Functional profiling to select chemotherapy in untreated, advanced or metastatic non-small cell lung cancer.

BACKGROUND/AIM: To assess the impact of drug selection upon the treatment of advanced and metastatic non-small cell lung cancer (NSCLC), we applied a functional platform that measures drug-induced cell death in human tumor primary-culture micro-spheroids isolated from surgical specimens. PATIENTS AND METHODS: At diagnosis, microspheroids isolated by mechanical and enzymatic disaggregation were examined for drug-induced cell-death by morphology and staining characteristics. Drugs were administered using standard protocols. Thirty-one patients, who received at least one cycle of therapy, were evaluable. All patients signed informed consent. RESULTS: Twenty out of 31 patients responded (64.5%), 1 completely and 19 partially, providing a two-fold improvement over historical control of 30% (p=0.00015), a median time-to-progression of 8.5 months and a median overall survival of 21.3 months. CONCLUSION: This functional platform is feasible and provides a favorable objective response rate, time-to-progression and survival in advanced, metastatic, untreated NSCLC, and warrants further evaluation.

Carotid intima-media thickness is increased in patients with mucopolysaccharidoses.

BACKGROUND: The feasibility of carotid artery intima-media thickness (C-IMT), an established cardiovascular disease marker, as a cardiac risk marker in mucopolysaccharidosis (MPS) patients was explored. OBJECTIVES: To determine if C-IMT is abnormal in MPS versus unaffected controls, and if C-IMT correlates with coronary artery diameter in MPS. MATERIAL AND METHODS: Measurements of C-IMT via neck ultrasound and echocardiographic parameters, including coronary artery diameters, were obtained from MPS and control patients, and compared. RESULTS: Sixteen MPS subjects (6 MPS I, 6 MPS II, 2 MPS III, 1 MPS VI, 1 MPS VII) and sixteen age, ethnicity, and gender-matched controls were enrolled. Median MPS and control subject ages were 8.3±4.5 and 8.6±4.3 years, respectively (p=0.73). Mean MPS and control C-IMTs were 0.54±0.070 and 0.48±0.034 mm (p=0.0029). No differences in left main, left anterior descending, or right coronary artery diameters were seen between MPS and controls. A significant proportion of MPS subjects had mitral insufficiency (14/16; p=0.0002), aortic insufficiency (10/16; p=0.0021), and left ventricular dilatation (7/16, p=0.037) versus controls. C-IMT did not correlate significantly with age, height, weight, coronary measurements, or duration of treatment. CONCLUSION: C-IMT in MPS patients is increased compared to matched controls, likely reflective of arterial intima-medial glycosaminoglycan accumulation. MPS subjects demonstrated a high percentage of left-sided valvular insufficiency and ventricular dilatation. Additional studies should be performed in MPS patients to determine if C-IMT correlates with arterial elasticity, biomarkers of vascular dysfunction, and higher risk of cardiovascular events.

Application of pulsed radiofrequency currents to rat dorsal root ganglia modulates nerve injury-induced tactile allodynia.

BACKGROUND: Application of pulsed radiofrequency (PRF) currents to the dorsal root ganglia (DRG) has been reported to produce relief from certain pain states without causing thermal ablation. In this study, we examined the direct correlation between PRF application to DRG associated with spinal nerve injury and reversal of injury-induced behavioral hypersensitivity in a rat neuropathic pain model. METHODS: Neuropathic lesioning was performed via left L5 spinal nerve ligation on male adult Sprague-Dawley rats. Once the injured rats had developed tactile allodynia, one group was then assigned to PRF treatment of the L5 DRG and another group was assigned to the sham treatment to the DRG. Behavioral testing was performed on both the control and treated paws using the von Frey filament test before the surgery and at indicated days. The resulting data were analyzed using a linear mixed model to assess the overall difference between the treatment groups and the overall difference among the study days. Cohen's d statistic was computed from paired difference-from-baseline scores for each of the 14 study days after treatment and these measures of effect size were then used to descriptively compare the recovery patterns over time for each study group. RESULTS: Spinal nerve injury resulted in the development of behavioral hypersensitivity to von Frey filament stimulation (allodynia) in the hindpaw of the left (injury) side. Mixed linear modeling showed a significant difference between the treatment groups (P = 0.0079) and a significant change of paw withdrawal threshold means over time (P = 0.0006) for all 12 animals. Evaluation of Cohen's d (effect size) revealed that the PRF-treated animals exhibited better recovery and recorded larger effect sizes than the sham-treated animals on 10 of the 14 post-PRF treatment days and exhibited moderate-to-strong effects posttreatment at days 8 to 10 and at and beyond day 32. CONCLUSIONS: Findings from this study support that PRF of the DRG causes reversal of nerve injury (spinal nerve ligation)-induced tactile allodynia in rats. This allodynia reversal indicates that nonablative PRF acting via modulation of the DRG can speed recovery in nerve injury-induced pain.

The relationship of the bronchodilator response phenotype to poor asthma control in children with normal spirometry.

