Bev-S patients (HR:0.3;CI, 0.1-0.6) (P = .0007). CONCLUSIONS: Bevacizumab discontinuation unrelated to disease progression does not appear to cause rebound recurrence or worsen PFS in patients who benefit from bevacizumab. Additionally, Bev-D patients had an improved response to salvage therapy, findings which provide a strong basis for a prospective study.

Two alphaherpesvirus latency-associated gene products influence calcitonin gene-related peptide levels in rat trigeminal neurons.

Herpes simplex virus type-1 (HSV-1) initially infects mucoepithelial tissues of the eye and the orofacial region. Subsequently, the virus is retrogradely transported through the axons of the trigeminal sensory neurons. HSV-1 establishes a life-long latent infection in these neurons, during which the transcription of the viral genome is silent, except for the sequences encoding the latency-associated transcript (LAT). To determine if HSV-1 latency might affect calcitonin gene-related peptide (CGRP) expression in trigeminal sensory neurons, we transfected primary neuronal cultures of trigeminal ganglia from rat embryos with plasmids expressing LAT. In the presence of Bone Morphogenetic Protein-7 (BMP7), CGRP was expressed in 49% of sensory neurons. However, this percentage was reduced to 19% in neurons transfected with LAT expressing plasmids. We also found that transfection of the IE63 gene of varicella-zoster virus (VZV) reduced the percentage of trigeminal neurons containing CGRP. However, the observed effect of IE63 in contrast to that of LAT was completely reversed by treatment of cultures with MgCl2, which indicates that the effect of IE63 was due to increased release of CGRP from trigeminal neurons. We provide here the first evidence that HSV-1 LAT decreases the level of CGRP in trigeminal neurons. These effects may be important for reducing the neuroinflammatory response, thus protecting host neuronal cells during HSV-1 latency in trigeminal neurons. In contrast, increased release of CGRP in the presence of IE63 protein may contribute to the neuralgias associated with VZV infection.

The latency-associated transcript of herpes simplex virus type 1 promotes survival and stimulates axonal regeneration in sympathetic and trigeminal neurons.

Herpes simplex virus type 1 (HSV-1) primarily infects mucoepithelial tissues of the eye, the orofacial region, and to a lesser extent the genitalia. The virus is retrogradely transported through the axons of sensory and sympathetic neurons to their cell bodies to establishe a life-long latent infection. Throughout this latency period, the viral genome is transcriptionally silent except for a single region encoding the latency-associated transcript (LAT). The function of LAT is still largely unknown. To understand how HSV-1 latency might affect neurons, the authors transfected primary cultures of sympathetic neurons and trigeminal sensory neurons obtained from rat embryos with LAT-expressing plasmids. LAT increased the survival of both sympathetic and trigeminal neurons after induction of cell death by nerve growth factor (NGF) deprivation. Because HSV-1 is transported through axons both after initial infection and during reactivation, the authors considered the possibility that LAT may affect axonal growth. They found that LAT expression increased axonal regeneration by twofold in both types of neurons. Inhibition of the mitogen-activated protein kinase (MAPK) pathway reverses stimulation of both neuronal survival and axonal regeneration, which indicates that these effects are mediated through the MAPK pathway. These data provide evidence that HSV-1 LAT promotes survival of sympathetic as well as trigeminal neurons. The authors show for the first time that LAT stimulates axonal regeneration in both sympathetic and trigeminal neurons.

Herpes simplex virus type-1 latency inhibits dendritic growth in sympathetic neurons.

Herpes simplex virus type-1 (HSV-1) initially infects mucoepithelial tissues of the orofacial region, the eye and to a lesser extent the genitalia. Subsequently, the virus is retrogradely transported through the axons of the sensory and sympathetic neurons to their nuclei, where the virus establishes a life-long latent infection. During this latency period, the viral genome is transcriptionally silent except for a single region encoding the latency-associated transcript (LAT). LAT has been shown to affect apoptosis, but little else is known regarding its effects on neurons. To understand how HSV-1 latency might affect dendrites in sympathetic neurons, we transfected primary cultures of sympathetic neurons obtained from rat embryos, with LAT expressing plasmids. LAT inhibited initial dendritic growth and induced dendritic retraction in sympathetic neurons. Latent HSV-1 infection of cultured sympathetic neurons inhibited dendritic growth indicating that this is likely also a consequence of natural infection.