OBJECTIVE: To determine the relationship of poor asthma control to bronchodilator response (BDR) phenotypes in children with normal spirometry. STUDY DESIGN: Children with asthma were assessed for clinical indexes of poorly controlled asthma. Pre- and post-bronchodilator spirometry were performed, and the percent BDR was determined. Multivariate logistic regression assessed the relationship of the clinical indices to BDR at ≥ 8%, ≥ 10%, and ≥ 12% BDR thresholds. RESULTS: There were 510 controller naïve children and 169 on controller medication. In the controller naïve population the mean age (± 1 SD) was 9.5 (3.4); 57.1% were male, 85.7% Hispanic. Demographics were similar in both populations. In the adjusted profile, significant clinical relationships were found particularly to positive BDR phenotypes ≥ 10% and ≥ 12% versus negative responses including younger age, (OR 2.0, 2.5; P < .05), atopy (OR 1.9, 2.6; P < .01), nocturnal symptoms in females (OR 3.4, 3.8; P < .01); ß2 agonist use (OR 1.7, 2.8; P < .01); and exercise limitation (OR 2.2, 2.5; P < .01) only in the controller naïve population. CONCLUSIONS: The BDR phenotype ≥ 10% is significantly related to poor asthma control, providing a potentially useful objective tool in controller naïve children even when the pre-bronchodilator spirometry result is normal.

Side effects and adverse events related to intraligamentous injection of sclerosing solutions (prolotherapy) for back and neck pain: A survey of practitioners.

OBJECTIVE: To study the side effects and adverse events related to intraligamentous injection of sclerosing solutions (prolotherapy) for back and neck pain. DESIGN: Practitioner postal survey. SETTING: Postal survey of practitioners of prolotherapy for back and neck pain in the United States and Canada. PARTICIPANTS: A sample of prolotherapy practitioners from 2 professional organizations were surveyed about their training and experience, use of specific treatment procedures, estimated prevalence of side effects, and adverse events related to prolotherapy for back and neck pain. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Prevalence of side effects and adverse events. RESULTS: Surveys were completed by 171 practitioners (response rate, 50%). Ninety-eight percent held medical degrees, and 83% were board certified in various disciplines. Respondents had a median of 10 years of experience, during which they had treated a median of 500 patients and given a median of 2000 treatments. Side effects with the highest median estimated prevalence were pain (70%), stiffness (25%), and bruising (5%). There were 472 reports of adverse events, including 69 that required hospitalization and 5 that resulted in permanent injury secondary to nerve injury. The vast majority (80%) were related to needle injuries such as spinal headache (n = 164), pneumothorax (n=123), temporary systemic reactions (n = 73), nerve damage (n = 54), hemorrhage (n = 27), nonsevere spinal cord insult (ie, meningitis, paralysis, spinal cord injury) (n = 9), and disk injury (n = 2). CONCLUSIONS: Side effects related to prolotherapy for back and neck pain, such as temporary postinjection pain, stiffness, and bruising, are common and benign. Adverse events related to prolotherapy for back and neck pain are similar in nature to other widely used spinal injection procedures. Further study is needed to fully describe the adverse event profile of prolotherapy for back and neck pain.

Exercise-induced bronchoconstriction alters airway nitric oxide exchange in a pattern distinct from spirometry.

Exhaled nitric oxide (NO) is altered in asthmatic subjects with exercise-induced bronchoconstriction (EIB). However, the physiological interpretation of exhaled NO is limited because of its dependence on exhalation flow and the inability to distinguish completely proximal (large airway) from peripheral (small airway and alveolar) contributions. We estimated flow-independent NO exchange parameters that partition exhaled NO into proximal and peripheral contributions at baseline, postexercise challenge, and postbronchodilator administration in steroid-naive mild-intermittent asthmatic subjects with EIB (24-43 yr old, n = 9) and healthy controls (20-31 yr old, n = 9). The mean +/- SD maximum airway wall flux and airway diffusing capacity were elevated and forced expiratory flow, midexpiratory phase (FEF(25-75)), forced expiratory volume in 1 s (FEV(1)), and FEV(1)/forced vital capacity (FVC) were reduced at baseline in subjects with EIB compared with healthy controls, whereas the steady-state alveolar concentration of NO and FVC were not different. Compared with the response of healthy controls, exercise challenge significantly reduced FEV(1) (-23 +/- 15%), FEF(25-75) (-37 +/- 18%), FVC (-12 +/- 12%), FEV(1)/FVC (-13 +/- 8%), and maximum airway wall flux (-35 +/- 11%) relative to baseline in subjects with EIB, whereas bronchodilator administration only increased FEV(1) (+20 +/- 21%), FEF(25-75) (+56 +/- 41%), and FEV(1)/FVC (+13 +/- 9%). We conclude that mild-intermittent steroid-naive asthmatic subjects with EIB have altered airway NO exchange dynamics at baseline and after exercise challenge but that these changes occur by distinct mechanisms and are not correlated with alterations in spirometry.

Incidence of acute endophthalmitis following penetrating keratoplasty: a systematic review.

OBJECTIVE: To determine the incidence of acute endophthalmitis following penetrating keratoplasty (PK) over time. METHODS: A systematic review of English-language articles was conducted by performing a broad search of the PubMed database from 1963 through March 2003 using such keywords as penetrating keratoplasty, endophthalmitis, and postoperative complication. Additional studies were identified from bibliographies of relevant articles and published proceedings. The proportion of eyes with acute endophthalmitis as a postoperative complication was recorded, and pooled incidence rates were assessed over time. RESULTS: From 1870 unique, potentially relevant citations, 66 original studies that addressed endophthalmitis and met the selection criteria were analyzed. A total of 90 549 PKs were pooled, resulting in an overall estimate of 0.382% post-PK endophthalmitis, but a change over time was noted. The rate of endophthalmitis was 0.200% in the 2000-2003 period, 0.453% in the 1990s, 0.376% in the 1980s, and 0.142% during the 1970s. Furthermore, a downward trend in the incidence of endophthalmitis after 1992 was observed compared with 1991 and earlier. CONCLUSIONS: This systematic review indicates that the incidence of endophthalmitis associated with PK has declined during the last decade.

Acute endophthalmitis following cataract surgery: a systematic review of the literature.

OBJECTIVES: To determine the reported incidence of acute endophthalmitis following cataract extraction over time and to explore possible contributing factors, such as type of cataract incision. METHODS: A systematic review of English-language articles was conducted by performing a broad search of PubMed from 1963 through March 2003 using such terms as cataract extraction, endophthalmitis, and postoperative complication. Additional studies were identified from bibliographies of relevant articles and published proceedings. Surgical approach was recorded, when available. Pooled incidence rates and relative risks of developing endophthalmitis using different incision techniques were assessed. RESULTS: From 4916 unique, potentially relevant citations, 215 studies that addressed endophthalmitis and met the selection criteria were analyzed. A total of 3 140 650 cataract extractions were pooled resulting in an overall rate of 0.128% of postcataract endophthalmitis. However, the incidence of acute endophthalmitis changed over time, with a significant increase since 2000 compared with previous decades (relative risk, 2.44 [95% confidence interval, 2.27-2.61]). The rate of endophthalmitis was 0.265% in the 2000-2003 period, 0.087% in the 1990s, 0.158% in the 1980s, and 0.327% during the 1970s. Furthermore, an upward trend in rates after 1992 was noted, compared with 1991 and prior. Incision type appeared to significantly influence risk, as endophthalmitis following clear corneal cataract extraction during the 1992-2003 period was 0.189% compared with 0.074% (relative risk, 2.55 [95% confidence interval, 1.75-3.71]) for scleral incision and 0.062% (relative risk, 3.06 [95% confidence interval, 2.48-3.76]) for limbal incision. CONCLUSIONS: This systematic review indicates that the incidence of endophthalmitis associated with cataract extraction has increased over the last decade. This upward trend in endophthalmitis frequency coincides temporally with the development of sutureless clear corneal incisions.

Airway diffusing capacity of nitric oxide and steroid therapy in asthma.

Exhaled nitric oxide (NO) concentration is a noninvasive index for monitoring lung inflammation in diseases such as asthma. The plateau concentration at constant flow is highly dependent on the exhalation flow rate and the use of corticosteroids and cannot distinguish airway and alveolar sources. In subjects with steroid-naive asthma (n = 8) or steroid-treated asthma (n = 12) and in healthy controls (n = 24), we measured flow-independent NO exchange parameters that partition exhaled NO into airway and alveolar regions and correlated these with symptoms and lung function. The mean (+/-SD) maximum airway flux (pl/s) and airway tissue concentration [parts/billion (ppb)] of NO were lower in steroid-treated asthmatic subjects compared with steroid-naive asthmatic subjects (1,195 +/- 836 pl/s and 143 +/- 66 ppb compared with 2,693 +/- 1,687 pl/s and 438 +/- 312 ppb, respectively). In contrast, the airway diffusing capacity for NO (pl.s-1.ppb-1) was elevated in both asthmatic groups compared with healthy controls, independent of steroid therapy (11.8 +/- 11.7, 8.71 +/- 5.74, and 3.13 +/- 1.57 pl.s-1.ppb-1 for steroid treated, steroid naive, and healthy controls, respectively). In addition, the airway diffusing capacity was inversely correlated with both forced expired volume in 1 s and forced vital capacity (%predicted), whereas the airway tissue concentration was positively correlated with forced vital capacity. Consistent with previously reported results from Silkoff et al. (Silkoff PE, Sylvester JT, Zamel N, and Permutt S, Am J Respir Crit Med 161: 1218-1228, 2000) that used an alternate technique, we conclude that the airway diffusing capacity for NO is elevated in asthma independent of steroid therapy and may reflect clinically relevant changes in airways.