Optimal timing of acustimulation for antiemetic prophylaxis as an adjunct to ondansetron in patients undergoing plastic surgery.

We designed this study to evaluate the antiemetic efficacy of transcutaneous electrical acupoint stimulation in combination with ondansetron when applied before, after, or both before and after plastic surgery. A randomized, double-blind, sham-controlled study design was used to compare three prophylactic acustimulation treatment schedules: preoperative--an active device was applied for 30 min before and a sham device for 72 h after surgery; postoperative--a sham device was applied for 30 min before and an active device for 72 h after surgery; and perioperative--an active device was applied for 30 min before and 72 h after surgery (n = 35 per group). All patients received a standardized general anesthetic, and ondansetron 4 mg IV was administered at the end of surgery. The incidence of vomiting/retching and the need for rescue antiemetics were determined at specific time intervals for up to 72 h after surgery. Nausea scores were recorded with an 11-point verbal rating scale. Other outcome variables assessed included discharge times (for outpatients), resumption of normal activities of daily living, complete antiemetic response rate, and patient satisfaction with antiemetic therapy and quality of recovery. Perioperative use of the ReliefBand significantly increased complete responses (68%) compared with use of the device before surgery only (43%). Median postoperative nausea scores were significantly reduced in the peri- and postoperative (versus preoperative) treatment groups. Finally, patient satisfaction with the quality of recovery (83 +/- 16 and 85 +/- 13 vs 72 +/- 18) and antiemetic management (96 +/- 9 and 94 +/- 10 vs 86 +/- 13) on an arbitrary scale from 0 = worst to 100 = best was significantly higher in the groups receiving peri- or postoperative (versus preoperative) acustimulation therapy. For patients discharged on the day of surgery, the time to home readiness was significantly reduced (114 +/- 41 min versus 164 +/- 50 min; P < 0.05) when acustimulation was administered perioperatively (versus preoperatively). In conclusion, acustimulation with the ReliefBand was most effective in reducing postoperative nausea and vomiting and improving patients' satisfaction with their antiemetic therapy when it was administered after surgery.

Comparison of a lower-lipid propofol emulsion with the standard emulsion for sedation during monitored anesthesia care.

BACKGROUND: The currently used emulsion formulations of 1% propofol contain 10% soybean oil. However, a new emulsion of 1% propofol (Ampofol) containing 50% less lipid has recently become available for clinical investigation. This study was designed to compare the pharmacodynamic properties of Ampofol with those of a standard formulation (Diprivan) when administered for intraoperative sedation. METHODS: Sixty healthy outpatients undergoing minor operations with local anesthesia were randomly assigned to receive either Ampofol (n = 31) or Diprivan (n = 29) for intravenous sedation. The sedation was initiated with an intravenous loading dose of propofol, 0.75 mg/kg, followed by an initial infusion rate of 50 microg x kg(-1) x min(-1) to achieve an Observer's Assessment of Alertness/Sedation score of 3. The targeted level of sedation was maintained with a variable-rate propofol infusion during the operation. The onset times to achieving a sedation score of 3, the severity of pain on injection of the loading dose, intraoperative hemodynamic variables, and electroencephalographic Bispectral Index values were recorded. In addition, recovery times, postoperative pain and nausea, and patient satisfaction with the sedative medication were assessed. RESULTS: There were no significant differences between Ampofol and Diprivan with respect to onset times, dosage requirements, Bispectral Index values, hemodynamic variables, recovery times, or patient satisfaction scores. The incidence of moderate pain on injection was higher in the Ampofol group (26%vs. 7% with Diprivan; P < 0.05). CONCLUSIONS: Ampofol was equipotent to Diprivan with respect to its sedative properties during monitored anesthesia care. Although both groups received pretreatment with intravenous lidocaine, Ampofol was associated with more pain on injection.